Next Article in Journal
A Novel Manganese-Rich Pokeweed Biochar for Highly Efficient Adsorption of Heavy Metals from Wastewater: Performance, Mechanisms, and Potential Risk Analysis
Next Article in Special Issue
MicroRNAs Encoded by Virus and Small RNAs Encoded by Bacteria Associated with Oncogenic Processes
Previous Article in Journal
Physical and Mechanical Characterization of Fibrin-Based Bioprinted Constructs Containing Drug-Releasing Microspheres for Neural Tissue Engineering Applications
Previous Article in Special Issue
Competing Endogenous RNAs in Cervical Carcinogenesis: A New Layer of Complexity
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Processes
Volume 9
Issue 7
10.3390/pr9071208
processes-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 thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Regulation and Role of piRNAs and PIWI Proteins in Cancer

by
Hyeseon Jeong
1,†,
Kyung Hwan Park
1,†,
Yuri Lee
1,
Ayoung Jeong
1,
Sooji Choi
1 and
Kyung Won Kim
1,2,*
1
Department of Life Science, Hallym University, Chuncheon 24252, Korea
2
Multidisciplinary Genome Institute, Hallym University, Chuncheon 24252, Korea
*
Author to whom correspondence should be addressed.
†
Hyeseon Jeong and Kyung Hwan Park contributed equally to this work.
Processes 2021, 9(7), 1208; https://doi.org/10.3390/pr9071208
Submission received: 27 May 2021 / Revised: 2 July 2021 / Accepted: 10 July 2021 / Published: 14 July 2021
(This article belongs to the Special Issue Biogenesis, Function and Role of MicroRNA in Cancer)
Browse Figures
Versions Notes

Abstract

:
P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are regulatory small non-coding RNAs that participate in transposon inactivation, chromatin regulation, and endogenous gene regulation. Numerous genetic and epigenetic factors regulate cell proliferation and tumor metastasis. PIWI proteins and piRNAs have been revealed to function in regulating upstream or downstream of oncogenes or tumor-suppressor genes in cancer tissues. In the present review, we summarize major recent findings in uncovering the regulation and role of PIWI proteins and piRNAs in tumorigenesis and highlight some of the promising applications of specific piRNAs in cancer therapeutics and as cancer biomarkers.

1. Introduction

Dysregulation of the piRNA pathway may cause epigenetic changes or gene dysregulation, which contributes to diverse diseases such as cancers [1,2,3]. piRNAs are small non-coding regulatory RNAs similar to microRNAs (miRNAs) and small interfering RNAs (siRNAs). piRNAs are 26–35 nucleotide long, with 2′-O-methylation at their 3′-end [4,5,6]. piRNAs are bound to PIWI, an Argonaute/PIWI family protein, and form a piRNA-induced silencing complex (piRISC). piRISC is thought to regulate its target gene through four mechanisms: transcriptional gene silencing (TGS) or activation (TGA), and post-transcriptional gene silencing (PTGS) or activation (PTGA) [7].
Both PIWI and piRNAs are highly abundant in germ cells and their initially identified functions include transposon silencing, which ensures genome integrity maintained in germ cells [8,9,10]. Accumulating evidence, however, supports that the PIWI-piRNA pathway not only serves as a transposon inactivator but also plays a crucial role in regulating endogenous gene expression, just like miRNAs or other mechanisms [11,12,13,14]. Numerous recent studies reveal that its role is not limited to the germ cells as it also has non-gonadal somatic roles, including stem cell self-renewal, axon regeneration, and memory formation [4,15,16,17]. Lately, its relationship with somatic cancers has been extensively studied and revealed unprecedented mechanisms regulating gene expression.
Here, we summarize the aberrant expression of PIWI proteins and piRNAs in various cancer tissues and cell lines and discuss recently disclosed molecular mechanisms of how these PIWI proteins or piRNAs cause tumorigenesis and metastasis. PIWI is known to function through interacting with piRNAs, but recent studies report novel actions of PIWI in a piRNA-independent manner. Although it remains unclear whether the dysregulated piRNA pathway directly contributes to cancer pathogenesis, both PIWI and piRNAs are promising therapeutic targets as well as novel biomarkers for cancer diagnosis and prognosis.

2. PIWI Proteins in Diverse Cancers

In humans, there are four PIWI proteins termed PIWIL (for PIWI-like RNA-mediated gene silencing) proteins: PIWIL1 (also called HIWI1 for Human PIWI), PIWIL2 (HILI for HIWI-like), PIWIL3 (HIWI3), and PIWIL4 (HIWI2) [18,19]. PIWI proteins have long been considered to be germline-specific; they help maintain the stemness of germ cells in sexually reproductive animals [20,21]. PIWI proteins also play a crucial role in stem cell regulation in planarians’ adult pluripotent stem cells (neoblasts) and fly intestinal stem cells [22,23]. These findings support the idea that PIWI proteins might maintain the ‘stemness’ of the cells. Thus, when a PIWI protein is ectopically expressed in the somatic cells, it probably gives a ‘stemness’ to the somatic cells and can potentially make cancerous cells or even cancer stem cells. However, the functional role of the ectopically expressed PIWI is still perplexing. A higher level of transposon expression, which is likely boosted by aging [24,25,26], is known to be tightly correlated with human cancers [27,28]. The higher expression of PIWI is likely suggested to be induced to suppress the transposon activity [29]. Then, is it just reactive to the high-level expression of transposon? Given the fact that an ectopic expression of PIWI is linked with more aggressive cancer behaviors and its inhibition reverses such phenotypes, PIWI likely has a pro-cancerous role [2,30].
Mentis and colleagues performed a meta-analysis to reveal the association of a cancer prognosis with the expression of PIWI family proteins by analyzing multiple databases [31]. Although highly variable results were seen across cancer types, higher PIWIL1 and lower PIWIL4 expression levels tend to be associated with a worse prognosis in cancer.
Here, we introduce several interesting recent findings of mainly PIWIL1 regulation in cancer cells (Table A1). In endometrial cancer, estrogen-estrogen receptor alpha (ERα) signaling upregulates the expression of oncogenic PIWIL1, likely via promoting the hypomethylation of the PIWIL1 promoter [32,33]. Similarly, promoter DNA hypomethylation of PIWIL1 has been reported to upregulate PIWIL1 expression in both lung adenocarcinoma cell lines and tissues [34]. The overexpressed PIWIL1 promotes cell proliferation, migration, and invasion, and vice versa, suggesting that PIWIL1 could promote the malignant phenotypes in lung cancer. Importantly, its high expression shows a correlation with shortened survival of lung cancer patients.
PIWIL1 is also found to be overexpressed in glioblastoma [35]. PIWIL1 is expressed at higher levels in glioma stem cells compared to non-glioma stem cells and this expression regulates the viability and self-renewal of glioma stem cells. PIWIL1 is localized in the cytoplasm and regulates target messenger RNA (mRNA) stability. In a mice model of glioblastoma, Piwil1 knockdown reduces tumor growth and promotes animal survival, supporting that PIWIL1 plays a regulatory role in stem cell maintenance. Interestingly, miRNA-154-5p is downregulated in glioblastoma and functions as a tumor suppressor by directly targeting PIWIL1 mRNA (Figure 1) [36]. Thus, these data present an important axis of the miRNA and PIWI pathway in malignant glioblastoma although it is yet unclear whether PIWIL1 functions with piRNAs in the brain.
Several studies have further focused on the prognostic effects of PIWI subcellular localization. In patients with esophageal squamous cell carcinoma, the cytoplasmic, but not nuclear, PIWIL1 expression is associated with poorer clinical survival, indicating its potential involvement in cancer development [37]. In patients with bladder cancer, a combination of cytoplasmic and absent nuclear expression of PIWIL2 is significantly associated with tumor progression and poorer clinical survival [38]. These results suggest that PIWI family proteins may have a distinct role in the nucleus and cytoplasm. Speculatively, PIWI proteins act as suppressors of the transposon activity in the nucleus, while they regulate endogenous RNA stability or translational efficiency in the cytoplasm. Recent studies have also revealed piRNA-independent roles of PIWIL1, which is likely occurred in the cytoplasm (see below). More research is needed to identify the subcellular localization of PIWI proteins and their target RNAs in diverse types of cancers. Further research should unravel their precise cytoplasmic roles, which would provide useful information for developing diagnostic strategies.

3. Oncogenic piRNAs and Tumor-Suppressor piRNAs

piRNAs are recently obtaining a greater appreciation for their role in carcinogenesis. During cancer development, the expression of certain piRNAs is increased, so these types of piRNAs are considered to be oncogenes. Oncogenic piRNAs contribute to cancer development and progression by increasing cell proliferation and growth, inhibiting apoptosis, and enhancing cell migration and invasion [2,39,40]. In contrast, the expression of certain piRNAs is decreased during tumorigenesis, so these types of piRNAs are considered to be tumor suppressor genes. Tumor suppressor piRNAs upregulate tumor suppressor genes and downregulate oncogenes to inhibit tumor development. There are growing examples of both oncogenic piRNAs and tumor suppressor piRNAs identified in various types of cancers. Here, we summarize a few examples of these piRNAs identified in recent studies (Table A2).
In breast cancer, both oncogenic and tumor-suppressing piRNAs were identified. piR-36026 is found to be an oncogenic piRNA, which is highly expressed in human breast cancer cell line MCF-7 and its downregulation inhibits cancer progression [41,42]. Lee and colleagues developed a double-stranded piR-36026 molecular beacon, which allows visualization of endogenous piR-36026 and simultaneously inactivates the function of piR-36026 [42]. They further identified at least two endogenous targets, SERPINA1 and LRAT, which contain piR-36026 binding sites in the 3′ untranslated region (3′ UTR) and coding region, respectively. These target genes are directly hybridized and downregulated by piR-36206. Importantly, the piR-36026 molecular beacon shows a therapeutic effect in breast cancer, supporting that it may serve as a breast cancer-targeting theragnostic probe.
Conversely, piR-36712 is found to be a tumor-suppressing piRNA in breast cancer. Tan and colleagues analyzed the expression profile of piRNAs in breast cancer using the Cancer Genome Atlas (TCGA) database and examined the expression levels of the top 20 highly expressed piRNAs in tissue samples of breast cancer patients [43]. They found that piR-36712 is significantly downregulated in breast tumors compared with their non-tumor tissues and associated with clinical outcomes. In breast cancer cell lines, the overexpression of piR-36712 suppresses cancer cell proliferation and malignant phenotypes, whereas its knockdown promotes cell proliferation. Furthermore, it has been demonstrated how piR-36712 suppresses breast cancer (Figure 2). piR-36712 interacts with RNAs produced by SEPW1P, a SEPW1 pseudogene, and destabilizes it. SEPW1P helps to increase SEPW1 RNA stability by acting as a molecular sponge for miRNA-7 and miRNA-324, resulting in the de-repression of SEPW1. Thus, piR-36712 subsequently inhibits SEPW1 expression by reducing SEPW1P levels. When piR-36712 is downregulated in breast cancer, SEPW1 is highly expressed, and consequently, P53, P21, and E-cadherin levels are suppressed. Eventually, it promotes cancer cell proliferation, invasion, and migration. Thus, piR-36712 suppresses cancer development by regulating endogenous gene expression. Interestingly, the treatment of piR-36712 analog enables to inhibit tumor growth and shows synergistic anticancer effects with chemotherapeutic agents, paclitaxel and doxorubicin, for breast cancer in mice. These findings support the combinatorial therapeutic strategy of piRNA-targeted therapy and standard chemotherapy, potentially also with immunotherapy [43].
In colorectal cancer, several piRNAs are suggested to be oncogenes. piR-54265 induces colorectal cancer in combination with PIWIL2/STAT3/phosphorylated-SRC (p-SRC) complex [44]. PIWIL2/p-SRC/piR-54265 promotes the phosphorylation of STAT3. The phosphorylated STAT3 enters into the nucleus and induces the expression of anti-apoptotic genes and invasion-related genes such as matrix metallopeptidases, leading to tumor proliferation, invasion, and metastasis. Thus, PIWI-piRNA enables the formation of a ribonucleoprotein complex with other proteins and helps protein phosphorylation that leads to colorectal cancer development. piR-54265 is found to be the only piRNA upregulated among the top 20 highly expressed piRNAs in colorectal cancer tissues, and interestingly, serum piR-54265 levels were found to be significantly elevated in periphery blood samples collected from colorectal cancer patients [44,45]. Thus, serum piR-54265 seems to be a promising biomarker for population screening, early diagnosis, and prognosis of colorectal cancer. Intriguingly, piR-54265 is suggested to be generated from a small nucleolar RNA (snoRNA), SNORD57, based on their sequence homology [46] (See below). A recent study reanalyzed the published data sets and revealed that SNORD57 rather than piR-54265 is expressed in blood samples of patients [46]. Thus, the expression and oncogenic role of piR-54265 should be re-evaluated thoroughly.
piR-1245 is also suggested to be an oncogenic piRNA for colorectal cancer [47]. piR-1245 is overexpressed in colorectal cancer patients and its expression is correlated with advanced and metastatic stages. piR-1245 appears to repress the expression of several tumor suppressor genes involved in cell proliferation and apoptosis. Similarly, piR-24000 and piR-823 are also identified as oncogenic piRNAs in colorectal cancer, which are overexpressed in colorectal cancer patients [48,49]. These results support that these oncogenic piRNAs could serve as diagnostic and prognostic biomarkers as well as potential therapeutic targets for colorectal cancer.
In glioma endothelial cells, PIWIL1 appears to act with piR-33221 (piRNA-DQ593109) and suppress blood-tumor barrier (BTB) permeability via regulating MEG3/miR-330-5p/RUNX3 axis [50]. The PIWIL1/piR-33221 piRISC complex decays MEG3, a long non-coding RNA. As a result, it eventually upregulates genes involved in tight junction formation, and in turn, BTB permeability is suppressed. Therefore, PIWIL1 suppresses BTB permeability via the formation of piRISC with piR-33221 in glioma endothelial cells. PIWI proteins and piRNAs in the germline are involved in germline development by forming piRISC. This mechanism seems to be reused in somatic cancer cells. Numerous examples of oncogenic piRNAs suggest that piRISC functions in cancer.
In blood cancer, several piRNAs are identified as oncogenes. piR-30473 promotes the progression of diffuse large B-cell lymphoma (DLBCL), the most common lymphoma, by regulating N6-methyladenosine (m6A) posttranscriptional RNA modification [51]. piR-30473 inhibition leads to decreased tumorigenesis of DLBCL by reducing the expression of Wilms’ tumor 1-associating protein (WTAP) (Figure 3A). piR-30473 targets WTAP 3′ UTR and, in this case, this interaction stabilizes WTAP mRNA. As WTAP forms an m6A methyltransferase complex, the aberrantly high expression of WTAP by piR-30473 increases m6A methylase activity [51,52]. Like piR-30473, the high expression of WTAP is associated with a poor prognosis in DLBCL patients. Thus, these results suggest that piR-30473 promotes DLBCL progression by regulating m6A RNA methylation.
piR-823 promotes the progression of multiple myeloma, another type of blood cancer by regulating de novo DNA methylation [53]. piR-823 is upregulated in multiple myeloma patients and cell lines and positively correlated with a poor prognosis [53,54]. piR-823 inhibition leads to decrease tumorigenesis of multiple myeloma by reducing DNA methyltransferases, with a consequent re-expression of tumor suppressor genes (Figure 3B). Furthermore, piR-823 leads to enhance ‘stemness’ of multiple myeloma stem cells at least partially by activation of DNA methyltransferase [24]. Interestingly, piR-823 can be delivered by multiple myeloma-derived extracellular vesicles and modulates the tumor microenvironment [55]. Multiple myeloma-derived extracellular vesicles transport piR-823 to endothelial cells, which leads to promoting the malignant transformation of endothelial cells. Thus, piR-823 directly contributes to myelomagenesis by silencing tumor-suppressor genes via regulating de novo DNA methylation, and encapsulated piR-823 is released to establish a favorable microenvironment that ultimately promotes myelomagenesis.
In addition to piR-823, piR-004800 is also found in multiple myeloma-derived extracellular vesicles, particularly in exosomes from the patient’s bone marrow supernatant as well as cell lines [54]. piR-004800 is positively correlated with a poor prognosis and plays an oncogenic role by regulating the sphingosine-1-phosphate receptor (S1PR) signaling pathway. Downregulation of piR-004800 induces autophagic cell death in multiple myeloma cell lines as well as in xenografts of mice induced by multiple myeloma cells. In addition, the downregulation of piR-004800 decreases the expression of protein kinase B (Akt) and mammalian target of rapamycin (mTOR), thus piR-004800 is suggested to promote phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway that inhibits autophagy and promotes cell proliferation and survival (Figure 3B). Thus, the presence of piR-004800 in multiple myeloma-derived exosomes might have a role that inhibits autophagic cell death although it remains to be tested.
Autophagy is recognized to have a dual role in cancer, generally, performing a tumor-suppressing role in non-cancerous cells and performing a tumor-promoting role in established tumors [56]. Thus, it suggests that piR-004800 promotes cancer initiation by inhibiting the autophagy performing a tumor-suppressing role in normal cells. The importance of the interplay between autophagy and exosome in cancer has only recently been recognized and has revealed an intricate relationship in the context of cancer initiation, progression, and recurrence [57].

4. The Role of PIWI in Cancer in a piRNA-Independent Manner

As mentioned above, some PIWI family proteins have been often observed to be induced in cancer cells, but other components in the piRNA pathway do not seem to be generally induced [58]. In many cases, the overall expression of piRNAs is not altered and remains low. Although there are still obvious examples of the piRNA-dependent manner of PIWI by forming a piRISC complex, a recent study shows that the aberrant expression of select genes in the piRNA pathway including PIWI does not reactivate piRNA silencing in colon cancer cell lines [58]. These lines of evidence suggest a piRNA-independent manner of PIWI in tumorigenesis. Here, we summarize this new strategy that contributes to tumorigenesis.
Two recent studies suggest the regulation of PIWI in tumorigenesis in a piRNA-independent manner. In pancreatic cancer, piRNA-unloaded PIWIL1 appears to act as an oncoprotein [59]. PIWIL1 is aberrantly induced in multiple types of human cancer tissues and cancer cell lines. Among the numerous cancer cell lines, the human pancreatic ductal adenocarcinoma cell line, BxPC-3, is found to express the highest level of PIWIL1, and this overexpressed PIWIL1 promotes pancreatic tumor growth and metastasis. Intriguingly, PIWIL1 plays this oncogenic role without a partner piRNA in this cell line. Instead, this unloaded PIWIL1 appears to interact with the anaphase-promoting complex/cyclosome (APC/C) E3 complex and acts as a co-activator to target a cell adhesion-related protein, PININ (Figure 4A). As PININ acts as a key regulator in pancreatic ductal adenocarcinomas cell metastasis, priming PININ proteolysis via APC/C-PIWIL1 complex regulates tumorigenesis. Further studies should identify additional substrates of APC/C-PIWIL1 in pancreatic ductal adenocarcinoma cells.
Another piRNA-independent role of PIWIL1 was revealed in gastric cancer [60]. Similar to the pancreatic ductal adenocarcinoma cell, PIWIL1 is highly expressed in gastric cancer tissues and cell lines and acts as an oncoprotein. Interestingly, abolishing the piRNA-binding activity of PIWIL1 does not affect its oncogenic function and piRNAs are not present in gastric cancer cells, suggesting that PIWIL1 functions in gastric cancer development in a piRNA-independent manner. PIWIL1 appears to degrade many target RNAs via the recruitment of UPF1-mediated nonsense-mediated mRNA decay (NMD) components (Figure 4B). The mechanism of how PIWIL1 binds target mRNAs without piRNAs should be addressed.
These studies start to reveal an emerging role for PIWI proteins independent of piRNAs, with many open questions remaining. Do piRNA-independent functions of PIWI in partnership occur only under pathological conditions, or do such functions also occur under normal physiological conditions? Is it possible to block the oncogenic functions of PIWIL1 when a sufficient amount of piRNAs is supplied? More examples should help address these remaining questions and further elucidate detailed mechanisms underlying a piRNA-independent regulation of PIWI proteins.

5. Databases of piRNA Expression in Cancers

Several piRNA expression databases have been generated within the last decade and recently some databases include information on cancer-related piRNA expression changes. piRBase (http://regulatoryrna.org/database/piRNA/, accessed on 12 July 2021) is a comprehensive database of piRNA sequences, which was launched in 2014 to assist piRNA functional study [61,62]. In the piRBase release v2.0, eight cancer types (breast, bladder, colorectal, gastric, kidney, liver, myeloma, and pancreas cancer)-related piRNAs were added with piRNA expression changes in cancer tissues or cell lines [61].
piRNA-eQTL (http://njmu-edu.cn:3838/piRNA-eQTL/, accessed on 12 July 2021), by using piRBase as reference data, has been developed, which is an expression quantitation trait locus (eQTL) database between single nucleotide polymorphisms (SNPs) and piRNA expression [63]. By combining piRNA expression and genotype data in 33 cancer types, piRNA-eQTL provides a systematic evaluation of the effects of various cancers on piRNA expression and the potential roles of piRNAs in the development of cancers. In the piRNA-eQTL, there are millions of SNP-piRNA pairs in tumor and normal tissues.
piRPheno (http://www.biomedical-web.com/pirpheno/, accessed on 12 July 2021) is a human disease-associated piRNA database [64]. Through manual curation of publications, piRPheno provides 9057 associations between 474 piRNAs and 204 diseases, including cancers. As piRPheno provides a confidence score and a clinical correlation on each of these associations, it enables easy exploration of the human disease-related piRNAs.
A recent study gives a caution that the current piRNA databases possibly contain erroneous entries, which are supposed to belong to other non-coding RNAs including miRNA, transfer RNA (tRNA), snoRNA, and long non-coding RNA (lncRNA) fragments [46]. The concept of miscellaneous-piRNAs (m-piRNAs) has been introduced to distinguish between ‘canonical’ piRNAs (90% of the piRNAs directly derived from the piRNA clusters) and other small RNAs circumstantially associated with PIWI proteins. However, the snoRNA-derived piRNAs have also been previously recognized by other researchers and they consider this group of piRNAs are also piRNAs that have just a different origin. Thus, some researchers classify piRNAs into five groups based on origin: transposon-derived, mRNA-derived, lncRNA-derived, tRNA-derived, and snoRNA-derived piRNAs [65]. Although research on piRNA biogenesis mechanisms remains insufficient, the piRNA community should soon have a clear definition of piRNA to avoid further confusion.

6. piRNAs as Non-Invasive Biomarkers for Cancer

piRNAs have been suggested to be promising tissue-based biomarkers for cancer diagnosis and prognosis as their expression changes are associated with cancer development and progression. piRNAs are also suggested to be non-invasive biomarkers since they are present in human body fluids such as blood, saliva, gastric juice, and urine (Figure 5) [66,67,68,69,70,71,72]. Fortunately, piRNAs are present in human serum and plasma samples and remain stable even after repetitive freeze-thaw cycles or long-term incubation at room temperature [73]. Such stability might be owing to the 2′-O-methyl modification in piRNAs by likely protecting them from 3′ uridylation and truncation, which are considered to influence small RNA stability [74,75]. Another, but not mutually exclusive possibility, is that piRNAs in the blood are encapsulated into the extracellular vesicles like microvesicles and exosomes, so they can be protected from ribonuclease digestions. We have mentioned above that piR-823 and piR-004800 are found in multiple myeloma-derived extracellular vesicles and such encapsulated piR-823 is released to establish a favorable tumor microenvironment [24,54,55].
Importantly, exosomal piRNAs in the serum have been quantified. Exosomes are nano-sized (30–120 nm) small membrane-bound extracellular vesicles released from cells, carrying biological large molecules, including DNA, mRNA, and various non-coding RNAs [76]. A growing body of evidence shows that exosomes regulate tumor progression by delivering special components to neighboring cells [77]. Since exosome production is continuous, the analysis of exosomes released from cancer cells could capture the dynamic complexity of cancer [78]. For example, piR-10506469 was found to be significantly increased in plasma exosomes of biliary tract cancer patients and decreased in patients who underwent surgeries [68]. As numerous other piRNAs are also found to be upregulated in the exosome of biliary tract cancer patients, it seems promising to develop more blood-based diagnostic and prognostic biomarkers for biliary tract cancer. Novel piRNA biomarkers should be further identified for cancer detection at an early stage or tracking of tumor progression over time and validated in independent studies with larger sample sets and long-term clinical datasets.

7. Concluding Remarks

Our understanding of PIWI and piRNA biology is rapidly growing. The pathological influence of aberrantly expressed PIWI family proteins in various cancers has been reported, which has triggered extensive research in the field of PIWI-piRNA biology. Many studies have focused on the identification of differentially expressed PIWIs or piRNAs in cancer tissues compared to adjacent non-cancerous normal tissues. In general, PIWIL1 proteins are highly expressed in many tested cancer tissues, which contributes to cancer development in many cases. Although most other components in piRNA biogenesis are still barely detectable in somatic cancer cells [58], at least some piRNAs are reported to be highly expressed in certain types of somatic cancers. Many studies show that these highly upregulated piRNAs in cancer tissues indeed contribute to cancer development. How is it possible that piRNAs are generated in the absence of piRNA biogenesis components? These mature piRNAs might be produced in other tissues and transferred into somatic tissues. Additionally, some RNAs currently classified as piRNAs might be noncanonical piRNAs, which are mistakenly included in the piRNA databases [46]. If canonical piRNAs are indeed generated in somatic cancer cells in the absence of known piRNA biogenesis components, there should be an alternative mechanism for piRNA biogenesis in somatic cells. In the absence of canonical piRNAs, PIWI could perhaps bind other types of RNAs, which seems to occur at least in cancerous tissues [60,79]. However, a functional readout of these interactions remains largely unknown. Depending on the protein partners of PIWI, these distinct complexes seem to either stabilize or destabilize their target RNAs.
Despite the accumulating information, it is still insufficient to entirely discriminate between a ‘passenger (or hitchhiker)’ role for the aberrant expression of PIWI and piRNAs in cancer from a ‘driver’ role in the cancer pathogenesis [80]. In whichever cases, PIWI and piRNAs are promising candidates for cancer biomarkers due to their specificity to cancers. Like circulating miRNAs, circulating piRNAs in body fluids are emerging as a new class of non-invasive biomarkers for cancer due to their high stability [81,82]. The combination of circulating miRNAs and piRNAs could enhance its specificity and sensitivity to detect cancers and provide new opportunities to develop a specific panel for early diagnosis and prognosis. Therefore, a challenge for future research is to elucidate all the context-dependent mechanisms of PIWI regulation in diverse cancers, which should advance our understanding of PIWI-piRNA biology. Ultimately, this advance will help develop not only clinically relevant and promising biomarkers but also therapeutic targets for treatment.

Author Contributions

Conceptualization, K.W.K.; investigation, writing—original draft preparation, review and editing, H.J., K.H.P., Y.L., A.J., S.C. and K.W.K.; supervision, K.W.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2019R1A2C1003329) and the Hallym university research funds (HRF-202012-010).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Appendix A

Table
Table A1. Expression and role of PIWIL1 in cancer.
Table A1. Expression and role of PIWIL1 in cancer.
CancerExpression in Cancer; MechanismSample TestedRole; MechanismRef.
Endometrial cancerUp;
Estrogen-ERα signaling and hypomethylation of PIWIL1 promoter		Patients,
Ishikawa, RL95–2 cell lines		Oncogenic; Inducing epithelial-mesenchymal transition[32,33]
Lung adenocarcinomaUp;
Hypomethylation of PIWIL1 promoter		Patients,
A549, H1299 cell lines		Oncogenic[34]
GlioblastomaUp;
Downregulation of miR-154-5p that targets PIWIL1 mRNA		Patients, glioma stem cell lines (4121, 3832, 387, 3359) & glioblastoma cell lines (U251, U87, A172, LN229, SNB19, LN308)Oncogenic[36]
Esophageal squamous cell carcinomaUp (cytoplasmic);
Unknown		Patients,
Kyse140 cell line		Oncogenic[37]
Pancreatic ductal adenocarcinomasUp;
Unknown		Patients,
BxPC-3, AsPC-1 cell lines		Oncogenic; piRNA-independent function; acting with APC/C to degrade PININ[59]
Gastric cancerUp;
Unknown		Patients,
AGS, HGC-27, N87, SNU-1/5/16 cell lines		Oncogenic; piRNA-independent function; acting with NMD components to likely degrade tumor suppressors mRNAs [60]
Table
Table A2. Oncogenic piRNA and tumor-suppressor piRNA.
Table A2. Oncogenic piRNA and tumor-suppressor piRNA.
CancerpiRNAExpression in CancerSamples TestedRoleMechanismRef.
Breast cancerpiR-36026
(DQ597960)		UpPatients,
MCF7 cell line		OncogenicTargeting SERINA1 and LRAT mRNA[41,42]
piR-36712DownPatientsTumor suppressingIncreasing P53 expression by targeting SEPW1P RNA[43]
Colorectal cancerpiR-54265UpPatients (tissue & blood),
HCT116, LoVo, SW480, SW620, HT-29, DLD-1 cell lines		OncogenicActivating STAT3 signaling by interacting with PIWIL2[44,45,46]
piR-1245UpPatients,
HCT116, SW480 cell lines		OncogenicLikely regulating a panel of tumor suppressor genes mRNA[47]
piR-823UpPatients,
HCT15/116, DLD-1 cell lines		OncogenicEnhancing the transcriptional activity of HSF1 by promoting its phosphorylation[49]
piR-24000UpPatientsOncogenicUnknown[48]
GliomapiR-33221
(DQ593109)		UpGlioma endothelial cellsOncogenicActing with PIWIL1 to suppress BTB permeability via regulating MEG3/miR-330-5p/RUNX3 axis[50]
Diffuse large B-cell lymphomapiR-30473UpPatientsOncogenicStabilizing WTAP mRNA via m6A RNA methylation[51,52]
Multiple myelomapiR-823UpPatients,
Plasma cell,
RPMI8226, ARH-77, U266, KM3 cell lines		OncogenicInducing de novo DNA methylation[53]
piR-004800UpPatients (exosomes from bone marrow supernatant),
RPMI8226, U266 cell lines		OncogenicRegulation of PI3K/Akt/mTOR pathway[54]

References

  1. Huang, X.; Wong, G. An old weapon with a new function: PIWI-interacting RNAs in neurodegenerative diseases. Transl. Neurodegener. 2021, 10, 9. [Google Scholar] [CrossRef] [PubMed]
  2. Liu, Y.; Dou, M.; Song, X.; Dong, Y.; Liu, S.; Liu, H.; Tao, J.; Li, W.; Yin, X.; Xu, W. The emerging role of the piRNA/piwi complex in cancer. Mol. Cancer 2019, 18, 123. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Wu, X.; Pan, Y.; Fang, Y.; Zhang, J.; Xie, M.; Yang, F.; Yu, T.; Ma, P.; Li, W.; Shu, Y. The biogenesis and functions of piRNAs in human diseases. Mol. Ther. Nucleic Acids 2020, 21, 108–120. [Google Scholar] [CrossRef]
  4. Kim, K.W. PIWI proteins and piRNAs in the nervous system. Mol. Cells 2019, 42, 828–835. [Google Scholar] [CrossRef] [PubMed]
  5. Ozata, D.M.; Gainetdinov, I.; Zoch, A.; O’Carroll, D.; Zamore, P.D. PIWI-interacting RNAs: Small RNAs with big functions. Nat. Rev. Genet. 2019, 20, 89–108. [Google Scholar] [CrossRef] [Green Version]
  6. Weick, E.M.; Miska, E.A. piRNAs: From biogenesis to function. Development 2014, 141, 3458–3471. [Google Scholar] [CrossRef] [Green Version]
  7. Su, J.-F.; Concilla, A.; Zhang, D.-Z.; Zhao, F.; Shen, F.-F.; Zhang, H.; Zhou, F.-Y. PIWI-interacting RNAs: Mitochondria-based biogenesis and functions in cancer. Genes Dis. 2020, 8, 603–622. [Google Scholar] [CrossRef]
  8. Czech, B.; Munafo, M.; Ciabrelli, F.; Eastwood, E.L.; Fabry, M.H.; Kneuss, E.; Hannon, G.J. piRNA-guided genome defense: From biogenesis to silencing. Annu. Rev. Genet. 2018, 52, 131–157. [Google Scholar] [CrossRef]
  9. Gamez, S.; Srivastav, S.; Akbari, O.S.; Lau, N.C. Diverse defenses: A perspective comparing Dipteran Piwi-piRNA pathways. Cells 2020, 9, 2180. [Google Scholar] [CrossRef]
  10. Parhad, S.S.; Theurkauf, W.E. Rapid evolution and conserved function of the piRNA pathway. Open Biol. 2019, 9, 180181. [Google Scholar] [CrossRef] [Green Version]
  11. Lee, H.C.; Gu, W.; Shirayama, M.; Youngman, E.; Conte, D., Jr.; Mello, C.C. C. elegans piRNAs mediate the genome-wide surveillance of germline transcripts. Cell 2012, 150, 78–87. [Google Scholar] [CrossRef] [Green Version]
  12. Ouyang, J.P.T.; Folkmann, A.; Bernard, L.; Lee, C.Y.; Seroussi, U.; Charlesworth, A.G.; Claycomb, J.M.; Seydoux, G. P Granules Protect RNA Interference Genes from Silencing by piRNAs. Dev. Cell 2019, 50, 716–728. [Google Scholar] [CrossRef]
  13. Shen, E.Z.; Chen, H.; Ozturk, A.R.; Tu, S.; Shirayama, M.; Tang, W.; Ding, Y.H.; Dai, S.Y.; Weng, Z.; Mello, C.C. Identification of piRNA binding sites reveals the Argonaute regulatory landscape of the C. elegans germline. Cell 2018, 172, 937–951.e918. [Google Scholar] [CrossRef] [Green Version]
  14. Zhang, D.; Tu, S.; Stubna, M.; Wu, W.S.; Huang, W.C.; Weng, Z.; Lee, H.C. The piRNA targeting rules and the resistance to piRNA silencing in endogenous genes. Science 2018, 359, 587–592. [Google Scholar] [CrossRef] [Green Version]
  15. Kim, K.W.; Tang, N.H.; Andrusiak, M.G.; Wu, Z.; Chisholm, A.D.; Jin, Y. A neuronal piRNA pathway inhibits axon regeneration in C. elegans. Neuron 2018, 97, 511–519. [Google Scholar] [CrossRef] [Green Version]
  16. Rajasethupathy, P.; Antonov, I.; Sheridan, R.; Frey, S.; Sander, C.; Tuschl, T.; Kandel, E.R. A role for neuronal piRNAs in the epigenetic control of memory-related synaptic plasticity. Cell 2012, 149, 693–707. [Google Scholar] [CrossRef] [Green Version]
  17. Ross, R.J.; Weiner, M.M.; Lin, H. PIWI proteins and PIWI-interacting RNAs in the soma. Nature 2014, 505, 353–359. [Google Scholar] [CrossRef] [Green Version]
  18. Carmell, M.A.; Xuan, Z.; Zhang, M.Q.; Hannon, G.J. The Argonaute family: Tentacles that reach into RNAi, developmental control, stem cell maintenance, and tumorigenesis. Genes Dev. 2002, 16, 2733–2742. [Google Scholar] [CrossRef] [Green Version]
  19. Sasaki, T.; Shiohama, A.; Minoshima, S.; Shimizu, N. Identification of eight members of the Argonaute family in the human genome. Genomics 2003, 82, 323–330. [Google Scholar] [CrossRef]
  20. Juliano, C.; Wang, J.; Lin, H. Uniting germline and stem cells: The function of Piwi proteins and the piRNA pathway in diverse organisms. Annu. Rev. Genet. 2011, 45, 447–469. [Google Scholar] [CrossRef] [Green Version]
  21. Ramat, A.; Simonelig, M. Functions of PIWI proteins in gene regulation: New arrows added to the piRNA quiver. Trends Genet. 2021, 37, 188–200. [Google Scholar] [CrossRef] [PubMed]
  22. Kashima, M.; Agata, K.; Shibata, N. What is the role of PIWI family proteins in adult pluripotent stem cells? Insights from asexually reproducing animals, planarians. Dev. Growth Differ. 2020, 62, 407–422. [Google Scholar] [CrossRef] [PubMed]
  23. Sousa-Victor, P.; Ayyaz, A.; Hayashi, R.; Qi, Y.; Madden, D.T.; Lunyak, V.V.; Jasper, H. Piwi is required to limit exhaustion of aging somatic stem cells. Cell Rep. 2017, 20, 2527–2537. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Ai, L.; Mu, S.; Sun, C.; Fan, F.; Yan, H.; Qin, Y.; Cui, G.; Wang, Y.; Guo, T.; Mei, H.; et al. Myeloid-derived suppressor cells endow stem-like qualities to multiple myeloma cells by inducing piRNA-823 expression and DNMT3B activation. Mol. Cancer 2019, 18, 88. [Google Scholar] [CrossRef]
  25. Sturm, A.; Ivics, Z.; Vellai, T. The mechanism of ageing: Primary role of transposable elements in genome disintegration. Cell. Mol. Life Sci. 2015, 72, 1839–1847. [Google Scholar] [CrossRef] [Green Version]
  26. Wood, J.G.; Helfand, S.L. Chromatin structure and transposable elements in organismal aging. Front. Genet. 2013, 4, 274. [Google Scholar] [CrossRef] [Green Version]
  27. Anwar, S.L.; Wulaningsih, W.; Lehmann, U. Transposable elements in human cancer: Causes and consequences of deregulation. Int. J. Mol. Sci. 2017, 18, 974. [Google Scholar] [CrossRef] [Green Version]
  28. Burns, K.H. Transposable elements in cancer. Nat. Rev. Cancer 2017, 17, 415–424. [Google Scholar] [CrossRef]
  29. Watanabe, T.; Lin, H. Posttranscriptional regulation of gene expression by Piwi proteins and piRNAs. Mol. Cell 2014, 56, 18–27. [Google Scholar] [CrossRef] [Green Version]
  30. Moyano, M.; Stefani, G. piRNA involvement in genome stability and human cancer. J. Hematol. Oncol. 2015, 8, 38. [Google Scholar] [CrossRef] [Green Version]
  31. Mentis, A.A.; Dardiotis, E.; Romas, N.A.; Papavassiliou, A.G. PIWI family proteins as prognostic markers in cancer: A systematic review and meta-analysis. Cell. Mol. Life Sci. 2020, 77, 2289–2314. [Google Scholar] [CrossRef]
  32. Chen, Z.; Che, Q.; He, X.; Wang, F.; Wang, H.; Zhu, M.; Sun, J.; Wan, X. Stem cell protein Piwil1 endowed endometrial cancer cells with stem-like properties via inducing epithelial-mesenchymal transition. BMC Cancer 2015, 15, 811. [Google Scholar] [CrossRef] [Green Version]
  33. Chen, Z.; Yang, H.J.; Lin, Q.; Zhu, M.J.; Yu, Y.Y.; He, X.Y.; Wan, X.P. Estrogen-ERalpha signaling and DNA hypomethylation co-regulate expression of stem cell protein PIWIL1 in ERalpha-positive endometrial cancer cells. Cell Commun. Signal. 2020, 18, 84. [Google Scholar] [CrossRef]
  34. Xie, K.; Zhang, K.; Kong, J.; Wang, C.; Gu, Y.; Liang, C.; Jiang, T.; Qin, N.; Liu, J.; Guo, X.; et al. Cancer-testis gene PIWIL1 promotes cell proliferation, migration, and invasion in lung adenocarcinoma. Cancer Med. 2018, 7, 157–166. [Google Scholar] [CrossRef] [Green Version]
  35. Huang, H.; Yu, X.; Han, X.; Hao, J.; Zhao, J.; Bebek, G.; Bao, S.; Prayson, R.A.; Khalil, A.M.; Jankowsky, E.; et al. Piwil1 regulates glioma stem cell maintenance and glioblastoma progression. Cell Rep. 2021, 34, 108522. [Google Scholar] [CrossRef]
  36. Wang, X.; Sun, S.; Tong, X.; Ma, Q.; Di, H.; Fu, T.; Sun, Z.; Cai, Y.; Fan, W.; Wu, Q.; et al. MiRNA-154-5p inhibits cell proliferation and metastasis by targeting PIWIL1 in glioblastoma. Brain Res. 2017, 1676, 69–76. [Google Scholar] [CrossRef]
  37. He, W.; Wang, Z.; Wang, Q.; Fan, Q.; Shou, C.; Wang, J.; Giercksky, K.E.; Nesland, J.M.; Suo, Z. Expression of HIWI in human esophageal squamous cell carcinoma is significantly associated with poorer prognosis. BMC Cancer 2009, 9, 426. [Google Scholar] [CrossRef] [Green Version]
  38. Taubert, H.; Wach, S.; Jung, R.; Pugia, M.; Keck, B.; Bertz, S.; Nolte, E.; Stoehr, R.; Lehmann, J.; Ohlmann, C.H.; et al. Piwil 2 expression is correlated with disease-specific and progression-free survival of chemotherapy-treated bladder cancer patients. Mol. Med. 2015, 21, 371–380. [Google Scholar] [CrossRef]
  39. Guo, B.; Li, D.; Du, L.; Zhu, X. piRNAs: Biogenesis and their potential roles in cancer. Cancer Metastasis Rev. 2020, 39, 567–575. [Google Scholar] [CrossRef]
  40. Weng, W.; Li, H.; Goel, A. Piwi-interacting RNAs (piRNAs) and cancer: Emerging biological concepts and potential clinical implications. Biochim. Biophys. Acta Rev. Cancer 2019, 1871, 160–169. [Google Scholar] [CrossRef]
  41. Hashim, A.; Rizzo, F.; Marchese, G.; Ravo, M.; Tarallo, R.; Nassa, G.; Giurato, G.; Santamaria, G.; Cordella, A.; Cantarella, C.; et al. RNA sequencing identifies specific PIWI-interacting small non-coding RNA expression patterns in breast cancer. Oncotarget 2014, 5, 9901–9910. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Lee, Y.J.; Moon, S.U.; Park, M.G.; Jung, W.Y.; Park, Y.K.; Song, S.K.; Ryu, J.G.; Lee, Y.S.; Heo, H.J.; Gu, H.N.; et al. Multiplex bioimaging of piRNA molecular pathway-regulated theragnostic effects in a single breast cancer cell using a piRNA molecular beacon. Biomaterials 2016, 101, 143–155. [Google Scholar] [CrossRef] [PubMed]
  43. Tan, L.; Mai, D.; Zhang, B.; Jiang, X.; Zhang, J.; Bai, R.; Ye, Y.; Li, M.; Pan, L.; Su, J.; et al. PIWI-interacting RNA-36712 restrains breast cancer progression and chemoresistance by interaction with SEPW1 pseudogene SEPW1P RNA. Mol. Cancer 2019, 18, 9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Mai, D.; Ding, P.; Tan, L.; Zhang, J.; Pan, Z.; Bai, R.; Li, C.; Li, M.; Zhou, Y.; Tan, W.; et al. PIWI-interacting RNA-54265 is oncogenic and a potential therapeutic target in colorectal adenocarcinoma. Theranostics 2018, 8, 5213–5230. [Google Scholar] [CrossRef]
  45. Mai, D.; Zheng, Y.; Guo, H.; Ding, P.; Bai, R.; Li, M.; Ye, Y.; Zhang, J.; Huang, X.; Liu, D.; et al. Serum piRNA-54265 is a New Biomarker for early detection and clinical surveillance of Human Colorectal Cancer. Theranostics 2020, 10, 8468–8478. [Google Scholar] [CrossRef]
  46. Tosar, J.P.; Garcia-Silva, M.R.; Cayota, A. Circulating SNORD57 rather than piR-54265 is a promising biomarker for colorectal cancer: Common pitfalls in the study of somatic piRNAs in cancer. RNA 2021, 27, 403–410. [Google Scholar] [CrossRef]
  47. Weng, W.; Liu, N.; Toiyama, Y.; Kusunoki, M.; Nagasaka, T.; Fujiwara, T.; Wei, Q.; Qin, H.; Lin, H.; Ma, Y.; et al. Novel evidence for a PIWI-interacting RNA (piRNA) as an oncogenic mediator of disease progression, and a potential prognostic biomarker in colorectal cancer. Mol. Cancer 2018, 17, 16. [Google Scholar] [CrossRef]
  48. Iyer, D.N.; Wan, T.M.; Man, J.H.; Sin, R.W.; Li, X.; Lo, O.S.; Foo, D.C.; Pang, R.W.; Law, W.L.; Ng, L. Small RNA profiling of piRNAs in colorectal cancer identifies consistent overexpression of piR-24000 that correlates clinically with an aggressive disease phenotype. Cancers 2020, 12, 188. [Google Scholar] [CrossRef] [Green Version]
  49. Yin, J.; Jiang, X.Y.; Qi, W.; Ji, C.G.; Xie, X.L.; Zhang, D.X.; Cui, Z.J.; Wang, C.K.; Bai, Y.; Wang, J.; et al. piR-823 contributes to colorectal tumorigenesis by enhancing the transcriptional activity of HSF1. Cancer Sci. 2017, 108, 1746–1756. [Google Scholar] [CrossRef]
  50. Shen, S.; Yu, H.; Liu, X.; Liu, Y.; Zheng, J.; Wang, P.; Gong, W.; Chen, J.; Zhao, L.; Xue, Y. PIWIL1/piRNA-DQ593109 regulates the permeability of the Blood-Tumor Barrier via the MEG3/miR-330-5p/RUNX3 axis. Mol. Ther. Nucleic Acids 2018, 10, 412–425. [Google Scholar] [CrossRef] [Green Version]
  51. Han, H.; Fan, G.; Song, S.; Jiang, Y.; Qian, C.; Zhang, W.; Su, Q.; Xue, X.; Zhuang, W.; Li, B. piRNA-30473 contributes to tumorigenesis and poor prognosis by regulating m6A RNA methylation in DLBCL. Blood 2020, 137, 1603–1614. [Google Scholar] [CrossRef]
  52. Ping, X.L.; Sun, B.F.; Wang, L.; Xiao, W.; Yang, X.; Wang, W.J.; Adhikari, S.; Shi, Y.; Lv, Y.; Chen, Y.S.; et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 2014, 24, 177–189. [Google Scholar] [CrossRef] [Green Version]
  53. Yan, H.; Wu, Q.L.; Sun, C.Y.; Ai, L.S.; Deng, J.; Zhang, L.; Chen, L.; Chu, Z.B.; Tang, B.; Wang, K.; et al. piRNA-823 contributes to tumorigenesis by regulating de novo DNA methylation and angiogenesis in multiple myeloma. Leukemia 2015, 29, 196–206. [Google Scholar] [CrossRef]
  54. Ma, H.; Wang, H.; Tian, F.; Zhong, Y.; Liu, Z.; Liao, A. PIWI-Interacting RNA-004800 is regulated by S1P receptor signaling pathway to keep myeloma cell survival. Front. Oncol. 2020, 10, 438. [Google Scholar] [CrossRef] [Green Version]
  55. Li, B.; Hong, J.; Hong, M.; Wang, Y.; Yu, T.; Zang, S.; Wu, Q. piRNA-823 delivered by multiple myeloma-derived extracellular vesicles promoted tumorigenesis through re-educating endothelial cells in the tumor environment. Oncogene 2019, 38, 5227–5238. [Google Scholar] [CrossRef]
  56. Xu, J.; Camfield, R.; Gorski, S.M. The interplay between exosomes and autophagy—Partners in crime. J. Cell Sci. 2018, 131. [Google Scholar] [CrossRef] [Green Version]
  57. Colletti, M.; Ceglie, D.; Di Giannatale, A.; Nazio, F. Autophagy and Exosomes Relationship in Cancer: Friends or Foes? Front. Cell Dev. Biol. 2020, 8, 614178. [Google Scholar] [CrossRef]
  58. Genzor, P.; Cordts, S.C.; Bokil, N.V.; Haase, A.D. Aberrant expression of select piRNA-pathway genes does not reactivate piRNA silencing in cancer cells. Proc. Natl. Acad. Sci. USA 2019, 116, 11111–11112. [Google Scholar] [CrossRef] [Green Version]
  59. Li, F.; Yuan, P.; Rao, M.; Jin, C.H.; Tang, W.; Rong, Y.F.; Hu, Y.P.; Zhang, F.; Wei, T.; Yin, Q.; et al. piRNA-independent function of PIWIL1 as a co-activator for anaphase promoting complex/cyclosome to drive pancreatic cancer metastasis. Nat. Cell Biol. 2020, 22, 425–438. [Google Scholar] [CrossRef]
  60. Shi, S.; Yang, Z.Z.; Liu, S.; Yang, F.; Lin, H. PIWIL1 promotes gastric cancer via a piRNA-independent mechanism. Proc. Natl. Acad. Sci. USA 2020, 117, 22390–22401. [Google Scholar] [CrossRef]
  61. Wang, J.; Zhang, P.; Lu, Y.; Li, Y.; Zheng, Y.; Kan, Y.; Chen, R.; He, S. piRBase: A comprehensive database of piRNA sequences. Nucleic Acids Res. 2019, 47, D175–D180. [Google Scholar] [CrossRef] [Green Version]
  62. Zhang, P.; Si, X.; Skogerbo, G.; Wang, J.; Cui, D.; Li, Y.; Sun, X.; Liu, L.; Sun, B.; Chen, R.; et al. piRBase: A web resource assisting piRNA functional study. Database (Oxford) 2014, 2014, bau110. [Google Scholar] [CrossRef] [Green Version]
  63. Xin, J.; Du, M.; Jiang, X.; Wu, Y.; Ben, S.; Zheng, R.; Chu, H.; Li, S.; Zhang, Z.; Wang, M. Systematic evaluation of the effects of genetic variants on PIWI-interacting RNA expression across 33 cancer types. Nucleic Acids Res. 2021, 49, 90–97. [Google Scholar] [CrossRef]
  64. Zhang, W.; Yao, G.; Wang, J.; Yang, M.; Wang, J.; Zhang, H.; Li, W. ncRPheno: A comprehensive database platform for identification and validation of disease related noncoding RNAs. RNA Biol. 2020, 17, 943–955. [Google Scholar] [CrossRef]
  65. Chen, S.; Ben, S.; Xin, J.; Li, S.; Zheng, R.; Wang, H.; Fan, L.; Du, M.; Zhang, Z.; Wang, M. The biogenesis and biological function of PIWI-interacting RNA in cancer. J. Hematol. Oncol. 2021, 14, 93. [Google Scholar] [CrossRef]
  66. Cui, L.; Lou, Y.; Zhang, X.; Zhou, H.; Deng, H.; Song, H.; Yu, X.; Xiao, B.; Wang, W.; Guo, J. Detection of circulating tumor cells in peripheral blood from patients with gastric cancer using piRNAs as markers. Clin. Biochem. 2011, 44, 1050–1057. [Google Scholar] [CrossRef]
  67. Zhou, X.; Liu, J.; Meng, A.; Zhang, L.; Wang, M.; Fan, H.; Peng, W.; Lu, J. Gastric juice piR-1245: A promising prognostic biomarker for gastric cancer. J. Clin. Lab. Anal. 2020, 34, e23131. [Google Scholar] [CrossRef] [Green Version]
  68. Gu, X.; Wang, C.; Deng, H.; Qing, C.; Liu, R.; Liu, S.; Xue, X. Exosomal piRNA profiling revealed unique circulating piRNA signatures of cholangiocarcinoma and gallbladder carcinoma. Acta Biochim. Biophys. Sin. (Shanghai) 2020, 52, 475–484. [Google Scholar] [CrossRef]
  69. Vychytilova-Faltejskova, P.; Stitkovcova, K.; Radova, L.; Sachlova, M.; Kosarova, Z.; Slaba, K.; Kala, Z.; Svoboda, M.; Kiss, I.; Vyzula, R.; et al. Circulating PIWI-interacting RNAs piR-5937 and piR-28876 are promising diagnostic biomarkers of colon cancer. Cancer Epidemiol. Biomark. Prev. 2018, 27, 1019–1028. [Google Scholar] [CrossRef] [Green Version]
  70. Wang, Z.; Yang, H.; Ma, D.; Mu, Y.; Tan, X.; Hao, Q.; Feng, L.; Liang, J.; Xin, W.; Chen, Y.; et al. Serum PIWI-interacting RNAs piR-020619 and piR-020450 are promising novel biomarkers for early detection of colorectal cancer. Cancer Epidemiol. Biomark. Prev. 2020, 29, 990–998. [Google Scholar] [CrossRef] [Green Version]
  71. Iliev, R.; Fedorko, M.; Machackova, T.; Mlcochova, H.; Svoboda, M.; Pacik, D.; Dolezel, J.; Stanik, M.; Slaby, O. Expression levels of PIWI-interacting RNA, piR-823, are deregulated in tumor tissue, blood serum and urine of patients with renal cell carcinoma. Anticancer Res. 2016, 36, 6419–6423. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Ogawa, Y.; Taketomi, Y.; Murakami, M.; Tsujimoto, M.; Yanoshita, R. Small RNA transcriptomes of two types of exosomes in human whole saliva determined by next generation sequencing. Biol. Pharm. Bull. 2013, 36, 66–75. [Google Scholar] [CrossRef] [Green Version]
  73. Yang, X.; Cheng, Y.; Lu, Q.; Wei, J.; Yang, H.; Gu, M. Detection of stably expressed piRNAs in human blood. Int. J. Clin. Exp. Med. 2015, 8, 13353–13358. [Google Scholar] [PubMed]
  74. Ji, L.; Chen, X. Regulation of small RNA stability: Methylation and beyond. Cell Res. 2012, 22, 624–636. [Google Scholar] [CrossRef] [PubMed]
  75. Kurth, H.M.; Mochizuki, K. 2′-O-methylation stabilizes Piwi-associated small RNAs and ensures DNA elimination in Tetrahymena. RNA 2009, 15, 675–685. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Zimta, A.A.; Sigurjonsson, O.E.; Gulei, D.; Tomuleasa, C. The malignant role of exosomes as nanocarriers of rare RNA species. Int. J. Mol. Sci 2020, 21, 5866. [Google Scholar] [CrossRef] [PubMed]
  77. LeBleu, V.S.; Kalluri, R. Exosomes as a Multicomponent Biomarker Platform in Cancer. Trends Cancer 2020, 6, 767–774. [Google Scholar] [CrossRef] [PubMed]
  78. Dai, J.; Su, Y.; Zhong, S.; Cong, L.; Liu, B.; Yang, J.; Tao, Y.; He, Z.; Chen, C.; Jiang, Y. Exosomes: Key players in cancer and potential therapeutic strategy. Signal Transduct. Target. Ther. 2020, 5, 145. [Google Scholar] [CrossRef]
  79. Vourekas, A.; Zheng, Q.; Alexiou, P.; Maragkakis, M.; Kirino, Y.; Gregory, B.D.; Mourelatos, Z. Mili and Miwi target RNA repertoire reveals piRNA biogenesis and function of Miwi in spermiogenesis. Nat. Struct. Mol. Biol. 2012, 19, 773–781. [Google Scholar] [CrossRef] [Green Version]
  80. Pon, J.R.; Marra, M.A. Driver and passenger mutations in cancer. Annu. Rev. Pathol. 2015, 10, 25–50. [Google Scholar] [CrossRef]
  81. Brase, J.C.; Wuttig, D.; Kuner, R.; Sultmann, H. Serum microRNAs as non-invasive biomarkers for cancer. Mol. Cancer 2010, 9, 306. [Google Scholar] [CrossRef] [Green Version]
  82. Rapisuwon, S.; Vietsch, E.E.; Wellstein, A. Circulating biomarkers to monitor cancer progression and treatment. Comput. Struct. Biotechnol. J. 2016, 14, 211–222. [Google Scholar] [CrossRef] [Green Version]
Processes 09 01208 g001 550
Figure 1. An axis of the miRNA and PIWI pathway in malignant glioblastoma. PIWIL1 is expressed at higher levels in glioma stem cells compared to non-glioma stem cells and localized in the cytoplasm [35]. Downregulated PIWIL1 by miRNA-154-5p (miR-154-5p) inhibits malignant behavior of glioblastoma, while upregulated PIWIL1 in the lack of miR-154-5p leads to malignant glioblastoma [36].
Figure 1. An axis of the miRNA and PIWI pathway in malignant glioblastoma. PIWIL1 is expressed at higher levels in glioma stem cells compared to non-glioma stem cells and localized in the cytoplasm [35]. Downregulated PIWIL1 by miRNA-154-5p (miR-154-5p) inhibits malignant behavior of glioblastoma, while upregulated PIWIL1 in the lack of miR-154-5p leads to malignant glioblastoma [36].
Processes 09 01208 g001
Processes 09 01208 g002 550
Figure 2. A tumor-suppressing piRNA in breast cancer. Left, piR-36712 binds and destabilizes SEPW1P RNA, a SEPW1 pseudogene, which inhibits SEPW1 expression by reducing SEPW1P levels. It increases P53, P21, and E-cadherin levels, and consequently, suppresses cancer development. Right, when piR-36712 is downregulated in breast cells, SEPW1 is highly expressed, and P53, P21, and E-cadherin levels are suppressed, which promotes breast cancer development [43].
Figure 2. A tumor-suppressing piRNA in breast cancer. Left, piR-36712 binds and destabilizes SEPW1P RNA, a SEPW1 pseudogene, which inhibits SEPW1 expression by reducing SEPW1P levels. It increases P53, P21, and E-cadherin levels, and consequently, suppresses cancer development. Right, when piR-36712 is downregulated in breast cells, SEPW1 is highly expressed, and P53, P21, and E-cadherin levels are suppressed, which promotes breast cancer development [43].
Processes 09 01208 g002
Processes 09 01208 g003 550
Figure 3. Oncogenic piRNAs in blood cancer. (A) piR-30473 promotes the progression of diffuse large B-cell lymphoma (DLBCL) by regulating N6-methyladenosine (m6A) posttranscriptional RNA modification [51,52]. (B) piR-823 and piR-004800 promote the progression of multiple myeloma (MM) and are found in MM-derived extracellular vesicles [24,53,54]. The encapsulated piR-823 is released to endothelial cells and leads to establish a favorable microenvironment that ultimately promotes myelomagenesis [55].
Figure 3. Oncogenic piRNAs in blood cancer. (A) piR-30473 promotes the progression of diffuse large B-cell lymphoma (DLBCL) by regulating N6-methyladenosine (m6A) posttranscriptional RNA modification [51,52]. (B) piR-823 and piR-004800 promote the progression of multiple myeloma (MM) and are found in MM-derived extracellular vesicles [24,53,54]. The encapsulated piR-823 is released to endothelial cells and leads to establish a favorable microenvironment that ultimately promotes myelomagenesis [55].
Processes 09 01208 g003
Processes 09 01208 g004 550
Figure 4. piRNA-independent regulation of PIWI protein. (A) In pancreatic cancer, unloaded PIWIL1 interacts with the anaphase-promoting complex/cyclosome (APC/C) E3 complex and acts as a co-activator to target a cell adhesion-related protein, PININ [59]. (B) In gastric cancer, unloaded PIWIL1 degrades many target RNAs via the recruitment of UPF1-mediated nonsense-mediated mRNA decay (NMD) components [60].
Figure 4. piRNA-independent regulation of PIWI protein. (A) In pancreatic cancer, unloaded PIWIL1 interacts with the anaphase-promoting complex/cyclosome (APC/C) E3 complex and acts as a co-activator to target a cell adhesion-related protein, PININ [59]. (B) In gastric cancer, unloaded PIWIL1 degrades many target RNAs via the recruitment of UPF1-mediated nonsense-mediated mRNA decay (NMD) components [60].
Processes 09 01208 g004
Processes 09 01208 g005 550
Figure 5. piRNAs as potential non-invasive biomarkers in cancer. (A) Gastric cancer. (B) Biliary tract cancer. (C) Colorectal cancer. (D) Renal cancer.
Figure 5. piRNAs as potential non-invasive biomarkers in cancer. (A) Gastric cancer. (B) Biliary tract cancer. (C) Colorectal cancer. (D) Renal cancer.
Processes 09 01208 g005
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Jeong, H.; Park, K.H.; Lee, Y.; Jeong, A.; Choi, S.; Kim, K.W. The Regulation and Role of piRNAs and PIWI Proteins in Cancer. Processes 2021, 9, 1208. https://doi.org/10.3390/pr9071208

AMA Style

Jeong H, Park KH, Lee Y, Jeong A, Choi S, Kim KW. The Regulation and Role of piRNAs and PIWI Proteins in Cancer. Processes. 2021; 9(7):1208. https://doi.org/10.3390/pr9071208

Chicago/Turabian Style

Jeong, Hyeseon, Kyung Hwan Park, Yuri Lee, Ayoung Jeong, Sooji Choi, and Kyung Won Kim. 2021. "The Regulation and Role of piRNAs and PIWI Proteins in Cancer" Processes 9, no. 7: 1208. https://doi.org/10.3390/pr9071208

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