Next Article in Journal
Systematic Review of Important Viral Diseases in Africa in Light of the ‘One Health’ Concept
Next Article in Special Issue
High-Risk Human Papillomaviruses and Epstein–Barr Virus in Colorectal Cancer and Their Association with Clinicopathological Status
Previous Article in Journal
Ethylicin Prevents Potato Late Blight by Disrupting Protein Biosynthesis of Phytophthora infestans
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Pathogens
Volume 9
Issue 4
10.3390/pathogens9040300
pathogens-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Human Papillomaviruses and Epstein–Barr Virus Interactions in Colorectal Cancer: A Brief Review

by
Queenie Fernandes
1,2,†,
Ishita Gupta
1,2,†,
Semir Vranic
1,* and
Ala-Eddin Al Moustafa
1,2,*
1
College of Medicine, QU Health, Qatar University, Doha 2713, Qatar
2
Biomedical Research Centre, Qatar University, Doha 2713, Qatar
*
Authors to whom correspondence should be addressed.
†
Both authors contributed equally to this review.
Pathogens 2020, 9(4), 300; https://doi.org/10.3390/pathogens9040300
Submission received: 9 March 2020 / Revised: 5 April 2020 / Accepted: 7 April 2020 / Published: 20 April 2020
(This article belongs to the Special Issue Host-Pathogen Interaction in Colorectal Carcinogenesis)
Browse Figure
Review Reports Versions Notes

Abstract

Human papillomaviruses (HPVs) and the Epstein–Barr virus (EBV) are the most common oncoviruses, contributing to approximately 10%–15% of all malignancies. Oncoproteins of high-risk HPVs (E5 and E6/E7), as well as EBV (LMP1, LMP2A and EBNA1), play a principal role in the onset and progression of several human carcinomas, including head and neck, cervical and colorectal. Oncoproteins of high-risk HPVs and EBV can cooperate to initiate and/or enhance epithelial-mesenchymal transition (EMT) events, which represents one of the hallmarks of cancer progression and metastasis. Although the role of these oncoviruses in several cancers is well established, their role in the pathogenesis of colorectal cancer is still nascent. This review presents an overview of the most recent advances related to the presence and role of high-risk HPVs and EBV in colorectal cancer, with an emphasis on their cooperation in colorectal carcinogenesis.

1. Introduction

Colorectal cancer is one of the most prevalent types of cancers worldwide [1] that is known to progress gradually over long periods of time [2]. Genetic factors and familial history are considered the principle causative factors for the disease, in addition to environmental factors such as obesity, smoking and consumption of alcohol and red meat [3]. Advanced age is also linked to the onset of colorectal cancer, with incidences increasing sharply between the ages of 30 to 50 years [4]. However, many recent studies have highlighted infectious agents such as oncoviruses as high-risk factors for the disease [5].
As the number of malignancies linked to oncoviruses increases, it is estimated that at least 20% of cancers are attributed to viral infections [6]. To date, a small number of viruses are associated with both solid and non-solid malignancies in humans. The most common oncoviruses include Epstein–Barr virus (EBV), hepatitis viruses B and C (HBV and HCV), human herpes virus 8 (HHV8, also known as Kaposi’s sarcoma-associated herpesvirus) and human papillomaviruses (HPVs) [7,8].
Today, around 150 types of HPVs are recognized and identified as either high- or low risk viruses. There are at least 17 high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 55, 56, 58, 59, 68, 73, 82 and 83); it is believed that persistent infection with high-risk HPVs may lead to malignancies in cooperation with other oncogenes [9,10]. On the other hand, low-risk HPVs (6 and 11) are not linked to cancer, and their infections result in the development of benign gynecological papillomas and skin warts [11,12]. HPVs-16 and 18 account for around 70% of cervical cancer cases, as well as other cancers of the anogenital tract, e.g., the vulva, vagina, penis and anus [13]. However, recently HPVs have been found to be associated with cancers of non-sexual regions like colon, rectum, esophagus, breast, skin, bladder and head and neck cancers [9,14,15,16,17]. HPV as an infectious agent can infect epithelial cells (like those of the colon), subsequently triggering carcinogenesis [18]. However, according to a few studies, the link between HPV and colorectal cancer is still controversial [19,20,21,22]; other studies have shown almost 40%–80% of colorectal and 30% of head and neck cancer cases are positive for high-risk HPVs [21,22,23,24,25].
On the other hand, EBV—a member of gamma-herpes viruses—is one of the first oncoviruses to be studied in human carcinogenesis [26]. The primary mode of transmission of the virus is through the saliva [27]. EBV is ubiquitously present among human adult populations, with an estimated prevalence of over 90% in individuals by the age of 35 years. EBV is known to cause infectious mononucleosis, as well as cancers such as Hodgkin’s, several subtypes of non-Hodgkin lymphomas [(B and T-cell, Natural Killer (NK)], as well as gastric and nasopharyngeal carcinomas [28,29,30]. Moreover, EBV has also commonly been linked to several other cancers such as breast, cervix, prostrate, oral cavity and salivary glands [10,31,32,33,34].
Currently, the role of HPVs and EBV in the pathogenesis of colorectal cancer is still ambiguous. In addition, reports detailing their oncogenic activity in colorectal cancer are sparse. Here we attempt to review and summarize the presence/co-presence and role of high-risk HPVs and EBV in the pathogenesis of colorectal cancer.

1.1. Human Papillomaviruses (HPVs) and Their Role in Colorectal Cancer

HPVs are non-enveloped double-stranded DNA viruses that are capable of infecting the epithelial cells of the skin and mucosa. The genome of HPVs consists of an 8-kb circular DNA encased in a capsid shell that is composed of a major (L1) and minor (L2) capsid proteins. The HPV viral genome codes for both early (E1, E2, E4, E5, E6 and E7) and late (L1 and L2) proteins that are critical for host infection [35,36].
HPV-inflicted carcinogenesis is a multistep process. It often begins through the primary infection of the proliferating epithelium. The virus maintains its DNA at low copy numbers in the infected basal cells of the host. However, during differentiation of epithelial cells, HPV displays its virulence by replicating to a high copy number, thus expressing the capsid envelope genes (L1 and L2) resulting in virion production that are subsequently released from the epithelial surface [37] spreading infection and leading to a hyperproliferative state [38]. Almost all high-risk HPV types prevent host immune recognition and promote persistent infection leading to neoplastic transformation. Moreover, the HPV cycle is entirely intraepithelial, non-lytic and inhibits activation of pro-inflammatory signals, leading to the recruitment of antigen presenting cells, followed by the subsequent release of cytokines triggering growth and proliferation [37].
In addition to binding and inhibiting the activity of tumor suppressor molecules like p53 and pRB [39,40], the E6/E7 oncoproteins display alternate mechanisms of inflicting oncogenesis. E6 functions to cause telomerase activation, causing deregulation of pathways involved in cellular proliferation, differentiation, immune recognition and survival signaling [37]. In contrast, E7 enhances genomic instability, thereby resulting in the accumulation of chromosomal abnormalities [41]. This cell-cycle deregulation, telomerase activation and induced genomic instability creates a favorable environment for neoplastic transformation of cells. Furthermore, HPVs can also trigger oncogenesis through the inactivation of the E2 gene, the main inhibitor of E6/E7 oncoproteins [42].
In recent years, a number of studies have attempted to examine the relationship between HPVs and colorectal cancer. Most of these studies are based on utilizing polymerase chain reaction (PCR) analyses to determine the presence of high-risk viral DNA in fresh and formalin fixed paraffin embedded tumor tissue. As mentioned above, high-risk HPVs have carcinogenic effects in around 40%–80% and 30% of colorectal as well as head and neck, respectively [21,22,23,24,25], especially in their invasive forms [43]. Several studies have highlighted the presence of high-risk HPVs (HPVs-16, 18, 31, 33 and 35) in human colorectal cancers [44,45,46,47]. A meta-analysis has also confirmed the presence of high-risk HPVs in colorectal cancers [48]; however, the prevalence of high-risk HPVs differs from one geographic location to another [49,50].
While studies carried out from the Middle East region, such as Iran [51,52,53,54] report low-to-medium frequencies of high-risk HPV types, in contrast, studies carried out in other parts of the world [14,24,55,56,57,58], report medium-to-high prevalence of high-risk HPV infections in adenocarcinoma colorectal tissue, in comparison to normal tissue. The most frequently expressed HPV types found in colorectal cancer include HPV 16, 18 and 33 [59]. Our group reported a frequency of around 54% of high-risk HPVs in colorectal samples in the Syrian population [44], and established an association between high-risk HPVs and invasive cancer phenotype. We also demonstrated that high-risk HPV type 16 oncoprotein converts non-invasive and non-metastatic human cancer cells into invasive and metastatic forms [9].
The underlying mechanism of HPV in cancer pathogenesis involves integration of its pro-viral DNA into host DNA resulting in direct inactivation of the E2 gene [23]. The E2 gene is a negative regulator of the E6/E7 oncoproteins that bind to tumor suppressor molecules like p53 and pRB respectively, thus disrupting their tumor suppressing activity [60]. This phenomenon is known to mark oncogenesis that further leads to genomic instability and consequently cellular transformation [61,62]; indicating mechanism of HPV-induced colorectal carcinogenesis.
In another study, we reported that E6/E7 oncoproteins of high-risk HPV type 16 cooperate with the ErbB-2 receptor to provoke cellular transformation of normal epithelial cells [63]. We also found that D-type cyclins (D1, D2 and D3) are elemental for cellular transformation induced by E6/E7/ErbB-2 cooperation [63,64,65] via β-catenin tyrosine phosphorylation through pp60 (c-Src) kinase activation [66,67,68]. Additionally, we found that E6/E7 of HPV type 16 provoke cell-invasive and metastatic abilities in vitro and in vivo, accompanied by Id-1 overexpression, which regulates cell invasion and metastasis of cancer cells [63]. To determine the role of high-risk HPVs in colorectal cancer, we assessed the effect of E6/E7 of HPV type 16 in two human primary normal colorectal “mesenchymal” cell lines (NCM1 and NCM5), established in our laboratory [69]. E6/E7 oncoproteins stimulated the upregulation of D-type cyclins and cyclin E as well as Id-1 to enhance cell proliferation, transformation and migration [65]. While it is important to state that the role of E5 oncoprotein in these malignancies still lies nascent, it has been reported that E5 of high-risk HPVs can affect cell alteration and consequently lead to oncogenesis via its interaction with EGF-R1 pathways, MAP kinase and PI3K-Akt, as well as pro-apoptotic proteins [70,71,72].
In general, the expression of E6 in cancer cells is associated with overexpression of Fascin, Id-1 and P-cadherin— all of which are actively involved in cell invasion and metastasis [44,73,74,75]. Also, it has been pointed out that E5 and E6/E7 oncoproteins can cooperate in cancer progression via the EMT event [76]; indicating the potential cooperation of HPVs oncoproteins in the progression of human cancers including colorectal.
Several other studies reveal that high-risk HPVs may also lead to the activation of oncogenes like KRAS and C-MYC. HPV DNA integration is often found in fragile sites around regions of the C-MYC locus [60,61,62,77,78]. C-MYC belongs to the multi-genic family of Myc, and is located on chromosome 8q21. It encodes for a transcription factor that is largely involved in differentiation, apoptosis and regulation of the cell cycle [79]. C-MYC is activated through the deregulation of DNA expression, followed by gene amplification that increases the production of excess gene copies, which is a hallmark of most malignancies, often known to increase with tumor grade [80,81,82]. Similarly, the proto-oncogene, KRAS—located on chromosome 12—encodes for a protein involved in proliferation, differentiation as well as signal transduction. Its pathogenesis in colorectal cancer is linked to several mutations at codons 12, 13 and 61 that lead to uncontrolled proliferation [83]. KRAS mutations are responsible for the transition of adenomas to carcinomas [84,85]; and are present in 56% of HPV positive tumors [46]. However, an earlier study showed no association between KRAS and C-MYC activation and infection through HPVs [46]. Therefore, roles of oncogenes like C-MYC and KRAS need to be further analyzed in order to understand the underlying mechanism of HPV-associated colorectal cancers.
Moreover, it has been revealed that tumors escape recognition by the immune system through the acquisition of apoptosis resistance that may occur due to the downregulation of pro-apoptotic molecules [86]. E6/E7 viral oncoproteins inhibit host-triggered apoptosis either through the inactivation of p53 or via the downregulation of TNF-R1 that leads to the disruption of apoptosis [87]. Studies have confirmed downregulation of two pro-apoptotic genes in particular, TNFRSF6 and DR5 in HPV-associated colorectal cancers [88,89].
Earlier studies have shown that HPV oncoproteins may play a co-stimulatory role with commonly known colorectal cancer mutations. However, one study shows a lack of association between HPV status and microsatellite instability that is a common biomarker of colorectal cancer [90]. Nevertheless, the role of HPV oncoproteins in cancer, particularly in colorectal cancer is not fully elucidated.

1.2. Epstein Barr Virus and its Role in Human Colorectal Cancer

The Epstein–Barr virus is a DNA virus that belongs to the family of the herpes virus and was first identified in a Burkitt lymphoma cell line. The virus was found to be distinct from other viruses including herpes simplex, herpes zoster or cytomegalovirus [91,92]. Its genome is represented by a double-helix DNA of approximately 1.1 × 108 Daltons in size [93] that mainly infects the epithelial as well as B-cells, often leading to malignancies. Infection is brought about through the fusion of the viral and cellular lipid bilayer membranes, involving complex mechanisms of multiple viral factors and host receptors.
The presence of EBV is found to be ubiquitous. Nearly 90% of the human adult population is infected by the virus [94,95]. Moreover, lifelong persistence is often the hallmark of most herpesvirus infections. EBV infections occur typically during early childhood. However, most of them are termed mild infections. While infections that occur during early adulthood are linked to infectious mononucleosis, this disease is defined by a triad of symptoms including fever, lymphadenopathy and pharyngitis [95].
The virus exhibits dual tropism; it is capable of infecting both B and epithelial cells [96] by alternating its envelop proteins [97]. EBV infection is commonly associated with B-cell lymphomas (Burkitt and Hodgkin lymphoma) as well as epithelial malignancies (nasopharyngeal [98], gastric [99] and probably rectal carcinomas [26]). Additionally, it is also associated with T-cell and/or Natural Killer (NK) cell lymphoproliferative disease as well as those found in immunosuppressed individuals (HIV infected or patients who have undergone transplantation surgeries) [100].
During lytic infection, genes encoded by EBV selectively replicate virion components (viral DNA genomes and proteins). However, during latent infection cycles, EBV encodes viral genes including the six nuclear antigens (EBNA-1, -2, -3A, -3B, -3C and LP), three Latent Membrane Proteins (LMP-1, -2A and -2B), two small non-coding Ribonucleic acids (EBER-1 and -2) as well as the BamHI-A rightward transcripts [101]. The main function of these EBV proteins is to help maintain viral existence by evading the natural mechanisms of immune surveillance [102]. In addition, it is established today that these genes can play an important role as “oncogenes” in infected cells.
EBV exerts a number of immune-suppressive effects that aid in carcinogenic transformation such as silencing the anti-EBV effect of interferon-gamma (INF-γ) in B cells and modulating the production of anti-viral cytokines like TNF-α, IL-1β and IL-6 [103]. Furthermore, EBV is capable of mimicking the characteristics of IL-10 thereby permitting its escape from the host’s anti-viral response [103,104]. On the whole, a compromised immune system and a chronic inflammatory microenvironment enhances the oncogenic properties of EBV [105].
When it comes to colorectal cancer, several studies have established a causative link between EBV and colorectal carcinogenesis [106,107,108]. The presence of viral EBV DNA was detected in tumor samples through the utilization of techniques like in situ hybridization (ISH), Immunohistochemistry (IHC) and Polymerase Chain Reaction (PCR)-based methods [26]. These techniques may have different sensitivities for detecting EBV targets (genes or proteins) which may partially explain discrepancies in the percentage of EBV positivity that has been reported in current literature (0%–46%) (Table 1). IHC and ISH assays typically detect EBNA or LMP family of proteins all of which can be readily visualized by a microscope (LMP proteins are cytoplasmic/membranous while EBNA proteins are nuclear products). In case of PCR-based assays, the detection of viral load by specific primers may be substantially affected (contaminated) by the EBV load within inflammatory cells (lymphocytes) that frequently accompany colorectal cancer samples [26].
EBV has also been associated with nasopharyngeal carcinomas, a distinct subtype of head and neck carcinoma with a prominent lymphoid component. Also, a particular type of primary colorectal cancer [119], lymphoepithelioma-like carcinoma (LEC) is morphologically similar to nasopharyngeal carcinoma [120] and is often associated with EBV infection [121,122,123]. Moreover, although rare, non-epithelial colorectal malignancies are also associated with EBV infection. Most of these are often hematological malignancies like Hodgkin’s or non-Hodgkin’s lymphomas originating from B-cells, T-cells or NK-cells. In addition, Burkitt lymphoma has also demonstrated the presence of EBV. Interestingly, ISH and IHC assays revealed that EBV may be linked with the onset of colorectal cancer in post-transplant patients [26,124,125,126,127]. Notably, studies conducted by three different groups [124,126,128] also analyzed EBV status in smooth muscle tumors of the colon using ISH, IHC and PCR. Although, the number of cases was small in these investigations, all three of them reported the presence of EBV in 100% of their population [124,126,128]. Worldwide, studies using RT-PCR and IHC assays have reported a prevalence of 20%–50% for EBV in colorectal cancer [116,129,130,131,132]. Although, reports pertaining to the presence of EBV in the Middle East are sparse; nevertheless, studies from Syria and Iran used PCR and revealed the presence of EBV in 36% [133] and 38% [116] of the cases, respectively. A particular investigation using methylation-specific PCR reported that although EBV infection was found in 19% of colorectal cancer cases, viral DNA showed no association with the methylation of thirteen cancer-related CpG islands that were addressed [134].
Table 2 briefly summarizes worldwide EBV prevalence in human colorectal cancers in different populations.
On the other hand, recent studies on colorectal and related gastric cancers have focused on a new tumor suppressor gene ARID1A (AT-rich Interactive Domain-containing 1A protein) [146,147,148,149,150,151,152,153,154,155,156]. The ARID1A gene encodes a large nuclear protein involved in the regulation of several cellular processes including cell differentiation and DNA repair [157]. ARID1A is mutated in colorectal and gastric cancers [146,147,148,149,150,151,152,153,154,157]. Interestingly, data pooled by a meta-analyses on colorectal and gastric cancer confirmed the presence of EBV infection [158] as well as reported loss of ARID1A protein expression associated with advanced grade and tumor differentiation [158]. However, further investigations are required to address the mechanism of interaction between EBV and mutation in ARID1A to gain a better understanding of their combined effect in initiating/mediating tumor progression.
In addition, a number of studies have reported the role of Fascin gene in the progression of several cancers including colorectal [159,160,161] as Fascin is often over-expressed in several types of invasive cancers [73,162,163,164]. Presence of EBV in colorectal cancer is frequently accompanied with an over-expression of Fascin [133]. Our previous study showed that expression of EBV oncoprotein (LMP1) correlates with Fascin overexpression and an invasive form of colorectal cancer (moderately to poorly differentiated adenocarcinomas) [133]. Earlier investigations reported that LMP1 and EBNA1 oncoproteins of EBV enhance cancer progression and metastasis of nasopharyngeal carcinoma through the initiation of the epithelial-mesenchymal transition (EMT) event [165,166,167]. Initial studies showed LMP1-mediated over-expression of Fascin is dependent on NF-κB as both, Fascin and NF-κB, aid in invasion and migration of LMP-1 expressing lymphocytes [168]. Similar to cancer progression in nasopharyngeal carcinoma, we postulated that the presence of EBV in colorectal cancer can promote cancer progression through the initiation of EMT event via EGF-receptor and/or Akt-signaling pathways as well as Wnt/β-catenin-signaling [166,169,170]. Thus, it is clear that EBV may play an important role in colorectal cancer progression; however, more comprehensive studies are necessary to test these hypotheses and determine the role of EBV in colorectal cancer.

1.3. The Interaction of High-Risk HPVs and EBV in Human Cancers

Epithelial cells can be co-infected with more than one viral species including HPVs and EBV [171,172,173]. Various studies showed co-infection of HPVs and EBV in different cancers including cervical, oral as well as breast [28,34,174,175,176,177,178]. HPVs and EBV co-infections may have a major role in the initiation and/or progression of cancer [175]; co-infection with more than one type of oncoviruses is necessary to attain complete transformation [10,64,65,171]. As stated above, E6/E7 onco-proteins of HPV 16 cooperate with HER-2 to provoke cellular transformation and initiate EMT of human normal oral epithelial cells [65,171]. Furthermore, HPVs and EBV can enhance the onset and spread of human carcinomas via the crosstalk of oncoproteins and signaling pathways (β-catenin, JAK/STAT/SRC, PI3k/Akt/mTOR and/or RAS/MEK/ERK pathways), as illustrated in Figure 1 [10,179].
As one of the most potent oncoviruses, HPVs and EBV infect epithelial tissues in a similar pattern that enables them to transform normal cells into malignant ones in cooperation with another oncogene. Both viruses can infect and replicate in upper aerodigestive epithelial cells as well as in the epithelium of the colon and rectum stimulating the productive and lytic phases of the HPV and EBV life cycle, respectively. A study by Makielski et al. revealed that high-risk HPV stabilizes the EBV genome and promotes EBV lytic reactivation in differentiated epithelial cells suggesting that EBV and HPV co-infection elevates EBV-mediated pathogenesis of cancer [173]. Although E6/E7 oncoproteins of HPV are essential to provoke EBV lytic reactivation in the suprabasal layer of oral epithelia, the underlying mechanisms still lies nascent.
Moreover, studies also state that EBV may play an indirect role in promoting the oncogenic pathogenesis of HPV by inhibiting natural immune responses directed towards HPV-transformed cells. This can take place through the production of the viral BCRF1 gene product, which is an interleukin-10 homolog [180,181]. If EBV gene products are secreted in the exosome, cells infected with EBV may affect tumor-tumor microenvironment, thus leading to the suppression of immune responses towards HPV [182,183]. Studies have also shown that the presence of EBV may also enhance the genomic instability of HPV-infected epithelial cells thereby further promoting the progression of cancer [184,185].
Interestingly, other than lytic replication, oncogenic viruses can enhance cancer by promoting immunosuppression in human virus-associated cancers and triggering DNA damage response [186,187]. Lately, the apo lipoprotein B mRNA editing enzyme catalytic polypeptide 3 (APOBEC3) was found to stimulate intrinsic immunity from several pathogens, including viral infection [188,189]. APOBEC3 can excise both HPV and EBV by stimulating cytidine-to-uracil mutations in viral DNA [190]. While in breast cancer, HPV-18 stimulates APOBEC3B activity—leading to genome instability [191]—in cervical cancer, beta interferon prompt E2 hypermutation in HPV-16 by APOBEC3 [192]; thus, suggesting viral infection results in APOBEC3 induced integration of viral DNA in the host genome via genome instability (Figure 1).
HPVs and EBV co-infections promote invasion ability of human oral cancer [193] as well as breast cancer [172,176,194,195]. While HPVs and EBV were detected in 15%–20% of oral SCCs [178,196], HPVs and EBV co-prevalence in tonsillar and tongue SCCs was 25% and 70%, respectively [197]. In our previous study using Syrian breast cancer samples, we found 32% of the cases were positive for both high-risk HPVs and EBV; co-infection was associated with high-grade invasive ductal carcinomas and lymph node involvement [10]. Furthermore, in cervical cancers, HPVs and EBV were co-present in approximately 29% of the cases and were correlated with an invasive cancer phenotype [28,198]. On the other hand, in prostate cancer co-presence of HPV and EBV was significantly higher (55%) than normal and benign tissues [32]. Additionally, experimental evidence show that HPV and EBV work together to promote the proliferation of cultured cervical cells [199], suggesting the same may be true for prostate epithelial cells. Although, studies examining co-presence of HPVs and EBV in colorectal cancers were performed [130,134], their co-presence was rarely detected [131]. A study performed by our group analyzed one-hundred and eight rectal cancers for the co-presence of EBV and HPV. Based on our findings, the co-incidence of these oncoviruses was detected in 11% of the samples [91]. We also recently reported that the co-presence of high-risk HPVs and EBV in colorectal cancer correlates with tumor aggressiveness in Syrian colorectal cancer patients [92].
Various plausible mechanisms have been proposed to further elucidate the mechanism of co-infection with HPVs and EBV in the pathogenesis of cancers originating from the epithelia. Increase in HPV results in loss of microRNA, miR-145 [200] which down-regulates KLF4 expression. Thus, HPV has shown to elevate the expression of KLF4, which further results in EBV lytic reactivation [201]. A study by Makielski et al. showed that EBV alone stimulates E2F-responsive protein expression; thus, indicating that EBV reprograms lethally differentiating cells to support cell cycle progression by HPV oncogenes [173]. Since HPV increases the capacity of epithelial cells to support the EBV life cycle during the lytic phase, EBV accumulation in epithelial cells may increase malignancy [173]. While stimulation of the lytic cycle in cells can also elevate the expression of different viral and cellular cytokines resulting in increased cellular differentiation by activating signaling pathways including the protein kinase R, mitogen-activated protein kinase (MAPK) pathways and NF-κB [202,203,204]. In addition, other studies state that infection through EBV can boost the invasive properties displayed by epithelial cells expressing E6 and E7 oncoproteins of HPV [179]. This further confirms that EBV may be responsible for the rapid progression of EBV/HPV–related cancers. Therefore, based on the various roles of HPVs and EBV in cancer pathogenesis, we postulate that oncoproteins of HPVs can interact with those of EBV (LMP1 and/or EBNA1) and result in progression and metastasis by enhancing the EMT event of different types of cancers including colorectal (Figure 1) [179].

2. Conclusions

Oncovirus-associated cancers are now becoming a worldwide concern. It has become evident that HPVs and EBV can be co-present in several types of human carcinomas including colorectal. Thus, the role of HPVs and EBV co-infection in cancer development should be further addressed including the epigenetic role of this cooperation, which can help to understand the underlying mechanism of this co-infection in the onset and development of malignant tumors. Additionally, chromatin control of viral co-infection also exemplifies a new field with candidate targets for the development of novel antiviral therapies.
The current research indicates a potentially plausible relationship between the co-presence of HPV and EBV in the pathogenesis of colorectal cancer. The functional roles of both viruses span over the beginning of oncogenesis or neoplastic transformation to tumor progression, and finally, the attainment of metastatic properties. The intricate mechanisms through which the viruses escape immune recognition are complex multi-stage processes that still need to be studied in considerable depth. However, further studies involving both translational and clinical aspects in a larger cohort are required to elucidate the oncogenic importance of their co-presence and its clinical impact.
Large-scale functional genomic analyses have previously identified viral lytic genes co-expressed with cellular cancer-associated pathways, indicating that the lytic cycle plays a role in virus-mediated oncogenesis [205,206]. Further research using genome-wide approaches can pave the way for the development of inclusive models of persistent HPV and EBV interactions and its underlying roles in infected cells.
Finally, understanding the mechanisms through which the viruses sustain and promote shared virulence is a major step towards developing therapeutic strategies in oncoviruses-related cancers. Meanwhile, EBV and HPVs vaccines, upcoming and available, respectively, can be used as a preventive strategy against infections with these oncoviruses and their associated cancers.

Author Contributions

†Both authors contributed equally to this review. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by research grants from Qatar University: QUHI-CMED-19/20-1, QUCG-CMED-20/21-2 and GCC-2017-002 QU/KU.

Acknowledgments

We would like to thank A. Kassab for her critical reading of the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Oliveira, R.G.; Faria, F.F.; Lima Junior, A.C.B.; Rodrigues, F.G.; Andrade, M.M.D.A.; Gomes, D.M.B.M.; Neves, P.M.; Constantino, J.R.M.; Braga, Á.C.G.; Ferreira, R.M.S.; et al. Surgery in colorectal cancer: Surgical approach of 74 patients from the Brazilian National Health System with colorectal cancer in a postgraduate program (residency) in coloproctology. Rev. Bras. Cancerol. 2011, 31, 44–57. [Google Scholar]
  2. Souto, R.; Falhari, J.P.B.; Cruz, A.D. Aparecido Divino da Cruz. O Papilomavírus Humano: Um fator relacionado com a formação de neoplasias. Rev. Bras. Cancerol. 2005, 51, 155–160. [Google Scholar]
  3. Haggar, F.A.; Boushey, R.P. Colorectal cancer epidemiology: Incidence, mortality, survival, and risk factors. Clin. Colon. Rectal Surg. 2009, 22, 191–197. [Google Scholar] [CrossRef] [PubMed]
  4. Fu, Z.; Shrubsole, M.J.; Smalley, W.E.; Wu, H.; Chen, Z.; Shyr, Y.; Ness, R.M.; Zheng, W. Lifestyle factors and their combined impact on the risk of colorectal polyps. Am. J. Epidemiol. 2012, 176, 766–776. [Google Scholar] [CrossRef]
  5. Siegel, R.; Desantis, C.; Jemal, A. Colorectal cancer statistics, 2014. CA Cancer J. Clin. 2014, 64, 104–117. [Google Scholar] [CrossRef]
  6. Zhang, X.; Zhang, Z.; Zheng, B.; He, Z.; Winberg, G.; Ernberg, I. An update on viral association of human cancers. Arch. Virol. 2013, 158, 1433–1443. [Google Scholar] [CrossRef]
  7. Aran, V.; Victorino, A.P.; Thuler, L.C.; Ferreira, C.G. Colorectal Cancer: Epidemiology, Disease Mechanisms and Interventions to Reduce Onset and Mortality. Clin. Colorectal Cancer 2016, 15, 195–203. [Google Scholar] [CrossRef]
  8. Leila, Z.; Arabzadeh, S.A.; Afshar, R.M.; Afshar, A.A.; Mollaei, H.R. Detection of Epstein-Barr Virus and Cytomegalovirus in Gastric Cancers in Kerman, Iran. Asian Pac. J. Cancer Prev. 2016, 17, 2423–2428. [Google Scholar]
  9. Al Moustafa, A.-E.; Al-Awadhi, R.; Missaoui, N.; Adam, I.; Durusoy, R.; Ghabreau, L.; Akil, N.; Ahmed, H.G.; Yasmeen, A.; Alsbeih, G. Human papillomaviruses-related cancers. Presence and prevention strategies in the Middle east and north African regions. Hum. Vaccines Immunother. 2014, 10, 1812–1821. [Google Scholar] [CrossRef]
  10. Al Moustafa, A.-E.; Al-Antary, N.; Aboulkassim, T.; Akil, N.; Batist, G.; Yasmeen, A. Co-prevalence of Epstein-Barr virus and high-risk human papillomaviruses in Syrian women with breast cancer. Hum. Vaccines Immunother. 2016, 12, 1936–1939. [Google Scholar] [CrossRef]
  11. De Villiers, E.M.; Fauquet, C.; Broker, T.R.; Bernard, H.U.; zur Hausen, H. Classification of papillomaviruses. Virology 2004, 324, 17–27. [Google Scholar] [CrossRef] [PubMed]
  12. Bernard, H.U. The clinical importance of the nomenclature, evolution and taxonomy of human papillomaviruses. J. Clin. Virol. 2005, 32, S1–S6. [Google Scholar] [CrossRef] [PubMed]
  13. Serrano, B.; Brotons, M.; Bosch, F.X.; Bruni, L. Epidemiology and burden of HPV-related disease. Best Pract. Res. Clin. Obstet. Gynaecol. 2018, 47, 14–26. [Google Scholar] [CrossRef] [PubMed]
  14. Tanzi, E.; Bianchi, S.; Frati, E.R.; Amicizia, D.; Martinelli, M.; Bragazzi, N.L.; Brisigotti, M.P.; Colzani, D.; Fasoli, E.; Zehender, G.; et al. Human papillomavirus detection in paraffin-embedded colorectal cancer tissues. J. Gen. Virol. 2015, 96, 206–209. [Google Scholar] [CrossRef][Green Version]
  15. Heng, B.; Glenn, W.K.; Ye, Y.; Tran, B.; Delprado, W.; Lutze-Mann, L.; Whitaker, N.J.; Lawson, J.S. Human papilloma virus is associated with breast cancer. Br. J. Cancer 2009, 101, 1345–1350. [Google Scholar] [CrossRef]
  16. Barghi, M.R.; Rahjoo, T.; Borghei, M.; Hosseini-Moghaddam, S.M.; Amani, D.; Farrokhi, B. Association between the evidence of human papilloma virus infection in bladder transitional cell carcinoma in men and cervical dysplasia in their spouses. Arch. Iran Med. 2012, 15, 572–574. [Google Scholar]
  17. Guo, F.; Liu, Y.; Wang, X.; He, Z.; Weiss, N.S.; Madeleine, M.M.; Liu, F.; Tian, X.; Song, Y.; Pan, Y.; et al. Human papillomavirus infection and esophageal squamous cell carcinoma: A case-control study. Cancer Epidemiol. Biomark. Prev. 2012, 21, 780–785. [Google Scholar] [CrossRef]
  18. Stanley, M.A. Epithelial cell responses to infection with human papillomavirus. Clin. Microbiol. Rev. 2012, 25, 215–222. [Google Scholar] [CrossRef]
  19. Gornick, M.C.; Castellsague, X.; Sanchez, G.; Giordano, T.J.; Vinco, M.; Greenson, J.K.; Capella, G.; Raskin, L.; Rennert, G.; Gruber, S.B.; et al. Human papillomavirus is not associated with colorectal cancer in a large international study. Cancer Causes Control 2010, 21, 737–743. [Google Scholar] [CrossRef]
  20. Lorenzon, L.; Mazzetta, F.; Pilozzi, E.; Uggeri, G.; Torrisi, M.R.; Ferri, M.; Ziparo, V.; French, D. Human papillomavirus does not have a causal role in colorectal carcinogenesis. World J. Gastroenterol. 2015, 21, 342–350. [Google Scholar] [CrossRef]
  21. Damin, D.C.; Caetano, M.B.; Rosito, M.A.; Schwartsmann, G.; Damin, A.S.; Frazzon, A.P.; Ruppenthal, R.D.; Alexandre, C.O.P. Evidence for an association of human papillomavirus infection and colorectal cancer. Eur. J. Surg. Oncol. EJSO 2007, 33, 569–574. [Google Scholar] [CrossRef]
  22. Ragin, C.; Taioli, E. Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: Review and meta-analysis. Int. J. Cancer 2007, 121, 1813–1820. [Google Scholar] [CrossRef]
  23. Bernabe-Dones, R.D.; Gonzalez-Pons, M.; Villar-Prados, A.; Lacourt-Ventura, M.; Rodríguez-Arroyo, H.; Fonseca-Williams, S.; Velazquez, F.E.; Diaz-Algorri, Y.; Lopez-Diaz, S.M.; Rodríguez, N.; et al. High Prevalence of Human Papillomavirus in Colorectal Cancer in Hispanics: A Case-Control Study. Gastroenterol. Res. Pract. 2016, 2016, 7896716. [Google Scholar] [CrossRef] [PubMed]
  24. Bodaghi, S.; Yamanegi, K.; Xiao, S.-Y.; Da Costa, M.; Palefsky, J.M.; Zheng, Z.-M. Colorectal papillomavirus infection in patients with colorectal cancer. Clin. Cancer Res. 2005, 11, 2862–2867. [Google Scholar] [CrossRef] [PubMed]
  25. Venuti, A.B.G.; Rizzo, C.; Mafera, B.; Rahimi, S.; Vigili, M. Presence of HPV in head and neck tumours: High prevalence in tonsillar localization. J. Exp. Clin. Cancer Res. 2004, 23, 561–566. [Google Scholar] [PubMed]
  26. Bedri, S.; Sultan, A.A.; Alkhalaf, M.; Al Moustafa, A.-E.; Vranic, S. Epstein-Barr virus (EBV) status in colorectal cancer: A mini review. Hum. Vaccines Immunother. 2019, 15, 603–610. [Google Scholar] [CrossRef]
  27. Mui, U.N.; Haley, C.T.; Tyring, S.K. Viral Oncology: Molecular Biology and Pathogenesis. J. Clin. Med. 2017, 6, 111. [Google Scholar] [CrossRef]
  28. De Lima, M.A.P.; Neto, P.J.N.; Lima, L.P.M.; Gonçalves Júnior, J.; Teixeira Junior, A.G.; Teodoro, I.P.P.; Facundo, H.T.; da Silva, C.G.L.; Lima, M.V.A. Association between Epstein-Barr virus (EBV) and cervical carcinoma: A meta-analysis. Gynecol. Oncol. 2018, 148, 317–328. [Google Scholar] [CrossRef]
  29. Vedham, V.; Verma, M.; Mahabir, S. Early-life exposures to infectious agents and later cancer development. Cancer Med. 2015, 4, 1908–1922. [Google Scholar] [CrossRef]
  30. Vockerodt, M.; Yap, L.F.; Shannon-Lowe, C.; Curley, H.; Wei, W.; Vrzalikova, K.; Murray, P.G. The Epstein-Barr virus and the pathogenesis of lymphoma. J. Pathol. 2015, 235, 312–322. [Google Scholar] [CrossRef]
  31. She, Y.; Nong, X.; Zhang, M.; Wang, M. Epstein-Barr virus infection and oral squamous cell carcinoma risk: A meta-analysis. PLoS ONE 2017, 12, e0186860. [Google Scholar] [CrossRef] [PubMed]
  32. Whitaker, N.J.; Glenn, W.K.; Sahrudin, A.; Orde, M.M.; Delprado, W.; Lawson, J.S. Human papillomavirus and Epstein Barr virus in prostate cancer: Koilocytes indicate potential oncogenic influences of human papillomavirus in prostate cancer. Prostate 2013, 73, 236–241. [Google Scholar] [CrossRef] [PubMed]
  33. Mozaffari, H.R.; Ramezani, M.; Janbakhsh, A.; Sadeghi, M. Malignant Salivary Gland Tumors and Epstein-Barr Virus (EBV) Infection: A Systematic Review and Meta-Analysis. Asian Pac. J. Cancer Prev. 2017, 18, 1201–1206. [Google Scholar] [CrossRef] [PubMed]
  34. Al-Thawadi, H.; Ghabreau, L.; Aboulkassim, T.; Yasmeen, A.; Vranic, S.; Batist, G.; Al Moustafa, A.-E. Co-Incidence of Epstein-Barr Virus and High-Risk Human Papillomaviruses in Cervical Cancer of Syrian Women. Front. Oncol. 2018, 8, 250. [Google Scholar] [CrossRef] [PubMed]
  35. Zur Hausen, H. Papillomaviruses causing cancer: Evasion from host-cell control in early events in carcinogenesis. J. Natl. Cancer Inst. 2000, 92, 690–698. [Google Scholar] [CrossRef] [PubMed]
  36. Stanley, M.; Lowy, D.R.; Frazer, I. Chapter 12: Prophylactic HPV vaccines: Underlying mechanisms. Vaccine 2006, 24, 106–113. [Google Scholar] [CrossRef]
  37. Ho, G.Y.; Bierman, R.; Beardsley, L.; Chang, C.J.; Burk, R.D. Natural history of cervicovaginal papillomavirus infection in young women. N. Engl. J. Med. 1998, 338, 423–428. [Google Scholar] [CrossRef]
  38. Pinidis, P.; Tsikouras, P.; Iatrakis, G.; Zervoudis, S.; Koukouli, Z.; Bothou, A.; Galazios, G.; Vladareanu, S. Human Papilloma Virus’ Life Cycle and Carcinogenesis. Maedica 2016, 11, 48–54. [Google Scholar]
  39. Psyrri, A.; DiMaio, D. Human papillomavirus in cervical and head-and-neck cancer. Nat. Clin. Pract. Oncol. 2008, 5, 24–31. [Google Scholar] [CrossRef]
  40. McLaughlin-Drubin, M.E.; Munger, K. Viruses associated with human cancer. Biochim. Biophys. Acta 2008, 1782, 127–150. [Google Scholar] [CrossRef]
  41. Korzeniewski, N.; Spardy, N.; Duensing, A.; Duensing, S. Genomic instability and cancer: Lessons learned from human papillomaviruses. Cancer Lett. 2011, 305, 113–122. [Google Scholar] [CrossRef] [PubMed]
  42. McBride, A.A.; Warburton, A. The role of integration in oncogenic progression of HPV-associated cancers. PLoS Pathog. 2017, 13, e1006211. [Google Scholar] [CrossRef] [PubMed]
  43. Daling, J.R.; Madeleine, M.M.; Johnson, L.G.; Schwartz, S.M.; Shera, K.A.; Wurscher, M.A.; Carter, J.J.; Porter, P.L.; Galloway, D.A.; McDougall, J.K. Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer. Cancer 2004, 101, 270–280. [Google Scholar] [CrossRef]
  44. Ghabreau, L.; Segal, E.; Yasmeen, A.; Kassab, A.; Akil, N.; Al Moustafa, A.-E. High-risk human papillomavirus infections in colorectal cancer in the Syrian population and their association with Fascin, Id-1 and P-cadherin expressions: A tissue microarray study. Clin. Cancer Investig. J. 2012, 1, 26–30. [Google Scholar] [CrossRef]
  45. Salepci, T.; Yazici, H.; Dane, F.; Topuz, E.; Dalay, N.; Onat, H.; Aykan, F.; Seker, M.; Aydiner, A. Detection of human papillomavirus DNA by polymerase chain reaction and southern blot hybridization in colorectal cancer patients. J. BUON 2009, 14, 495–499. [Google Scholar] [PubMed]
  46. Buyru, N.; Tezol, A.; Dalay, N. Coexistence of K-ras mutations and HPV infection in colon cancer. BMC Cancer 2006, 6, 115. [Google Scholar] [CrossRef] [PubMed]
  47. Yavuzer, D.; Karadayi, N.; Salepci, T.; Baloglu, H.; Dabak, R.; Bayramicli, O.U. Investigation of human papillomavirus DNA in colorectal carcinomas and adenomas. Med. Oncol. 2011, 28, 127–132. [Google Scholar] [CrossRef]
  48. Damin, D.C.; Ziegelmann, P.K.; Damin, A.P. Human papillomavirus infection and colorectal cancer risk: A meta-analysis. Colorectal Dis. 2013, 15, e420–e428. [Google Scholar] [CrossRef]
  49. Li, N.; Franceschi, S.; Howell-Jones, R.; Snijders, P.J.F.; Clifford, G.M. Human papillomavirus type distribution in 30,848 invasive cervical cancers worldwide: Variation by geographical region, histological type and year of publication. Int.J. Cancer 2011, 128, 927–935. [Google Scholar] [CrossRef]
  50. Al Moustafa, A.-E. Role of high-risk human papillomaviruses in breast carcinogenesis. In Breast Carcinogenesis; Oncoviruses and Their Inhibitors; Gupta, S., Ed.; CRC Press; Taylor and Francis Group: Boca Raton, FL, USA, 2014; pp. 245–262. [Google Scholar]
  51. Malekpour Afshar, R.; Deldar, Z.; Mollaei, H.R.; Arabzadeh, S.A.; Iranpour, M. Evaluation of HPV DNA positivity in colorectal cancer patients in Kerman, Southeast Iran. Asian Pac. J. Cancer Prev. 2018, 19, 193–198. [Google Scholar] [CrossRef]
  52. Mahmoudvand, S.; Safaei, A.; Erfani, N.; Sarvari, J. Presence of Human Papillomavirus DNA in Colorectal Cancer Tissues in Shiraz, Southwest Iran. Asian Pac. J. Cancer Prev. 2015, 16, 7883–7887. [Google Scholar] [CrossRef] [PubMed]
  53. Ranjbar, R.; Saberfar, E.; Shamsaie, A.; Ghasemian, E. The aetiological role of human papillomavirus in colorectal carcinoma: An Iranian population- based case control study. Asian Pac. J. Cancer Prev. 2014, 15, 1521–1525. [Google Scholar] [CrossRef] [PubMed]
  54. Motlagh, A.; Azadeh, P.; Hashemi, M.; Molaei, M.; MajidSheibani, K.; Alidoosti, A.; Fazlalizadeh, A.; Shafaghi, B.; Fudazi, M.; Valaei, N.; et al. Human Papillomavirus Infection, p53 Overexpression and Histopathologic Characteristics in Colorectal Cancer. Govaresh 2012, 12, 8. [Google Scholar]
  55. Kirgan, D.; Manalo, P.; McGregor, B. Immunohistochemical demonstration of human papilloma virus antigen in human colon neoplasms. J. Surg. Res. 1990, 48, 397–402. [Google Scholar] [CrossRef]
  56. Cheng, J.Y.; Sheu, L.F.; Meng, C.L.; Lee, W.H.; Lin, J.C. Detection of human papillomavirus DNA in colorectal carcinomas by polymerase chain reaction. Gut 1995, 37, 87–90. [Google Scholar] [CrossRef][Green Version]
  57. McGregor, B.; Byrne, P.; Kirgan, D.; Albright, J.; Manalo, P.; Hall, M. Confirmation of the association of human papillomavirus with human colon cancer. Am. J. Surg. 1993, 166, 738–740. [Google Scholar] [CrossRef]
  58. Soto, Y.; Limia, C.M.; Gonzalez, L.; Gra, B.; Hano, O.M.; Martinez, P.A.; Kouri, V. Molecular evidence of high-risk human papillomavirus infection in colorectal tumours from Cuban patients. Mem. Inst. Oswaldo Cruz 2016, 111, 731–736. [Google Scholar] [CrossRef]
  59. Ibragimova, M.K.; Tsyganov, M.M.; Litviakov, N.V. Human papillomavirus and colorectal cancer. Med. Oncol. 2018, 35, 140. [Google Scholar] [CrossRef]
  60. Chakrabarti, O.; Krishna, S. Molecular interactions of ‘high risk’ human papillomaviruses E6 and E7 oncoproteins: Implications for tumour progression. J. Biosci. 2003, 28, 337–348. [Google Scholar] [CrossRef]
  61. Pett, M.R.; Alazawi, W.O.; Roberts, I.; Dowen, S.; Smith, D.I.; Stanley, M.A.; Coleman, N. Acquisition of high-level chromosomal instability is associated with integration of human papillomavirus type 16 in cervical keratinocytes. Cancer Res. 2004, 64, 1359–1368. [Google Scholar] [CrossRef]
  62. Badaracco, G.; Venuti, A.; Sedati, A.; Marcante, M.L. HPV16 and HPV18 in genital tumors: Significantly different levels of viral integration and correlation to tumor invasiveness. J. Med. Virol. 2002, 67, 574–582. [Google Scholar] [CrossRef] [PubMed]
  63. Yasmeen, A.; Bismar, T.A.; Kandouz, M.; Foulkes, W.D.; Desprez, P.-Y.; Al Moustafa, A.-E. E6/E7 of HPV Type 16 Promotes Cell Invasion and Metastasis of Human Breast Cancer Cells. Cell Cycle 2007, 6, 2038–2042. [Google Scholar] [CrossRef] [PubMed]
  64. Yasmeen, A.; Hosein, A.N.; Yu, Q.; Al Moustafa, A.-E. Critical role for D-type cyclins in cellular transformation induced by E6/E7 of human papillomavirus type 16 and E6/E7/ErbB-2 cooperation. Cancer Sci. 2007, 98, 973–977. [Google Scholar] [CrossRef] [PubMed]
  65. Al Moustafa, A.-E.; Foulkes, W.D.; Wong, A.; Jallal, H.; Batist, G.; Yu, Q.; Herlyn, M.; Sicinski, P.; Alaoui-Jamali, M.A. Cyclin D1 is essential for neoplastic transformation induced by both E6/E7 and E6/E7/ErbB-2 cooperation in normal cells. Oncogene 2004, 23, 5252–5256. [Google Scholar] [CrossRef][Green Version]
  66. Yasmeen, A.; Alachkar, A.; Dekhil, H.; Gambacorti-Passerini, C.; Al Moustafa, A.-E. Locking Src/Abl Tyrosine Kinase Activities Regulate Cell Differentiation and Invasion of Human Cervical Cancer Cells Expressing E6/E7 Oncoproteins of High-Risk HPV. J. Oncol. 2010. [Google Scholar] [CrossRef]
  67. Coluccia, A.M.L.; Benati, D.; Dekhil, H.; De Filippo, A.; Lan, C.; Gambacorti-Passerini, C. SKI-606 Decreases Growth and Motility of Colorectal Cancer Cells by Preventing pp60(c-Src)–Dependent Tyrosine Phosphorylation of β-Catenin and Its Nuclear Signaling. Cancer Res. 2006, 66, 2279–2286. [Google Scholar] [CrossRef]
  68. Al Moustafa, A.; Kassab, A.; Darnel, A.; Yasmeen, A. High-risk HPV/ErbB-2 interaction on E-cadherin/catenin regulation in human carcinogenesis. Curr. Pharm. Des. 2008, 14, 2159–2172. [Google Scholar] [CrossRef]
  69. Ricciardi, R.; Ghabreau, L.; Yasmeen, A.; Darnel, A.D.; Akil, N.; Al Moustafa, A.E. Role of E6/E7 onco-proteins of high-risk human papillomaviruses in human colorectal carcinogenesis. Cell Cycle 2009, 8, 1964–1965. [Google Scholar] [CrossRef]
  70. Kim, S.H.; Juhnn, Y.S.; Kang, S.; Park, S.W.; Sung, M.W.; Bang, Y.J.; Song, Y.S. Human papillomavirus 16 E5 up-regulates the expression of vascular endothelial growth factor through the activation of epidermal growth factor receptor, MEK/ERK1,2 and PI3K/Akt. Cell. Mol. Life Sci. CMLS 2006, 63, 930–938. [Google Scholar] [CrossRef]
  71. Suprynowicz, F.A.; Disbrow, G.L.; Krawczyk, E.; Simic, V.; Lantzky, K.; Schlegel, R. HPV-16 E5 oncoprotein upregulates lipid raft components caveolin-1 and ganglioside GM1 at the plasma membrane of cervical cells. Oncogene 2008, 27, 1071–1078. [Google Scholar] [CrossRef]
  72. Oh, J.-M.; Kim, S.-H.; Cho, E.-A.; Song, Y.-S.; Kim, W.-H.; Juhnn, Y.-S. Human papillomavirus type 16 E5 protein inhibits hydrogen peroxide-induced apoptosis by stimulating ubiquitin–proteasome-mediated degradation of Bax in human cervical cancer cells. Carcinogenesis 2009, 31, 402–410. [Google Scholar] [CrossRef] [PubMed]
  73. Oh, S.Y.; Kim, Y.B.; Suh, K.W.; Paek, O.J.; Moon, H.Y. Prognostic Impact of Fascin-1 Expression is More Significant in Advanced Colorectal Cancer. J. Sur. Res. 2012, 172, 102–108. [Google Scholar] [CrossRef] [PubMed]
  74. Ling, M.-T.; Wang, X.; Zhang, X.; Wong, Y.-C. The multiple roles of Id-1 in cancer progression. Differentiation 2006, 74, 481–487. [Google Scholar] [CrossRef] [PubMed]
  75. Van Marck, V.; Stove, C.; Jacobs, K.; Van den Eynden, G.; Bracke, M. P-cadherin in adhesion and invasion: Opposite roles in colon and bladder carcinoma. Int. J. Cancer 2011, 128, 1031–1044. [Google Scholar] [CrossRef]
  76. Al Moustafa, A.-E. E5 and E6/E7 of high-risk HPVs cooperate to enhance cancer progression through EMT initiation. Cell Adh. Migr. 2015, 9, 392–393. [Google Scholar] [CrossRef]
  77. Ferber, M.J.; Thorland, E.C.; Brink, A.A.; Rapp, A.K.; Phillips, L.A.; McGovern, R.; Gostout, B.S.; Cheung, T.H.; Chung, T.K.; Fu, W.Y.; et al. Preferential integration of human papillomavirus type 18 near the c-myc locus in cervical carcinoma. Oncogene 2003, 22, 7233–7242. [Google Scholar] [CrossRef]
  78. Thorland, E.C.; Myers, S.L.; Gostout, B.S.; Smith, D.I. Common fragile sites are preferential targets for HPV16 integrations in cervical tumors. Oncogene 2003, 22, 1225–1237. [Google Scholar] [CrossRef]
  79. Ryan, K.M.; Birnie, G.D. Myc oncogenes: The enigmatic family. Biochem. J. 1996, 314, 713–721. [Google Scholar] [CrossRef][Green Version]
  80. Augenlicht, L.H.; Wadler, S.; Corner, G.; Richards, C.; Ryan, L.; Multani, A.S.; Pathak, S.; Benson, A.; Haller, D.; Heerdt, B.G. Low-level c-myc amplification in human colonic carcinoma cell lines and tumors: A frequent, p53-independent mutation associated with improved outcome in a randomized multi-institutional trial. Cancer Res. 1997, 57, 1769–1775. [Google Scholar]
  81. Obara, K.; Yokoyama, M.; Asano, G.; Tanaka, S. Evaluation of myc and chromosome 8 copy number in colorectal cancer using interphase cytogenetics. Int. J. Oncol. 2001, 18, 233–239. [Google Scholar] [CrossRef] [PubMed]
  82. Zaharieva, B.; Simon, R.; Ruiz, C.; Oeggerli, M.; Mihatsch, M.J.; Gasser, T.; Sauter, G.; Toncheva, D. High-throughput tissue microarray analysis of CMYC amplificationin urinary bladder cancer. Int. J. Cancer 2005, 117, 952–956. [Google Scholar] [CrossRef] [PubMed]
  83. Bos, J.L. Ras oncogenes in human cancer: A review. Cancer Res. 1989, 49, 4682–4689. [Google Scholar] [PubMed]
  84. Vogelstein, B.; Fearon, E.R.; Hamilton, S.R.; Kern, S.E.; Preisinger, A.C.; Leppert, M.; Nakamura, Y.; White, R.; Smits, A.M.; Bos, J.L. Genetic alterations during colorectal-tumor development. N. Engl. J. Med. 1988, 319, 525–532. [Google Scholar] [CrossRef] [PubMed]
  85. Fearon, E.R.; Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 1990, 61, 759–767. [Google Scholar] [CrossRef]
  86. Igney, F.H.; Krammer, P.H. Immune escape of tumors: Apoptosis resistance and tumor counterattack. J. Leukoc. Biol. 2002, 71, 907–920. [Google Scholar]
  87. Jiang, P.; Yue, Y. Human papillomavirus oncoproteins and apoptosis (Review). Exp. Ther. Med. 2014, 7, 3–7. [Google Scholar] [CrossRef]
  88. Kabsch, K.; Alonso, A. The human papillomavirus type 16 E5 protein impairs TRAIL- and FasL-mediated apoptosis in HaCaT cells by different mechanisms. J. Virol. 2002, 76, 12162–12172. [Google Scholar] [CrossRef]
  89. Karbasi, A.; Borhani, N.; Daliri, K.; Kazemi, B.; Manoochehri, M. Downregulation of external death receptor genes FAS and DR5 in colorectal cancer samples positive for human papillomavirus infection. Pathol. Res. Pract. 2015, 211, 444–448. [Google Scholar] [CrossRef]
  90. Burnett-Hartman, A.N.; Feng, Q.; Popov, V.; Kalidindi, A.; Newcomb, P.A. Human papillomavirus DNA is rarely detected in colorectal carcinomas and not associated with microsatellite instability: The Seattle colon cancer family registry. Cancer Epidemiol. Biomark. Prev. 2013, 22, 317–319. [Google Scholar] [CrossRef]
  91. Epstein, M.A.; Achong, B.G. Various forms of Epstein-Barr virus infection in man: Established facts and a general concept. Lancet 1973, 2, 836–839. [Google Scholar] [CrossRef]
  92. Epstein, M.A.; Henle, G.; Achong, B.G.; Barr, Y.M. Morphological and biological studies on a virus in cultured lymphoblasts from Burkitt’s lymphoma. J. Exp. Med. 1965, 121, 761–770. [Google Scholar] [CrossRef] [PubMed]
  93. Kieff, E.; Given, D.; Powell, A.L.; King, W.; Dambaugh, T.; Raab-Traub, N. Epstein-Barr virus: Structure of the viral DNA and analysis of viral RNA in infected cells. Biochim. Biophys. Acta 1979, 560, 355–373. [Google Scholar] [CrossRef]
  94. Evans, A.S. The spectrum of infections with Epstein-Barr virus: A hypothesis. J. Infect. Dis. 1971, 124, 330–337. [Google Scholar] [CrossRef] [PubMed]
  95. Williams, H.; Crawford, D.H. Epstein-Barr virus: The impact of scientific advances on clinical practice. Blood 2006, 107, 862–869. [Google Scholar] [CrossRef]
  96. Borza, C.M.; Hutt-Fletcher, L.M. Alternate replication in B cells and epithelial cells switches tropism of Epstein-Barr virus. Nat. Med. 2002, 8, 594–599. [Google Scholar] [CrossRef] [PubMed]
  97. Tsang, C.M.; Tsao, S.W. The role of Epstein-Barr virus infection in the pathogenesis of nasopharyngeal carcinoma. Virol. Sin. 2015, 30, 107–121. [Google Scholar] [CrossRef]
  98. Fernandes, Q.; Merhi, M.; Raza, A.; Inchakalody, V.P.; Abdelouahab, N.; Zar Gul, A.R.; Uddin, S.; Dermime, S. Role of Epstein-Barr Virus in the Pathogenesis of Head and Neck Cancers and Its Potential as an Immunotherapeutic Target. Front. Oncol. 2018, 8, 257. [Google Scholar] [CrossRef]
  99. Chen, X.Z.; Chen, H.; Castro, F.A.; Hu, J.K.; Brenner, H. Epstein-Barr virus infection and gastric cancer: A systematic review. Medicine 2015, 94, e792. [Google Scholar] [CrossRef]
  100. Longnecker, R.M.; Kieff, E.; Cohen, J.I. Epstein-Barr virus. In Fields Virology, 6th ed.; Wolters Kluwer Health Adis (ESP): Alphen aan den Rijn, The Netherlands, 2013; Volume 1. [Google Scholar]
  101. Rickinson, A. Epstein-Barr virus. Virus. Res. 2002, 82, 109–113. [Google Scholar] [CrossRef]
  102. Ambinder, R.F.; Browning, P.J.; Lorenzana, I.; Leventhal, B.G.; Cosenza, H.; Mann, R.B.; MacMahon, E.M.; Medina, R.; Cardona, V.; Grufferman, S. Epstein-Barr virus and childhood Hodgkin’s disease in Honduras and the United States. Blood 1993, 81, 462–467. [Google Scholar] [CrossRef]
  103. Fox, R.I.; Luppi, M.; Pisa, P.; Kang, H.I. Potential role of Epstein-Barr virus in Sjögren’s syndrome and rheumatoid arthritis. J. Rheumatol. Suppl. 1992, 32, 18–24. [Google Scholar] [PubMed]
  104. Evans, A.S. The history of infectious mononucleosis. Am. J. Med. Sci. 1974, 267, 189–195. [Google Scholar] [CrossRef] [PubMed]
  105. Rickinson, A.B. Co-infections, inflammation and oncogenesis: Future directions for EBV research. Semin. Cancer Biol. 2014, 26, 99–115. [Google Scholar] [CrossRef] [PubMed]
  106. Tafvizi, F.; Fard, Z.T.; Assareh, R. Epstein-Barr virus DNA in colorectal carcinoma in Iranian patients. Pol. J. Pathol. 2015, 66, 154–160. [Google Scholar] [CrossRef]
  107. Liu, H.X.; Ding, Y.Q.; Li, X.; Yao, K.T. Investigation of Epstein-Barr virus in Chinese colorectal tumors. World J. Gastroenterol. 2003, 9, 2464–2468. [Google Scholar] [CrossRef]
  108. Sarvari, J.; Mahmoudvand, S.; Pirbonyeh, N.; Safaei, A.; Hosseini, S.Y. The Very Low Frequency of Epstein-Barr JC and BK Viruses DNA in Colorectal Cancer Tissues in Shiraz, Southwest Iran. Pol. J. Microbiol. 2018, 67, 73–79. [Google Scholar] [CrossRef]
  109. Gupta, I.; Jabeen, A.; Skenderi, F.; Malki, M.I.; Al-Thawadi, H.; Al Moustafa, A.E.; Vranic, S. High-risk Human Papillomaviruses (HPV) and Epstein—Barr virus (EBV) are Commonly Present in Rectal Cancer. Mod. Pathol. 2020, 33, 676. [Google Scholar]
  110. Malki, M.I.; Gupta, I.; Fernandes, Q.; Aboulkassim, T.; Yasmeen, A.; Vranic, S.; Al Moustafa, A.E.; Al-Thawadi, H.A. Co-presence of Epstein-Barr virus and high-risk human papillomaviruses in Syrian colorectal cancer samples. Hum. Vaccins Immunother. 2020, 1–5. [Google Scholar] [CrossRef]
  111. Martins, S.F.; Mariano, V.; Rodrigues, M.; Longatto-Filho, A. Human papillomavirus (HPV) 16 infection is not detected in rectal carcinoma. Infect. Agents Cancer 2020, 15, 17. [Google Scholar] [CrossRef]
  112. Jarzyński, A.; Zając, P.; Żebrowski, R.; Boguszewska, A.; Polz-Dacewicz, M. Occurrence of BK Virus and Human Papilloma Virus in colorectal cancer. Ann. Agric. Environ. Med. 2017, 24, 440–445. [Google Scholar] [CrossRef]
  113. Pelizzer, T.; Dias, C.P.; Poeta, J.; Torriani, T.; Roncada, C. Colorectal cancer prevalence linked to human papillomavirus: A systematic review with meta-analysis. Braz. J. Epidemiol. 2016, 19, 791–802. [Google Scholar] [CrossRef]
  114. Pérez, L.O.; Barbisan, G.; Ottino, A.; Pianzola, H.; Golijow, C.D. Human papillomavirus DNA and oncogene alterations in colorectal tumors. Pathol. Oncol. Res. 2010, 16, 461–468. [Google Scholar] [CrossRef] [PubMed]
  115. Giuliani, L.; Ronci, C.; Bonifacio, D.; Di Bonito, L.; Favalli, C.; Perno, C.F.; Syrjänen, K.; Ciotti, M. Detection of oncogenic DNA viruses in colorectal cancer. Anticancer Res. 2008, 28, 1405–1410. [Google Scholar] [PubMed]
  116. Bodaghi, S.; Wood, L.V.; Roby, G.; Ryder, C.; Steinberg, S.M.; Zheng, Z.-M. Could human papillomaviruses be spread through blood? J. Clin. Microbiol. 2005, 43, 5428–5434. [Google Scholar] [CrossRef]
  117. Pérez, L.O.; Abba, M.C.; Laguens, R.M.; Golijow, C.D. Analysis of adenocarcinoma of the colon and rectum: Detection of human papillomavirus (HPV) DNA by polymerase chain reaction. Colorectal Dis. 2005, 7, 492–495. [Google Scholar] [CrossRef] [PubMed]
  118. Shah, K.V.; Daniel, R.W.; Simons, J.W.; Vogelstein, B. Investigation of colon cancers for human papillomavirus genomic sequences by polymerase chain reaction. J. Surg. Oncol. 1992, 51, 5–7. [Google Scholar] [CrossRef] [PubMed]
  119. Samaha, S.; Tawfik, O.; Horvat, R.; Bhatia, P. Lymphoepithelioma-like carcinoma of the colon: Report of a case with histologic, immunohistochemical, and molecular studies for Epstein-Barr virus. Dis. Colon. Rectum 1998, 41, 925–928. [Google Scholar] [CrossRef]
  120. Young, L.S.; Dawson, C.W. Epstein-Barr virus and nasopharyngeal carcinoma. Chin. J. Cancer 2014, 33, 581–590. [Google Scholar] [CrossRef]
  121. Terada, T. Epstein-Barr virus associated lymphoepithelial carcinoma of the esophagus. Int. J. Clin. Exp. Med. 2013, 6, 219–226. [Google Scholar]
  122. Liu, C.-Y.; Huang, S.-H. EBV-associated lymphoepithelioma-like thyroid carcinoma with favorable outcome: Case report with cytopathologic and histopathologic study. Diagn. Pathol. 2018, 13, 39. [Google Scholar] [CrossRef]
  123. Hong, S.; Liu, D.; Luo, S.; Fang, W.; Zhan, J.; Fu, S.; Zhang, Y.; Wu, X.; Zhou, H.; Chen, X.; et al. The genomic landscape of Epstein-Barr virus-associated pulmonary lymphoepithelioma-like carcinoma. Nat. Commun. 2019, 10, 3108. [Google Scholar] [CrossRef] [PubMed]
  124. Elawabdeh, N.; Cone, B.M.; Abramowsky, C.R.; Wrubel, D.M.; Grossniklaus, H.; Walrath, J.; Bashir, M.Z.; Shehata, B.M. Epstein-Barr virus associated smooth muscle tumors in post transplant pediatric patients two cases of rare locations, and review of the literature. Fetal Pediatr. Pathol. 2013, 32, 184–191. [Google Scholar] [CrossRef] [PubMed]
  125. Albright, J.B.; Bonatti, H.; Stauffer, J.; Dickson, R.C.; Nguyen, J.; Harnois, D.; Jeanpierre, C.; Hinder, R.; Steers, J.; Chua, H.; et al. Colorectal and anal neoplasms following liver transplantation. Colorectal Dis. 2010, 12, 657–666. [Google Scholar] [CrossRef] [PubMed]
  126. Lee, E.S.; Locker, J.; Nalesnik, M.; Reyes, J.; Jaffe, R.; Alashari, M.; Nour, B.; Tzakis, A.; Dickman, P.S. The association of Epstein-Barr virus with smooth-muscle tumors occurring after organ transplantation. N. Engl. J. Med. 1995, 332, 19–25. [Google Scholar] [CrossRef] [PubMed]
  127. Park, J.M.; Choi, M.-G.; Kim, S.W.; Chung, I.-S.; Yang, C.W.; Kim, Y.S.; Jung, C.K.; Lee, K.Y.; Kang, J.-H. Increased Incidence of Colorectal Malignancies in Renal Transplant Recipients: A Case Control Study. Am. J. Transplant. 2010, 10, 2043–2050. [Google Scholar] [CrossRef]
  128. Medlicott, S.A.; Devlin, S.; Helmersen, D.S.; Yilmaz, A.; Mansoor, A. Early post-transplant smooth muscle neoplasia of the colon presenting as diminutive polyps: A case complicating post-transplant lymphoproliferative disorder. Int. J. Surg. Pathol. 2006, 14, 155–161. [Google Scholar] [CrossRef]
  129. Song, L.B.; Zhang, X.; Zhang, C.Q.; Zhang, Y.; Pan, Z.Z.; Liao, W.T.; Li, M.Z.; Zeng, M.S. Infection of Epstein-Barr virus in colorectal cancer in Chinese. Chin. J. Cancer 2006, 25, 1356–1360. [Google Scholar]
  130. Fiorina, L.; Ricotti, M.; Vanoli, A.; Luinetti, O.; Dallera, E.; Riboni, R.; Paolucci, S.; Brugnatelli, S.; Paulli, M.; Pedrazzoli, P.; et al. Systematic analysis of human oncogenic viruses in colon cancer revealed EBV latency in lymphoid infiltrates. Infect. Agents Cancer 2014, 9, 18. [Google Scholar] [CrossRef]
  131. Salyakina, D.; Tsinoremas, N.F. Viral expression associated with gastrointestinal adenocarcinomas in TCGA high-throughput sequencing data. Hum. Genom. 2013, 7, 23. [Google Scholar] [CrossRef]
  132. Guan, X.; Yi, Y.; Huang, Y.; Hu, Y.; Li, X.; Wang, X.; Fan, H.; Wang, G.; Wang, D. Revealing potential molecular targets bridging colitis and colorectal cancer based on multidimensional integration strategy. Oncotarget 2015, 6, 37600–37612. [Google Scholar] [CrossRef]
  133. Al-Antary, N.; Farghaly, H.; Aboulkassim, T.; Yasmeen, A.; Akil, N.; Al Moustafa, A.-E. Epstein-Barr virus and its association with Fascin expression in colorectal cancers in the Syrian population: A tissue microarray study. Hum. Vaccines Immunother. 2017, 13, 1573–1578. [Google Scholar] [CrossRef] [PubMed]
  134. Karpinski, P.; Myszka, A.; Ramsey, D.; Kielan, W.; Sasiadek, M.M. Detection of viral DNA sequences in sporadic colorectal cancers in relation to CpG island methylation and methylator phenotype. Tumour Biol. 2011, 32, 653–659. [Google Scholar] [CrossRef] [PubMed]
  135. Mehrabani-Khasraghi, S.; Ameli, M.; Khalily, F. Demonstration of Herpes Simplex Virus, Cytomegalovirus, and Epstein-Barr Virus in Colorectal Cancer. Iran Biomed. J. 2016, 20, 302–306. [Google Scholar] [CrossRef] [PubMed]
  136. Sole, C.V.; Calvo, F.A.; Ferrer, C.; Alvarez, E.; Carreras, J.L.; Ochoa, E. Human cytomegalovirus and Epstein-Barr virus infection impact on (18)F-FDG PET/CT SUVmax, CT volumetric and KRAS-based parameters of patients with locally advanced rectal cancer treated with neoadjuvant therapy. Eur. J. Nucl. Med. Mol. Imaging 2015, 42, 186–196. [Google Scholar] [CrossRef]
  137. Nishigami, T.; Kataoka, T.R.; Torii, I.; Sato, A.; Tamura, K.; Hirano, H.; Hida, N.; Ikeuchi, H.; Tsujimura, T. Concomitant adenocarcinoma and colonic non-Hodgkin’s lymphoma in a patient with ulcerative colitis: A case report and molecular analysis. Pathol. Res. Pract. 2010, 206, 846–850. [Google Scholar] [CrossRef]
  138. Militello, V.; Trevisan, M.; Squarzon, L.; Biasolo, M.A.; Rugge, M.; Militello, C.; Palù, G.; Barzon, L. Investigation on the presence of polyomavirus, herpesvirus, and papillomavirus sequences in colorectal neoplasms and their association with cancer. Int. J. Cancer 2009, 124, 2501–2503. [Google Scholar] [CrossRef]
  139. Wong, N.A.; Herbst, H.; Herrmann, K.; Kirchner, T.; Krajewski, A.S.; Moorghen, M.; Niedobitek, F.; Rooney, N.; Shepherd, N.A.; Niedobitek, G. Epstein-Barr virus infection in colorectal neoplasms associated with inflammatory bowel disease: Detection of the virus in lymphomas but not in adenocarcinomas. J. Pathol. 2003, 201, 312–318. [Google Scholar] [CrossRef]
  140. Grinstein, S.; Preciado, M.V.; Gattuso, P.; Chabay, P.A.; Warren, W.H.; De Matteo, E.; Gould, V.E. Demonstration of Epstein-Barr Virus in Carcinomas of Various Sites. Cancer Res. 2002, 62, 4876–4878. [Google Scholar]
  141. Kijima, Y.; Hokita, S.; Takao, S.; Baba, M.; Natsugoe, S.; Yoshinaka, H.; Aridome, K.; Otsuji, T.; Itoh, T.; Tokunaga, M.; et al. Epstein-Barr virus involvement is mainly restricted to lymphoepithelial type of gastric carcinoma among various epithelial neoplasms. J. Med. Virol. 2001, 64, 513–518. [Google Scholar] [CrossRef]
  142. Cho, Y.J.; Chang, M.S.; Park, S.H.; Kim, H.S.; Kim, W.H. In situ hybridization of Epstein-Barr virus in tumor cells and tumor-infiltrating lymphocytes of the gastrointestinal tract. Hum. Pathol. 2001, 32, 297–301. [Google Scholar] [CrossRef]
  143. Yuen, S.T.; Chung, L.P.; Leung, S.Y.; Luk, I.S.; Chan, S.Y.; Ho, J. In situ detection of Epstein-Barr virus in gastric and colorectal adenocarcinomas. Am. J. Surg. Pathol. 1994, 18, 1158–1163. [Google Scholar] [CrossRef] [PubMed]
  144. Boguszaková, L.; Hirsch, I.; Brichácek, B.; Faltýn, J.; Fric, P.; Dvoráková, H.; Vonka, V. Absence of cytomegalovirus, Epstein-Barr virus, and papillomavirus DNA from adenoma and adenocarcinoma of the colon. Acta Virol. 1988, 32, 303–308. [Google Scholar] [PubMed]
  145. Morewaya, J.; Koriyama, C.; Akiba, S.; Shan, D.; Itoh, T.; Eizuru, Y. Epstein-Barr virus-associated gastric carcinoma in Papua New Guinea. Oncol. Rep. 2004, 12, 1093–1098. [Google Scholar] [CrossRef] [PubMed]
  146. Wang, K.; Kan, J.; Yuen, S.T.; Shi, S.T.; Chu, K.M.; Law, S.; Chan, T.L.; Kan, Z.; Chan, A.S.; Tsui, W.Y.; et al. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat. Genet. 2011, 43, 1219–1223. [Google Scholar] [CrossRef] [PubMed]
  147. Zang, Z.J.; Cutcutache, I.; Poon, S.L.; Zhang, S.L.; McPherson, J.R.; Tao, J.; Rajasegaran, V.; Heng, H.L.; Deng, N.; Gan, A.; et al. Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nat. Genet. 2012, 44, 570–574. [Google Scholar] [CrossRef]
  148. Cancer Genome Atlas Research Network; Analysis Working Group. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014, 513, 202–209. [Google Scholar] [CrossRef]
  149. Chen, K.; Yang, D.; Li, X.; Sun, B.; Song, F.; Cao, W.; Brat, D.J.; Gao, Z.; Li, H.; Liang, H.; et al. Mutational landscape of gastric adenocarcinoma in Chinese: Implications for prognosis and therapy. Proc. Natl. Acad. Sci. USA 2015, 112, 1107–1112. [Google Scholar] [CrossRef]
  150. Kim, T.M.; Jung, S.H.; Kim, M.S.; Baek, I.P.; Park, S.W.; Lee, S.H.; Lee, H.H.; Kim, S.S.; Chung, Y.J. The mutational burdens and evolutionary ages of early gastric cancers are comparable to those of advanced gastric cancers. J. Pathol. 2014, 234, 365–374. [Google Scholar] [CrossRef]
  151. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012, 487, 330–337. [Google Scholar] [CrossRef]
  152. Cajuso, T.; Hanninen, U.A.; Kondelin, J.; Gylfe, A.E.; Tanskanen, T.; Katainen, R.; Pitkanen, E.; Ristolainen, H.; Kaasinen, E.; Taipale, M.; et al. Exome sequencing reveals frequent inactivating mutations in ARID1A, ARID1B, ARID2 and ARID4A in microsatellite unstable colorectal cancer. Int. J. Cancer 2014, 135, 611–623. [Google Scholar] [CrossRef]
  153. Jones, S.; Li, M.; Parsons, D.W.; Zhang, X.; Wesseling, J.; Kristel, P.; Schmidt, M.K.; Markowitz, S.; Yan, H.; Bigner, D.; et al. Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types. Hum. Mutat. 2012, 33, 100–103. [Google Scholar] [CrossRef] [PubMed]
  154. Chong, I.Y.; Cunningham, D.; Barber, L.J.; Campbell, J.; Chen, L.; Kozarewa, I.; Fenwick, K.; Assiotis, I.; Guettler, S.; Garcia-Murillas, I.; et al. The genomic landscape of oesophagogastric junctional adenocarcinoma. J. Pathol. 2013, 231, 301–310. [Google Scholar] [CrossRef] [PubMed]
  155. Kato, S.; Schwaederle, M.; Daniels, G.A.; Piccioni, D.; Kesari, S.; Bazhenova, L.; Shimabukuro, K.; Parker, B.A.; Fanta, P.; Kurzrock, R. Cyclin-dependent kinase pathway aberrations in diverse malignancies: Clinical and molecular characteristics. Cell Cycle 2015, 14, 1252–1259. [Google Scholar] [CrossRef] [PubMed]
  156. Ling, C.; Wang, L.; Wang, Z.; Xu, L.; Sun, L.; Yang, H.; Li, W.D.; Wang, K. A pathway-centric survey of somatic mutations in Chinese patients with colorectal carcinomas. PLoS ONE 2015, 10, e0116753. [Google Scholar] [CrossRef] [PubMed]
  157. Reisman, D.; Glaros, S.; Thompson, E.A. The SWI/SNF complex and cancer. Oncogene 2009, 28, 1653–1668. [Google Scholar] [CrossRef]
  158. Kim, Y.S.; Jeong, H.; Choi, J.W.; Oh, H.E.; Lee, J.H. Unique characteristics of ARID1A mutation and protein level in gastric and colorectal cancer: A meta-analysis. Saudi J. Gastroenterol. 2017, 23, 268–274. [Google Scholar] [CrossRef]
  159. Alam, H.; Bhate, A.V.; Gangadaran, P.; Sawant, S.S.; Salot, S.; Sehgal, L.; Dange, P.P.; Chaukar, D.A.; D’cruz, A.K.; Kannanl, S.; et al. Fascin overexpression promotes neoplastic progression in oral squamous cell carcinoma. BMC Cancer 2012, 12, 32. [Google Scholar] [CrossRef]
  160. Papaspyrou, K.; Brochhausen, C.; Schmidtmann, I.; Fruth, K.; Gouveris, H.; Kirckpatrick, J.; Mann, W.; Brieger, J. Fascin upregulation in primary head and neck squamous cell carcinoma is associated with lymphatic metastasis. Oncol. Lett. 2014, 7, 2041–2046. [Google Scholar] [CrossRef]
  161. Qualtrough, D.; Singh, K.; Banu, N.; Paraskeva, C.; Pignatelli, M. The actin-bundling protein fascin is overexpressed in colorectal adenomas and promotes motility in adenoma cells in vitro. Br. J. Cancer 2009, 101, 1124–1129. [Google Scholar] [CrossRef][Green Version]
  162. Yao, J.; Qian, C.-J.; Ye, B.; Zhao, Z.-Q.; Wei, J.; Liang, Y.; Zhang, X. Signal transducer and activator of transcription 3 signaling upregulates fascin via nuclear factor-κB in gastric cancer: Implications in cell invasion and migration. Oncol. Lett. 2014, 7, 902–908. [Google Scholar] [CrossRef]
  163. Omran, O.M.; Al Sheeha, M. Cytoskeletal Focal Adhesion Proteins Fascin-1 and Paxillin Are Predictors of Malignant Progression and Poor Prognosis in Human Breast Cancer. J. Environ. Pathol. Toxicol. Oncol. 2015, 34, 201–212. [Google Scholar] [CrossRef] [PubMed]
  164. Tan, V.Y.; Lewis, S.J.; Adams, J.C.; Martin, R.M. Association of fascin-1 with mortality, disease progression and metastasis in carcinomas: A systematic review and meta-analysis. BMC Med. 2013, 11, 52. [Google Scholar] [CrossRef] [PubMed]
  165. Kong, Q.-L.; Hu, L.-J.; Cao, J.-Y.; Huang, Y.-J.; Xu, L.-H.; Liang, Y.; Xiong, D.; Guan, S.; Guo, B.-H.; Mai, H.-Q.; et al. Epstein-Barr virus-encoded LMP2A induces an epithelial-mesenchymal transition and increases the number of side population stem-like cancer cells in nasopharyngeal carcinoma. PLoS Pathog. 2010, 6, e1000940. [Google Scholar] [CrossRef] [PubMed]
  166. Horikawa, T.; Yoshizaki, T.; Kondo, S.; Furukawa, M.; Kaizaki, Y.; Pagano, J.S. Epstein-Barr Virus latent membrane protein 1 induces Snail and epithelial-mesenchymal transition in metastatic nasopharyngeal carcinoma. Br. J. Cancer 2011, 104, 1160–1167. [Google Scholar] [CrossRef] [PubMed]
  167. Wang, L.; Tian, W.-D.; Xu, X.; Nie, B.; Lu, J.; Liu, X.; Zhang, B.; Dong, Q.; Sunwoo, J.B.; Li, G.; et al. Epstein-Barr virus nuclear antigen 1 (EBNA1) protein induction of epithelial-mesenchymal transition in nasopharyngeal carcinoma cells. Cancer 2014, 120, 363–372. [Google Scholar] [CrossRef]
  168. Jass, J.R. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 2007, 50, 113–130. [Google Scholar] [CrossRef]
  169. Raab-Traub, N. Novel mechanisms of EBV-induced oncogenesis. Curr. Opin. Virol. 2012, 2, 453–458. [Google Scholar] [CrossRef]
  170. QingLing, Z.; LiNa, Y.; Li, L.; Shuang, W.; YuFang, Y.; Yi, D.; Divakaran, J.; Xin, L.; YanQing, D. LMP1 antagonizes WNT/β-catenin signalling through inhibition of WTX and promotes nasopharyngeal dysplasia but not tumourigenesis in LMP1B95-8 transgenic mice. J. Pathol. 2011, 223, 574–583. [Google Scholar] [CrossRef]
  171. Al Moustafa, A.; Foulkes, W.D.; Benlimame, N.; Wong, A.; Yen, L.; Bergeron, J.; Batist, G.; Alpert, L.; Alaoui-Jamali, M.A. E6/E7 proteins of HPV type 16 and ErbB-2 cooperate to induce neoplastic transformation of primary normal oral epithelial cells. Oncogene 2004, 23, 350–358. [Google Scholar] [CrossRef]
  172. Glenn, W.K.; Heng, B.; Delprado, W.; Iacopetta, B.; Whitaker, N.J.; Lawson, J.S. Epstein-Barr virus, human papillomavirus and mouse mammary tumour virus as multiple viruses in breast cancer. PLoS ONE 2012, 7, e48788. [Google Scholar] [CrossRef]
  173. Makielski, K.R.; Lee, D.; Lorenz, L.D.; Nawandar, D.M.; Chiu, Y.-F.; Kenney, S.C.; Lambert, P.F. Human papillomavirus promotes Epstein-Barr virus maintenance and lytic reactivation in immortalized oral keratinocytes. Virology 2016, 495, 52–62. [Google Scholar] [CrossRef] [PubMed]
  174. Guidry, J.T.; Scott, R.S. The interaction between human papillomavirus and other viruses. Virus Res. 2017, 231, 139–147. [Google Scholar] [CrossRef] [PubMed]
  175. Al Moustafa, A.-E.; Chen, D.; Ghabreau, L.; Akil, N. Association between human papillomavirus and Epstein-Barr virus infections in human oral carcinogenesis. Med. Hypotheses 2009, 73, 184–186. [Google Scholar] [CrossRef] [PubMed]
  176. Lawson, J.S.; Salmons, B.; Glenn, W.K. Oncogenic Viruses and Breast Cancer: Mouse Mammary Tumor Virus (MMTV), Bovine Leukemia Virus (BLV), Human Papilloma Virus (HPV), and Epstein-Barr Virus (EBV). Front. Oncol. 2018, 8, 1. [Google Scholar] [CrossRef] [PubMed]
  177. Mirzaei, H.; Goudarzi, H.; Eslami, G.; Faghihloo, E. Role of viruses in gastrointestinal cancer. J. Cell. Physiol. 2018, 233, 4000–4014. [Google Scholar] [CrossRef]
  178. Polz-Gruszka, D.; Stec, A.; Dworzański, J.; Polz-Dacewicz, M. EBV, HSV, CMV and HPV in Laryngeal and Oropharyngeal Carcinoma in Polish Patients. Anticancer Res. 2015, 35, 1657–1661. [Google Scholar]
  179. Cyprian, F.S.; Al-Farsi, H.F.; Vranic, S.; Akhtar, S.; Al Moustafa, A.-E. Epstein-Barr Virus and Human Papillomaviruses Interactions and Their Roles in the Initiation of Epithelial-Mesenchymal Transition and Cancer Progression. Front. Oncol. 2018, 8, 111. [Google Scholar] [CrossRef]
  180. Al-Daraji, W.I.; Smith, J.H. Infection and cervical neoplasia: Facts and fiction. Int. J. Clin. Exp. Pathol. 2009, 2, 48–64. [Google Scholar]
  181. Polz-Dacewicz, M.; Strycharz-Dudziak, M.; Dworzanski, J.; Stec, A.; Kocot, J. Salivary and serum IL-10, TNF-alpha, TGF-beta, VEGF levels in oropharyngeal squamous cell carcinoma and correlation with HPV and EBV infections. Infect. Agent Cancer 2016, 11, 45. [Google Scholar] [CrossRef]
  182. Meckes, D.G.; Gunawardena, H.P.; Dekroon, R.M.; Heaton, P.R.; Edwards, R.H.; Ozgur, S.; Griffith, J.D.; Damania, B.; Raab-Traub, N. Modulation of B-cell exosome proteins by gamma herpesvirus infection. Proc. Natl. Acad. Sci. USA 2013, 110, E2925–E2933. [Google Scholar] [CrossRef]
  183. Pegtel, D.M.; van de Garde, M.D.; Middeldorp, J.M. Viral miRNAs exploiting the endosomal-exosomal pathway for intercellular cross-talk and immune evasion. Biochim. Biophys. Acta 2011, 1809, 715–721. [Google Scholar] [CrossRef] [PubMed]
  184. Kahla, S.; Oueslati, S.; Achour, M.; Kochbati, L.; Chanoufi, M.B.; Maalej, M.; Oueslati, R. Correlation between ebv co-infection and HPV16 genome integrity in Tunisian cervical cancer patients. Braz. J. Microbiol. 2012, 43, 744–753. [Google Scholar] [CrossRef] [PubMed]
  185. Szostek, S.; Zawilinska, B.; Kopec, J.; Kosz-Vnenchak, M. Herpesviruses as possible cofactors in HPV-16-related oncogenesis. Acta Biochim. Pol. 2009, 56, 337–342. [Google Scholar] [CrossRef] [PubMed]
  186. Mesri, E.; Feitelson, M.A.; Munger, K. Human viral oncogenesis: A cancer hallmarks analysis. Cell Host. Microbe 2014, 15, 266–282. [Google Scholar] [CrossRef]
  187. Nikitin, P.A.; Yan, C.M.; Forte, E.; Bocedi, A.; Tourigny, J.P.; White, R.E.; Allday, M.J.; Patel, A.; Dave, S.S.; Kim, W.; et al. An ATM/Chk2-mediated DNA damage-responsive signaling pathway suppresses Epstein-Barr virus transformation of primary human B cells. Cell Host Microbe 2010, 8, 510–522. [Google Scholar] [CrossRef]
  188. Harris, R.S.; Dudley, J.P. APOBECs and virus restriction. Virology 2015, 479, 131–145. [Google Scholar] [CrossRef]
  189. Cullen, B.R. Role and mechanism of action of the APOBEC3 family of antiretroviral resistance factors. J. Virol. 2006, 80, 1067–1076. [Google Scholar] [CrossRef]
  190. Suspène, R.; Aynaud, M.-M.; Koch, S.; Pasdeloup, D.; Labetoulle, M.; Gaertner, B.; Vartanian, J.-P.; Meyerhans, A.; Wain-Hobson, S. Genetic editing of herpes simplex virus 1 and Epstein-Barr herpesvirus genomes by human APOBEC3 cytidine deaminases in culture and in vivo. J. Virol. 2011, 85, 7594–7602. [Google Scholar] [CrossRef]
  191. Ohba, K.; Ichiyama, K.; Yajima, M.; Gemma, N.; Nikaido, M.; Wu, Q.; Chong, P.; Mori, S.; Yamamoto, R.; Wong, J.E.L.; et al. In vivo and in vitro studies suggest a possible involvement of HPV infection in the early stage of breast carcinogenesis via APOBEC3B induction. PLoS ONE 2014, 9, e97787. [Google Scholar] [CrossRef]
  192. Wang, Z.; Wakae, K.; Kitamura, K.; Aoyama, S.; Liu, G.; Koura, M.; Monjurul, A.M.; Kukimoto, I.; Muramatsu, M. APOBEC3 deaminases induce hypermutation in human papillomavirus 16 DNA upon beta interferon stimulation. J. Virol. 2014, 88, 1308–1317. [Google Scholar] [CrossRef]
  193. Sun, Z.; Hu, W.; Xu, J.; Kaufmann, A.M.; Albers, A.E. MicroRNA-34a regulates epithelial-mesenchymal transition and cancer stem cell phenotype of head and neck squamous cell carcinoma in vitro. Int. J. Oncol. 2015, 47, 1339–1350. [Google Scholar] [CrossRef] [PubMed]
  194. Aguayo, F.; Khan, N.; Koriyama, C.; González, C.; Ampuero, S.; Padilla, O.; Solís, L.; Eizuru, Y.; Corvalán, A.; Akiba, S. Human papillomavirus and Epstein-Barr virus infections in breast cancer from chile. Infect. Agents Cancer 2011, 6, 7. [Google Scholar] [CrossRef] [PubMed]
  195. Naushad, W.; Surriya, O.; Sadia, H. Prevalence of EBV, HPV and MMTV in Pakistani breast cancer patients: A possible etiological role of viruses in breast cancer. Infect. Genet. Evol. 2017, 54, 230–237. [Google Scholar] [CrossRef] [PubMed]
  196. Jalouli, J.; Jalouli, M.M.; Sapkota, D.; Ibrahim, S.O.; Larsson, P.A.; Sand, L. Human Papilloma Virus, Herpes Simplex Virus and Epstein Barr Virus in Oral Squamous Cell Carcinoma from Eight Different Countries. Anticancer Res. 2012, 32, 571–580. [Google Scholar] [PubMed]
  197. Jiang, R.; Ekshyyan, O.; Moore-Medlin, T.; Rong, X.; Nathan, S.; Gu, X.; Abreo, F.; Rosenthal, E.L.; Shi, M.; Guidry, J.T.; et al. Association between human papilloma virus/Epstein–Barr virus coinfection and oral carcinogenesis. J.Oral Pathol. Med. 2015, 44, 28–36. [Google Scholar] [CrossRef]
  198. Vranic, S.; Cyprian, F.S.; Akhtar, S.; Al Moustafa, A.-E. The Role of Epstein-Barr Virus in Cervical Cancer: A Brief Update. Front. Oncol. 2018, 8, 113. [Google Scholar] [CrossRef]
  199. Ammatuna, P.; Giovannelli, L.; Giambelluca, D.; Mancuso, S.; Rubino, E.; Colletti, P.; Mazzola, G.; Belfiore, P.; Lima, R. Presence of human papillomavirus and Epstein-Barr virus in the cervix of women infected with the human immunodeficiency virus. J. Med. Virol. 2000, 62, 410–415. [Google Scholar] [CrossRef]
  200. Gunasekharan, V.; Laimins, L.A. Human Papillomaviruses Modulate MicroRNA 145 Expression To Directly Control Genome Amplification. J. Virol. 2013, 87, 6037–6043. [Google Scholar] [CrossRef]
  201. Nawandar, D.M.; Wang, A.; Makielski, K.; Lee, D.; Ma, S.; Barlow, E.; Reusch, J.; Jiang, R.; Wille, C.K.; Greenspan, D.; et al. Differentiation-Dependent KLF4 Expression Promotes Lytic Epstein-Barr Virus Infection in Epithelial Cells. PLoS Pathog. 2015, 11, e1005195. [Google Scholar] [CrossRef]
  202. Katsumura, K.R.; Maruo, S.; Takada, K. EBV lytic infection enhances transformation of B-lymphocytes infected with EBV in the presence of T-lymphocytes. J. Med. Virol. 2012, 84, 504–510. [Google Scholar] [CrossRef]
  203. Ma, S.-D.; Hegde, S.; Young, K.H.; Sullivan, R.; Rajesh, D.; Zhou, Y.; Jankowska-Gan, E.; Burlingham, W.J.; Sun, X.; Gulley, M.L.; et al. A new model of Epstein-Barr virus infection reveals an important role for early lytic viral protein expression in the development of lymphomas. J. Virol. 2011, 85, 165–177. [Google Scholar] [CrossRef] [PubMed]
  204. Meusel, T.R.; Imani, F. Viral Induction of Inflammatory Cytokines in Human Epithelial Cells Follows a p38 Mitogen-Activated Protein Kinase-Dependent but NF-κB-Independent Pathway. J. Immunol. 2003, 171, 3768–3774. [Google Scholar] [CrossRef] [PubMed]
  205. Arvey, A.; Tempera, I.; Tsai, K.; Chen, H.-S.; Tikhmyanova, N.; Klichinsky, M.; Leslie, C.; Lieberman, P.M. An atlas of the Epstein-Barr virus transcriptome and epigenome reveals host-virus regulatory interactions. Cell Host Microbe 2012, 12, 233–245. [Google Scholar] [CrossRef] [PubMed]
  206. Arvey, A.; Tempera, I.; Lieberman, P.M. Interpreting the Epstein-Barr Virus (EBV) epigenome using high-throughput data. Viruses 2013, 5, 1042–1054. [Google Scholar] [CrossRef]
Pathogens 09 00300 g001
Figure 1. Schematic outline showing plausible crosstalk between the oncoproteins of high-risk human papillomaviruses (HPVs) and Epstein–Barr virus (EBV) in the induction of angiogenesis, cancer progression, apoptosis as well as cell cycle progression. We note that high-risk HPVs and EBV oncoproteins share various downstream-signaling pathways including MAPK/ERK/JNK/JNK3, PI3k/Akt and p53/p21 as well APOBEC; HPVs/EBV oncoproteins can closely cooperate in cancer development and/or enhance cancer progression.
Figure 1. Schematic outline showing plausible crosstalk between the oncoproteins of high-risk human papillomaviruses (HPVs) and Epstein–Barr virus (EBV) in the induction of angiogenesis, cancer progression, apoptosis as well as cell cycle progression. We note that high-risk HPVs and EBV oncoproteins share various downstream-signaling pathways including MAPK/ERK/JNK/JNK3, PI3k/Akt and p53/p21 as well APOBEC; HPVs/EBV oncoproteins can closely cooperate in cancer development and/or enhance cancer progression.
Pathogens 09 00300 g001
Table 1. Human papillomaviruses (HPV) prevalence in human colorectal cancers in different populations around the world.
Table 1. Human papillomaviruses (HPV) prevalence in human colorectal cancers in different populations around the world.
Population
(Year)		Number of SamplesHPV Status
(%)		Assay
(Detection Method)		References
Bosnian
(2020)		106Positive
(50%)		PCR and IHC[109]
Syrian
(2020)		102Positive
(37%)		PCR and IHC[110]
Portuguese
(2020)		144NegativeRT-PCR[111]
Polish
(2017)		50Positive
(20%)		PCR[112]
Puerto Rican
(2016)		45Positive
(42%)		PCR[23]
Brazilian
(2016)		1,549Positive
(52%)		Meta-analysis[113]
Syrian
(2012)		78Positive
(54%)		PCR and IHC[44]
Turkish
(2011)		106NegativePCR[47]
Argentinian
(2010)		75Positive
(44%)		PCR[114]
Israeli
(2010)		106NegativeRLB and LiPA[19]
USA
(2010)		73NegativeRLB and LiPA[19]
Spain
(2010)		100NegativeRLB and LiPA[19]
Turkish
(2009)		56Positive
(82%)		PCR and southern blot hybridization[45]
Italian
(2008)		66Positive
(33%)		PCR[115]
Brazilian
(2007)		72Positive
(83%)		PCR[21]
Turkish
(2006)		53Positive
(81%)		PCR[46]
USA
(2005)		55Positive
(51%)		PCR[116]
Argentinian
(2005)		27Positive
(74%)		PCR[117]
USA
(1992)		50NegativePCR[118]
IHC: immunohistochemistry; ISH: in situ hybridization; PCR: polymerase chain reaction: RLB: Reverse line blot; LiPA: Line Probe Assay.
Table 2. Epstein–Barr virus (EBV) incidence in colorectal cancer samples in different populations.
Table 2. Epstein–Barr virus (EBV) incidence in colorectal cancer samples in different populations.
Population
(Year)		Number of SamplesEBV Status
(%)		Assay
(Detection Method)		References
Bosnian
(2019)		108Positive
(25%)		PCR and IHC[92]
Iranian
(2018)		210Positive
(1.4%)		PCR[118]
Syrian
(2017)		102Positive
(36%)		PCR and IHC[133]
Iranian
(2016)		35NegativePCR[135]
Iranian
(2015)		50Positive
(38%)		PCR[116]
Chile
(2015)		37Positive
(46%)		PCR[136]
Italian
(2014)		44NegativeRT-PCR and IHC[130]
North America
(2013)		117Positive
(21%)		PCR[131]
Polish
(2011)		186Positive
(19%)		PCR[134]
South Korean
(2010)		72Positive
(30.6%)		IHC and ISH[127]
Japanese
(2010)		1NegativeIHC[137]
Italian
(2009)		100Positive
(2.8–39%)		RT-PCR and sequencing[138]
Chinese
(2006)		90Positive
(30%)		IHC and ISH[129]
Chinese
(2003)		130Positive
(5–8%)		IHC, ISH and PCR[117]
Scotland
(2003)		26NegativeISH[139]
Argentina
(2002)		19Positive
(5%)		ISH[140]
Japanese
(2001)		102NegativeISH[141]
South Korean
(2001)		274NegativeISH[142]
Chinese
(1994)		36NegativeISH[143]
Czechoslovakia
(1988)		13NegativePCR[144]
New Guinean
(2004)		46Positive
(46%)		ISH[145]
IHC: immunohistochemistry; ISH: in situ hybridization; PCR: polymerase chain reaction.

Share and Cite

MDPI and ACS Style

Fernandes, Q.; Gupta, I.; Vranic, S.; Al Moustafa, A.-E. Human Papillomaviruses and Epstein–Barr Virus Interactions in Colorectal Cancer: A Brief Review. Pathogens 2020, 9, 300. https://doi.org/10.3390/pathogens9040300

AMA Style

Fernandes Q, Gupta I, Vranic S, Al Moustafa A-E. Human Papillomaviruses and Epstein–Barr Virus Interactions in Colorectal Cancer: A Brief Review. Pathogens. 2020; 9(4):300. https://doi.org/10.3390/pathogens9040300

Chicago/Turabian Style

Fernandes, Queenie, Ishita Gupta, Semir Vranic, and Ala-Eddin Al Moustafa. 2020. "Human Papillomaviruses and Epstein–Barr Virus Interactions in Colorectal Cancer: A Brief Review" Pathogens 9, no. 4: 300. https://doi.org/10.3390/pathogens9040300

APA Style

Fernandes, Q., Gupta, I., Vranic, S., & Al Moustafa, A.-E. (2020). Human Papillomaviruses and Epstein–Barr Virus Interactions in Colorectal Cancer: A Brief Review. Pathogens, 9(4), 300. https://doi.org/10.3390/pathogens9040300

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop