International Journal of Molecular Sciences

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19 pages, 2743 KiB

Open AccessArticle

Involvement of Small Non-Coding RNA and Cell Antigens in Pathogenesis of Extramedullary Multiple Myeloma

by Monika Vlachová, Jana Gregorová, Petra Vychytilová-Faltejsková, Natalia Anna Gabło, Lenka Radová, Lenka Pospíšilová, Martina Almáši, Martin Štork, Zdeňka Knechtová, Jiří Minařík, Tereza Popková, Tomáš Jelínek, Roman Hájek, Luděk Pour, Lucie Říhová and Sabina Ševčíková

Int. J. Mol. Sci. 2022, 23(23), 14765; https://doi.org/10.3390/ijms232314765 - 25 Nov 2022

Viewed by 1715

Abstract

Extramedullary multiple myeloma (EMD) is an aggressive disease; malignant plasma cells lose their dependence in the bone marrow microenvironment and migrate into tissues. EMD is a negative prognostic factor of survival. Using flow cytometry and next-generation sequencing, we aimed to identify antigens and [...] Read more.

Extramedullary multiple myeloma (EMD) is an aggressive disease; malignant plasma cells lose their dependence in the bone marrow microenvironment and migrate into tissues. EMD is a negative prognostic factor of survival. Using flow cytometry and next-generation sequencing, we aimed to identify antigens and microRNAs (miRNAs) involved in EMD pathogenesis. Flow cytometry analysis revealed significant differences in the level of clonal plasma cells between MM and EMD patients, while the expression of CD markers was comparable between these two groups. Further, miR-26a-5p and miR-30e-5p were found to be significantly down-regulated in EMD compared to MM. Based on the expression of miR-26a-5p, we were able to distinguish these two groups of patients with high sensitivity and specificity. In addition, the involvement of deregulated miRNAs in cell cycle regulation, ubiquitin-mediated proteolysis and signaling pathways associated with infections or neurological disorders was observed using GO and KEGG pathways enrichment analysis. Subsequently, a correlation between the expression of analyzed miRNAs and the levels of CD molecules was observed. Finally, clinicopathological characteristics as well as CD antigens associated with the prognosis of MM and EMD patients were identified. Altogether, we identified several molecules possibly involved in the transformation of MM into EMD. Full article

(This article belongs to the Special Issue Clarification of Mechanism of Carcinogenesis 2.0)

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21 pages, 13568 KiB

Open AccessArticle

Assessment of RACGAP1 as a Prognostic and Immunological Biomarker in Multiple Human Tumors: A Multiomics Analysis

by Refaat A. Eid, Mohamed A. Soltan, Muhammad Alaa Eldeen, Ayed A. Shati, Samy A. Dawood, Mohamed Eissa, Mohamed Samir A. Zaki, Mohammad Algahtani, Abdulrahman Theyab, Mohamed M. Abdel-Daim and Bonglee Kim

Int. J. Mol. Sci. 2022, 23(22), 14102; https://doi.org/10.3390/ijms232214102 - 15 Nov 2022

Cited by 8 | Viewed by 2060

Abstract

Several recent studies have pointed out that arc GTPase activating protein 1 (RACGAP1) is a putative oncogene in many human tumors. However, to date, no pan-cancer analysis has been performed to study the different aspects of this gene expression and behavior in tumor [...] Read more.

Several recent studies have pointed out that arc GTPase activating protein 1 (RACGAP1) is a putative oncogene in many human tumors. However, to date, no pan-cancer analysis has been performed to study the different aspects of this gene expression and behavior in tumor tissues. Here, we applied several bioinformatics tools to perform a comprehensive analysis for RACGAP1. First, we assessed the expression of RACGAP1 in several types of human tumors and tried to correlate that with the stage of the tumors analyzed. We then performed a survival analysis to study the correlation between RACGAP1 upregulation in tumors and the clinical outcome. Additionally, we investigated the mutation forms, the correlation with several immune cell infiltration, the phosphorylation status of the interested protein in normal and tumor tissues, and the potential molecular mechanisms of RACGAP1 in cancerous tissue. The results demonstrated that RACGAP1, a highly expressed gene across several types of tumors, correlated with a poor prognosis in several types of human cancers. Moreover, it was found that RACGAP1 affects the tumor immune microenvironment by influencing the infiltration level of several immune cells. Collectively, the current study provides a comprehensive overview of the oncogenic roles of RACGAP1, where our results nominate it as a potential prognostic biomarker and a target for antitumor therapy development. Full article

(This article belongs to the Special Issue Clarification of Mechanism of Carcinogenesis 2.0)

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12 pages, 1981 KiB

Open AccessArticle

IsomiR-eQTL: A Cancer-Specific Expression Quantitative Trait Loci Database of miRNAs and Their Isoforms

by Afshin Moradi, Paul Whatmore, Samaneh Farashi, Roberto A. Barrero and Jyotsna Batra

Int. J. Mol. Sci. 2022, 23(20), 12493; https://doi.org/10.3390/ijms232012493 - 18 Oct 2022

Viewed by 1792

Abstract

The identification of expression quantitative trait loci (eQTL) is an important component in efforts to understand how genetic variants influence disease risk. MicroRNAs (miRNAs) are short noncoding RNA molecules capable of regulating the expression of several genes simultaneously. Recently, several novel isomers of [...] Read more.

The identification of expression quantitative trait loci (eQTL) is an important component in efforts to understand how genetic variants influence disease risk. MicroRNAs (miRNAs) are short noncoding RNA molecules capable of regulating the expression of several genes simultaneously. Recently, several novel isomers of miRNAs (isomiRs) that differ slightly in length and sequence composition compared to their canonical miRNAs have been reported. Here we present isomiR-eQTL, a user-friendly database designed to help researchers find single nucleotide polymorphisms (SNPs) that can impact miRNA (miR-eQTL) and isomiR expression (isomiR-eQTL) in 30 cancer types. The isomiR-eQTL includes a total of 152,671 miR-eQTLs and 2,390,805 isomiR-eQTLs at a false discovery rate (FDR) of 0.05. It also includes 65,733 miR-eQTLs overlapping known cancer-associated loci identified through genome-wide association studies (GWAS). To the best of our knowledge, this is the first study investigating the impact of SNPs on isomiR expression at the genome-wide level. This database may pave the way for researchers toward finding a model for personalised medicine in which miRNAs, isomiRs, and genotypes are utilised. Full article

(This article belongs to the Special Issue Clarification of Mechanism of Carcinogenesis 2.0)

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17 pages, 2881 KiB

Open AccessArticle

Alterations in Gene Pair Correlations as Potential Diagnostic Markers for Colon Cancer

by Bonnie Yang Yang and Meena Kishore Sakharkar

Int. J. Mol. Sci. 2022, 23(20), 12463; https://doi.org/10.3390/ijms232012463 - 18 Oct 2022

Cited by 1 | Viewed by 1408

Abstract

Colorectal cancer (CRC) is a leading cause of death from cancer in Canada. Early detection of CRC remains crucial in managing disease prognosis and improving patient survival. It can also facilitate prevention, screening, and treatment before the disease progresses to a chronic stage. [...] Read more.

Colorectal cancer (CRC) is a leading cause of death from cancer in Canada. Early detection of CRC remains crucial in managing disease prognosis and improving patient survival. It can also facilitate prevention, screening, and treatment before the disease progresses to a chronic stage. In this study, we developed a strategy for identifying colon cancer biomarkers from both gene expression and gene pair correlation. Using the RNA-Seq dataset TCGA-COAD, a panel of 71 genes, including the 20 most upregulated genes, 20 most downregulated genes and 31 genes involved in the most significantly altered gene pairs, were selected as potential biomarkers for colon cancer. This signature set of genes could be used for early diagnosis. Furthermore, this strategy could be applied to other types of cancer. Full article

(This article belongs to the Special Issue Clarification of Mechanism of Carcinogenesis 2.0)

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11 pages, 2370 KiB

Open AccessArticle

Identification of Candidate mRNA Isoforms for Prostate Cancer-Risk SNPs Utilizing Iso-eQTL and sQTL Methods

by Afshin Moradi, Harsh Sharma, Ravi Datta Sharma, Achala Fernando, Roberto A. Barrero and Jyotsna Batra

Int. J. Mol. Sci. 2022, 23(20), 12406; https://doi.org/10.3390/ijms232012406 - 17 Oct 2022

Viewed by 1983

Abstract

Single nucleotide polymorphisms (SNPs) impacting the alternative splicing (AS) process (sQTLs) or isoform expression (iso-eQTL) are implicated as important cancer regulatory elements. To find the sQTL and iso-eQTL, we retrieved prostate cancer (PrCa) tissue RNA-seq and genotype data originating from 385 PrCa European [...] Read more.

Single nucleotide polymorphisms (SNPs) impacting the alternative splicing (AS) process (sQTLs) or isoform expression (iso-eQTL) are implicated as important cancer regulatory elements. To find the sQTL and iso-eQTL, we retrieved prostate cancer (PrCa) tissue RNA-seq and genotype data originating from 385 PrCa European patients from The Cancer Genome Atlas. We conducted RNA-seq analysis with isoform-based and splice event-based approaches. The MatrixEQTL was used to identify PrCa-associated sQTLs and iso-eQTLs. The overlap between sQTL and iso-eQTL with GWAS loci and those that are differentially expressed between cancer and normal tissue were identified. The cis-acting associations (FDR < 0.05) for PrCa-risk SNPs identified 42, 123, and 90 PrCa-associated cassette exons, intron retention, and mRNA isoforms belonging to 25, 95, and 83 genes, respectively; while assessment of trans-acting association (FDR < 0.05) yielded 59, 65, and 196 PrCa-associated cassette exons, intron retention and mRNA isoforms belonging to 35, 55, and 181 genes, respectively. The results suggest that functional PrCa-associated SNPs can play a role in PrCa genesis by making an important contribution to the dysregulation of AS and, consequently, impacting the expression of the mRNA isoforms. Full article

(This article belongs to the Special Issue Clarification of Mechanism of Carcinogenesis 2.0)

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13 pages, 1987 KiB

Open AccessArticle

Immune State Conversion of the Mesenteric Lymph Node in a Mouse Breast Cancer Model

by Tsukasa Shigehiro, Maho Ueno, Mayumi Kijihira, Ryotaro Takahashi, Chiho Umemura, Eman A. Taha, Chisaki Kurosaka, Megumi Asayama, Hiroshi Murakami, Ayano Satoh, Yoshimasa Nakamura, Junichiro Futami and Junko Masuda

Int. J. Mol. Sci. 2022, 23(19), 11035; https://doi.org/10.3390/ijms231911035 - 20 Sep 2022

Viewed by 2008

Abstract

Secondary lymphoid tissues, such as the spleen and lymph nodes (LNs), contribute to breast cancer development and metastasis in both anti- and pro-tumoral directions. Although secondary lymphoid tissues have been extensively studied, very little is known about the immune conversion in mesenteric LNs [...] Read more.

Secondary lymphoid tissues, such as the spleen and lymph nodes (LNs), contribute to breast cancer development and metastasis in both anti- and pro-tumoral directions. Although secondary lymphoid tissues have been extensively studied, very little is known about the immune conversion in mesenteric LNs (mLNs) during breast cancer development. Here, we demonstrate inflammatory immune conversion of mLNs in a metastatic 4T1 breast cancer model. Splenic T cells were significantly decreased and continuously suppressed IFN-γ production during tumor development, while myeloid-derived suppressor cells (MDSCs) were dramatically enriched. However, T cell numbers in the mLN did not decrease, and the MDSCs only moderately increased. T cells in the mLN exhibited conversion from a pro-inflammatory state with high IFN-γ expression to an anti-inflammatory state with high expression of IL-4 and IL-10 in early- to late-stages of breast cancer development. Interestingly, increased migration of CD103⁺CD11b⁺ dendritic cells (DCs) into the mLN, along with increased (1→3)-β-D-glucan levels in serum, was observed even in late-stage breast cancer. This suggests that CD103⁺CD11b⁺ DCs could prime cancer-reactive T cells. Together, the data indicate that the mLN is an important lymphoid tissue contributing to breast cancer development. Full article

(This article belongs to the Special Issue Clarification of Mechanism of Carcinogenesis 2.0)

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Review

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16 pages, 2276 KiB

Open AccessReview

An Overview of the Role of MicroRNAs on Carcinogenesis: A Focus on Cell Cycle, Angiogenesis and Metastasis

by Leonel Pekarek, Diego Torres-Carranza, Oscar Fraile-Martinez, Cielo García-Montero, Tatiana Pekarek, Miguel A. Saez, Francisco Rueda-Correa, Carolina Pimentel-Martinez, Luis G. Guijarro, Raul Diaz-Pedrero, Melchor Alvarez-Mon and Miguel A. Ortega

Int. J. Mol. Sci. 2023, 24(8), 7268; https://doi.org/10.3390/ijms24087268 - 14 Apr 2023

Cited by 8 | Viewed by 1547

Abstract

In recent years, the importance of epigenetic markers in the carcinogenesis of different malignant neoplasms has been demonstrated, also demonstrating their utility for understanding metastatic spread and tumor progression in cancer patients. Among the different biomarkers, microRNAs represent a set of non-coding RNAs [...] Read more.

In recent years, the importance of epigenetic markers in the carcinogenesis of different malignant neoplasms has been demonstrated, also demonstrating their utility for understanding metastatic spread and tumor progression in cancer patients. Among the different biomarkers, microRNAs represent a set of non-coding RNAs that regulate gene expression, having been involved in a wide variety of neoplasia acting in different oncogenic pathways. Both the overexpression and downregulation of microRNAs represent a complex interaction with various genes whose ultimate consequence is increased cell proliferation, tumor invasion and interaction with various driver markers. It should be noted that in current clinical practice, even though the combination of different microRNAs has been shown to be useful by different authors at diagnostic and prognostic levels, there are no diagnostic kits that can be used for the initial approach or to assess recurrences of oncological diseases. Previous works have cited microRNAs as having a critical role in several carcinogenic mechanisms, ranging from cell cycle alterations to angiogenesis and mechanisms of distant metastatic dissemination. Indeed, the overexpression or downregulation of specific microRNAs seem to be tightly involved in the modulation of various components related to these processes. For instance, cyclins and cyclin-dependent kinases, transcription factors, signaling molecules and angiogenic/antiangiogenic products, among others, have been recognized as specific targets of microRNAs in different types of cancer. Therefore, the purpose of this article is to describe the main implications of different microRNAs in cell cycle alterations, metastasis and angiogenesis, trying to summarize their involvement in carcinogenesis. Full article

(This article belongs to the Special Issue Clarification of Mechanism of Carcinogenesis 2.0)

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27 pages, 2903 KiB

Open AccessReview

Targeting Cancer Stem Cells as the Key Driver of Carcinogenesis and Therapeutic Resistance

by Refaat A. Eid, Muhammad Alaa Edeen, Eslam M. Shedid, Al Shaimaa S. Kamal, Mona M. Warda, Farag Mamdouh, Sohila A. Khedr, Mohamed A. Soltan, Hee Won Jeon, Mohamed Samir A. Zaki and Bonglee Kim

Int. J. Mol. Sci. 2023, 24(2), 1786; https://doi.org/10.3390/ijms24021786 - 16 Jan 2023

Cited by 14 | Viewed by 4436

Abstract

The emerging concept of cancer stem cells (CSCs) as the key driver behind carcinogenesis, progression, and diversity has displaced the prior model of a tumor composed of cells with similar subsequently acquired mutations and an equivalent capacity for renewal, invasion, and metastasis. This [...] Read more.

The emerging concept of cancer stem cells (CSCs) as the key driver behind carcinogenesis, progression, and diversity has displaced the prior model of a tumor composed of cells with similar subsequently acquired mutations and an equivalent capacity for renewal, invasion, and metastasis. This significant change has shifted the research focus toward targeting CSCs to eradicate cancer. CSCs may be characterized using cell surface markers. They are defined by their capacity to self-renew and differentiate, resist conventional therapies, and generate new tumors following repeated transplantation in xenografted mice. CSCs’ functional capabilities are governed by various intracellular and extracellular variables such as pluripotency-related transcription factors, internal signaling pathways, and external stimuli. Numerous natural compounds and synthetic chemicals have been investigated for their ability to disrupt these regulatory components and inhibit stemness and terminal differentiation in CSCs, hence achieving clinical implications. However, no cancer treatment focuses on the biological consequences of these drugs on CSCs, and their functions have been established. This article provides a biomedical discussion of cancer at the time along with an overview of CSCs and their origin, features, characterization, isolation techniques, signaling pathways, and novel targeted therapeutic approaches. Additionally, we highlighted the factors endorsed as controlling or helping to promote stemness in CSCs. Our objective was to encourage future studies on these prospective treatments to develop a framework for their application as single or combined therapeutics to eradicate various forms of cancer. Full article

(This article belongs to the Special Issue Clarification of Mechanism of Carcinogenesis 2.0)

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