Role of PIWI and/or piRNA in carcinogenesis. This table shows recent evidences that deregulation (overexpression and/ or underexpression) of the PIWI-piRNA and PIWI proteins pathway in different cancer types has important implications in cancer hallmarks.
Abstract
Epigenetic abnormalities are early events in carcinogenesis and associate heterogeneity of DNA methylation, modifications of histones, and deregulation of noncoding RNAs. Aberrant expressions of PIWI proteins and piRNAs were recently observed in numerous subtypes of malignant tumors and were implicated in occurrence of most cancer hallmarks such as cell proliferation, genomic stability, apoptosis inhibition, invasion, and metastatic spread. However, this pathway is a new emerging research field, and further investigations are necessary to elucidate their oncogenic or tumor-suppressing status. Since the aberrant expression of this pathway may induce stemness, analysis of relationship between PIWI proteins, piRNAs, and cancer stem cells may open new avenues in cancer research. The objective of this review is to provide a broad overview of the emerging implication of PIWI proteins and piRNAs in carcinogenesis and their potential clinical interest as diagnostic and prognostic biomarkers and therapeutic tools.
Keywords
- piRNA
- PIWI proteins
- transposable element (TE)
- transcriptional and post-transcriptional silencing
- piRNA cluster
- heterochromatin
- DNA methylation
- ping-pong cycle
- Nuage
1. Deregulation of the PIWI-piRNA pathway in cancer
Recent evidences have suggested that activation of the PIWI-piRNA pathway has important implications in carcinogenesis (Table 1). PIWI proteins and piRNAs are deregulated in numerous human cancers such as breast cancer, prostate cancer, hepatic cancer, gastric cancer, malignant melanoma, and lung cancer. Experimental analyses have demonstrated that PIWI proteins and piRNAs altered levels of expression are associated with major hallmarks of cancer, including genomic chronic proliferation, differentiation, and survival [1]. Emerging roles of PIWI-piRNA-mediated epigenetic alterations in cancer seem related to promotion of a stem-like state of tumor cells through aberrant DNA methylation. Experimental studies in
PIWI proteins | PiRNAs | Cancer type | Expression | Cancer hallmarks | Mechanisms in cancer | References |
---|---|---|---|---|---|---|
Breast cancer | Overexpression | Proliferation and stemness | Cell-cycle regulation | [10] | ||
Lung cancer | Overexpression | CSC self-renewal | Maintenance of CSCs | [9] | ||
Ovary cancer | Overexpression | Migration and invasion | [72] | |||
Gastric cancer | Overexpression | Proliferation | Cell-cycle regulation | [8, 22, 62] | ||
Colon cancer | Overexpression | Proliferation and stemness | Interactions with OCT4 and SOX2 | [17] | ||
Liver cancer | Overexpression | Proliferation | [12] | |||
Cervix cancer | Overexpression | Migration and invasion | [5] | |||
Seminoma | Overexpression | Proliferation | [21] | |||
Glioblastoma | Overexpression | Proliferation, migration, and invasion | Overexpression of MMP2 and MMP9 | [11] | ||
Sarcomas | Overexpression | Genomic instability | Decreasing of differentiation and inhibition of TSGs (p15, p21, and p27) | [73] | ||
Colon cancer | Overexpression | Proliferation, migration, and invasion | MMP9 transcriptional activation | [14, 24] | ||
Breast cancer | Overexpression | Proliferation, apoptosis inhibition, migration, and invasion | Maintenance of CSCs, proliferation via STAT3/cyclin D1 activation, and apoptosis inhibition via STAT3/Bcl-xL activation | [16, 26] | ||
Liver cancer | Overexpression | Apoptosis inhibition | PIWIL2/STAT3/c-Src activation and repression of p53 transcription | [12, 13] | ||
Cervix cancer | Overexpression | Apoptosis inhibition | PIWIL2/STAT3/c-Src activation and repression of p53 transcription | [29] | ||
Ovary cancer | Overexpression | Genomic instability | Chromatin decondensation, cell survival, and DNA repair | [65] | ||
Colon cancer | Overexpression | Migration and invasion | [74] | |||
Lung cancer | Overexpression | Proliferation | Increasing of cyclin A and cdk2 expression | [68] | ||
Cervix cancer | Overexpression | Proliferation, migration, and invasion | Impairing apoptosis via p14ARF/p53 pathway | [34] | ||
Breast, colon, gastric, and lung cancers | Overexpression | Proliferation, invasion, and metastasis | Cyclin D1 and CDK4 overexpression | [28, 43, 69, 70] | ||
Breast cancer | Overexpression | Stemness, EMT, and invasion | TGF-β pathway activation and hypermethylation of the TSG Latexin | [48] | ||
Gastric cancer | Underexpression | Chromatin regulation and angiogenesis | Hypomethylation via decreased DNMT3A/B and decreased pro-angiogenic activity | [5] | ||
Multiple myeloma | Overexpression | DNA methylation and angiogenesis | Hypomethylation via decreased DNMT3A/B and decreased pro-angiogenic activity | [44] | ||
Liver cancer | Overexpression | Migration and invasion | Akt phosphorylation and apoptosis inhibition via STAT3/Bcl-xL pathway | [41, 71] | ||
Pancreatic cancer | Underexpression | [42] | ||||
Lung cancer | Underexpression | Proliferation and invasion | Cell-cycle regulation | [38] | ||
Bladder cancer | Underexpression | Inhibition of proliferation apoptosis promotion | TNFSF4 regulation | [75] |
1.1. Deregulation of PIWI proteins in cancer
Based mainly on both
1.1.1. Proliferation, apoptosis, and stemness
Furthermore, overexpression of PIWI proteins contributes to carcinogenesis by decreasing differentiation and promoting cancer stemness. PIWIL1 and PIWIL2 are implicated in maintenance and proliferation of lung and breast cancer stem cells, respectively [15].
1.1.2. Genomic integrity
Cancer cells overexpressing PIWI proteins often have genomic alterations partially resulting from reactivation of TEs. In sarcomas, PIWIL1, and p15, p21 and p27 expression levels are inversely correlated [7]. PIWI proteins maintain genome integrity in tumor cells by using epigenetic mechanisms. PIWIL1-induced carcinomas were characterized by global DNA hypermethylation at nonpromoter CpG regions. In mouse embryonic fibroblasts, PIWIL2 was implicated in DNA repair by promoting histone acetylation, chromatin relaxation, and DNA damage response [1].
1.1.3. EMT, invasion, and metastasis
Reciprocal interactions between PIWI proteins and transcription factors involved in EMT have been identified [19]. In colon carcinomas, PIWI proteins and piRNA 34736 activate genes implicated in EMT [20].
The four PIWI proteins identified in humans are variably overexpressed in numerous cancers and implicated in invasion and metastatic spread. The first example of PIWI protein deregulated in carcinogenesis was that of PIWIL1 overexpression in seminomas [21]. Since then, increased levels of PIWIL1 have been detected in lung, breast, gastrointestinal tract, pancreas, liver, cervical, ovarian, and endometrial carcinomas. In most of these malignant tumors, PIWIL1 overexpression is associated with large tumor size, high histologic grade, advanced stage, and poorer prognosis [22, 23, 24]. Compared with PIWIL1 and PIWIL2, PIWIL3 and PIWIL4 have been studied in few cancers.
PIWIL1 upregulation was implicated in carcinogenesis by promoting expression of CSC transcription factors OCT4, NANOG, and BMI1 with increased self-renewal properties and resistance to chemotherapies [25]. In breast cancer, PIWIL1 modified cell cycle progression through regulating levels of TGF-β receptors, CDK4, CDK6, and CDK8 [26]. During gastric carcinogenesis, PIWIL1 levels of expression were gradually increased in normal tissues, atrophic gastritis, intestinal metaplasia, and invasive carcinoma [25]. In colon cancer, PIWIL1 overexpression induced global DNA methylation and proliferation. In hepatocellular carcinomas, PIWIL1 overexpression promoted invasion and metastatic spread, whereas PIWIL1 inactivation decreased metastatic evolution [27]. In glioblastomas, PIWIL1 inactivation reduced migration by inactivating expression of MMP2 and MMP9 [1]. Conversely, PIWIL1 had an inhibiting effect on invasion in ovarian cancer [28].
PIWIL2 upregulation was identified in various stages of cervical low-grade and high-grade squamous, intraepithelial lesions, and invasive cervical carcinomas and had the potential to be used as a complementary biomarker for p16 [29]. In colon cancer, PIWIL2 overexpression was significantly correlated with more aggressive clinical and pathological parameters, including lymph node and distant metastasis and poor prognosis [30]. PIWIL2 overexpression induced invasion through activation of MMP9, whereas PIWIL2 inhibition decreased migration via E-cadherin upregulation and TWIST, vimentin, and N-cadherin downregulation [30]. Experimental PIWIL2 knockdown was associated with inhibition of colon cancer cells invasion through MMP9 downregulation. In breast cancer, PIWIL2 upregulation in cancer stem cells was correlated with large tumor size, high histological grade, estrogen receptor expression, proliferation marker Ki67, advanced tumor stage, and lymph node metastasis [26]. In prostate cancer, PIWIL2 overexpression was associated with deregulation of EMT factors. In breast cancer, PIWIL2 and piRNA 932 overexpression promoted EMT in CD44+/CD24− CSCs [31].
PIWIL4 was upregulated in breast and renal cell cancers, as compared with normal tissue [32, 33]. PIWIL4 can also induce cervical cancer cell invasion through inhibiting p14/ARF and p53 expression [34].
1.2. Deregulation of piRNAs in cancer
Compared to PIWI proteins, few literatures are available about piRNAs in carcinogenesis. Despite numerous piRNAs are generated in the human genome, only a small number is consistently expressed in normal and tumor tissues [1]. With the previously established evidence on PIWI proteins deregulation in cancer, the hypothesis that piRNAs are also aberrantly expressed in various cancers is very likely because piRNAs are pivotal part of the pi-RISC effector complexes that allow recognition of TEs. Deregulation of piRNAs that target mRNA transcripts containing TE-derived sequences could induce alterations of TSGs and oncogenes [15]. Deregulation of both PIWI proteins and molecules implicated in biogenesis of the PIWI-piRNA are also in favor of a driver role for piRNAs in cancer. Recent evidence suggests that piRNAs control transcriptional and post-transcriptional genes regulation in cancer cells through epigenetic mechanisms associating global DNA hypomethylation, gene-specific DNA hypermethylation, and histones hypoacetylation, which result in oncogenes activation, TSG repression, genomic silencing, and induction of a stem-like state [35, 36]. Furthermore, piRNAs drive carcinogenesis by using nonepigenetic mechanisms such as cell cycle deregulation, proliferation, and invasion [37, 38]. Differential expressions of few piRNAs were reported between malignant tumors and normal tissues. Transcriptomic analysis of 6260 human piRNAs from 11 types of tumors and normal tissues has revealed that among the 20,831 known piRNAs, only 522 piRNAs were expressed in tumor tissues in a cancer-type specific manner, whereas 273 piRNAs were expressed in normal tissues [39].
The first examples of piRNAs deregulated in cancer were piR-651, piR-823, and piR-932. PiR-651 was aberrantly overexpressed in numerous tumors, such as breast, gastric, colon, and lung cancers, compared to normal tissues. By using small RNA sequencing techniques in breast cancer, over 100 deregulated piRNAs were identified in tumors compared to normal tissues, including piR-34736, piR-36249, piR-35407, piR-36318, piR-34377, piR-36743, piR-36026, and piR-31106. Among them, piR-36743, piR-36026, and piR-31106 were overexpressed, whereas piR-34736, piR-36249, piR-35407, piR-36318, and piR-34377 were underexpressed [33]. Furthermore, estrogen deficiency and the estrogen receptor ERβ controlled metastatic spread of breast cancer cells by directly modulating piRNA expression. Eight piRNAs were significantly differentially expressed between breast tumors and normal tissue, with overexpression of piR-4987, piR-20365, piR-20485, and piR-20582 correlated with lymph node metastasis [33]. In lung cancer, 555 piRNAs were differentially expressed between lung adenocarcinomas and squamous cell carcinomas and normal bronchial tissue. The most frequently underexpressed piRNA in lung cancer was piR-L-163, localized in intron 10 of the
1.2.1. Proliferation, survival, and apoptosis
In bladder cancer, piRNAs microarray study identified 106 overexpressed piRNAs and 91 underexpressed piRNAs, including piRNA DQ594040. PiRABC repressed cancer cells proliferation and increased cell apoptosis through TNFSF4 protein overexpression. In multiple myeloma, PiR-823 was upregulated and implicated in proliferation, apoptosis, cell-cycle regulation, and angiogenesis related to DNMT3A and p16-INK4A repression and associated with advanced clinical stage [44]. PiRNA-823 repression promoted deregulation of cell cycle regulators and apoptosis-related proteins and inhibited pro-angiogenic activity [44]. In glioblastoma, piR-598 promoted cancer cells survival and proliferation [46]. In lung carcinoma, piR-55490 underexpression was associated with increased proliferation through reduction of piRNA-induced 3’UTR mTOR mRNA binding and degradation. Furthermore, inhibition of piR-L-163 enhanced DNA synthesis and promoted tumor cells survival and proliferation [38, 47].
1.2.2. Invasion and metastatic spread
In breast cancer, piR-4987 upregulation was significantly associated with lymph node metastasis and PIWIL2-piR-932 complex enhanced EMT through Latexin methylation of its promoter region [31, 48, 49]. In clear cell renal cell carcinoma, 19 piRNAs were differentially expressed between tumor and normal tissues and 46 piRNAs were associated with metastasis and poor survival [43]. PiRNA microarray analysis revealed 235 piRNAs upregulated and 369 piRNAs downregulated in malignant tissue from 106 patient samples. RT-qPCR analysis confirmed that piR-57125 was downregulated in metastatic tumors, whereas piR-30924 and piR-38756 were upregulated [50]. In gastric cancer, downregulated blood levels of piR-823 were correlated with stage, lymph node, and distant metastasis, suggesting that piRNAs may be pertinent blood biomarkers [51]. Furthermore, PiR-651 inhibition promoted growth suppression and cell cycle arrest at the G2/M stage [40]. In hepatocellular carcinoma (HCC), deep sequencing analysis identified oncogenic piR-Hep1 upregulation associated with PIWIL2 overexpression. Inhibition of piR-Hep1 repressed Akt phosphorylation, motility, and invasion [41]. In pancreatic ductal adenocarcinoma, piR-017061 located within HBII-296A snoRNA was found to be downregulated in tumors compared to normal tissues [42]. In lung cancer, PiR-651 overexpression promoted survival, invasion, and metastatic progression through cyclin D1 and CDK4 overexpression [70]. In colon cancer, PiR-823 upregulation was correlated with lymph node and distant metastasis, whereas in gastric cancer, piR-823 overexpression suppressed tumor cell growth [1, 69].
1.3. Mechanisms of the PIWI-piRNA pathway deregulation in cancer
Few studies have identified molecular mechanisms implicating PIWI proteins and piRNAs reactivation in carcinogenesis [52, 53]. The first hypothesis concerning deregulation of the PIWI-piRNA pathway in cancer results from its control of TEs propagation. In normal germline stem cells, piRNAs cooperate with abundant PIWI proteins to regulate TEs inactivation
2. PIWIs and piRNAs as potential biomarkers and therapeutic tools
2.1. PIWI proteins as biomarkers
PIWIL1 overexpression was correlated with poor 5-year survival in malignant glioma, hepatocellular, gastric cancer, colon cancer, pancreatic ductal adenocarcinoma, and ovarian cancer [1]. In hepatocarcinoma, PIWIL1 high levels of expression were correlated with larger tumor size, intrahepatic metastasis, overall survival, and recurrence-free survival [41]. PIWIL2 upregulation was observed in breast cancer, colon cancer, gastrointestinal stromal tumors, renal cell carcinoma, and endometrial carcinoma. In colorectal cancer, PIWIL2 overexpression was associated with aggressive clinico-pathological characteristics and poorer prognostic [30]. In esophageal cancer, PIWIL2 was significantly correlated to high histological grade, advanced clinical stage, and poorer clinical outcomes. Furthermore, PIWIL2 upregulation was identified in a cancer cell subpopulation expressing OCT4 and NANOG stemness factors, suggesting a role in stem-cell maintenance and self-renewal. In breast cancer, PIWIL2 was mainly located in cancer stem cells and showed different expression patterns, with slight nuclear localization in preneoplastic lesions and cytoplasmic/nucleus topography in invasive and metastatic cancers. Its upregulation was correlated with poorer survival [33]. PIWIL2 can promote invasion and metastasis among various cancers by increasing c-Myc expression through binding of NM/NM23 nucleoside diphosphate kinase 2 (NME2) to G4-motif region within c-Myc. In hepatocellular carcinoma, nuclear co-expression of PIWIL2 and PIWIL4 had a worse prognostic phenotype [71]. In ovarian cancer, PIWIL2 overexpression was associated with cisplatin resistance and poorer prognostic [28]. PIWIL3 and PIWIL4 overexpression were associated with worse prognosis in breast cancer. In gastric cancer, PIWIL1-4 upregulation was significantly associated with TNM stage histological grade and lymph node metastasis [15, 40, 62].
2.2. PiRNAS as biomarkers
PiRNAs are increasingly investigated as diagnostic and prognostic biomarkers [69]. PiRNAs are small RNAs of only 24–32 nt in length which can pass through cell membrane. Like miRNAs, piRNAs are not degraded in circulation and possess the capability to resist incubation and storage conditions used in laboratories. They are thus detectable in patient samples like blood plasma and serum, saliva, sputum, and urine. Furthermore, piRNAs possess higher sensitivity and specificity compared to an existing lncRNA and miRNA-based biomarkers. They are highly expressed in germinal tissues, but also although at lower levels in various somatic normal tissues, saliva, and plasma-derived exosomes. Furthermore, piRNAs present higher specificity and sensitivity, when compared to miRNAs. In breast cancer, 8 piRNAs were identified as independent prognostic markers and associated with overall survival [63]. Moreover, piR-4987 upregulation in peripheral blood was correlated with lymph node metastasis [48]. In gastric cancer, piR-651 high level of expression in peripheral blood was associated with poor differentiation, advanced TNM stage, and metastasis. A three-piRNA signature, including piR-59056, piR-54878, and piR-62701, could separate patients by risk of recurrence [5]. PiR-651 was also upregulated in other cancers, including lung, colon, and breast tumors. In clear cell renal cell carcinoma, piR-30924 and piR-57125 were shown to be independent prognostic predictors in nonmetastatic patients. In colon cancer, piR59056, piR-54878, and piR-62701 were associated with recurrence-free survival. Few studies have investigated on interactions between piRNAs and PIWI proteins in cancer [70, 72, 73, 74, 75]. Actually, it remains unclear whether PIWI proteins independently possess cytoplasmic pro-oncogenic properties that promote cancer cell proliferation, invasion, and metastasis or PIWI proteins located in the nucleus epigenetically modulate numerous biological processes by edifying ribonucleoproteic complexes with piRNAs.
2.3. PIWI proteins and piRNAs as therapeutic tools
Recent studies have revealed the potential for piRNAs as therapeutic tools that target PIWI proteins and oncoproteins [71]. Mounting evidence has revealed that upregulation of PIWI proteins was negatively correlated with patient survival, and that downregulation of PIWI proteins could reduce the number of G2/M phase cells and enhance expression of p53 protein, thus inhibiting proliferation and promoting apoptosis. In addition, PIWI proteins could increase resistance to chemotherapy drugs such as cisplatin, and their downregulation could increase sensitivity of cancer cells to cisplatin. In this way, synthetic piRNAs targeting PIWI genes are potential pertinent tools in transcriptional silencing during cancer progression, and PIWI antibodies targeting PIWI proteins constitute another approach to antagonize cancer cells proliferation at post-transcriptional level. Synthetic piRNAs could also block synthesis of cancer-related proteins by binding to mRNAs. Compared to miRNAs, piRNAs do not require enzymes processing and have better specificity to targets. In a mouse model, artificial piRNAs could be obtained through expression of sense and antisense transcripts, resulting in epigenetic silencing of target genes [1, 72]. Furthermore, piRNAs could be considered as tools to regulate expression levels of TSGs. A lncRNA (
3. Conclusion and perspectives
PiRNAs and PIWI proteins were first recognized more than a decade ago and are coming into attention with development of high-throughput sequencing technologies and bioinformatics methods. This pathway is considered as a conserved immune-like surveillance process to suppress propagation of TEs in germline cells and various types of somatic mostly nonaging cells. Furthermore, the PIWI-piRNA pathway seems to be implicated in maintain of the genome organization, epigenetic modifications of genes expression, and identification of self and nonself genes that are trans-generationally inherited. Moreover, this axis could be implicated in dual DNA/RNA-level regulation of genes expression. Nevertheless, there is still lack of complete understanding of the functions and interactions of piRNAs and PIWI proteins. Therefore, the complicated biogenesis and functions of piRNAs need further elucidation to improve our understanding of the implication of these molecules in cancer. Since discovery of the unexpected role of this pathway in seminoma, aberrant levels of expression of these molecules have been observed across numerous malignant tumors, though further research is needed to elucidate their oncogenic or tumor-suppressing status. Growing evidence suggests that the PIWI-piRNA pathway modulates occurrence of most of cancer hallmarks. PIWI proteins and piRNAs could be pertinent diagnostic/prognostic biomarkers in cancer and therapeutic tools in targeted therapies. However, the potential driver role of a deregulated PIWI-piRNA pathway in cancer needs to be further evaluated. Furthermore, it remains unclear whether PIWI proteins regulate cancer cell proliferation, apoptosis, metastasis, and invasion in the cytoplasm independently or PIWI proteins perform epigenetic control of homeostasis by taken to the nucleus with piRNAs. Most importantly, since the aberrant expression of this pathway may induce stemness, analysis of relationship between PIWI proteins, piRNAs, and cancer stem cells may open new avenues in future investigations.
Disclosure/conflict of interest
The authors declare that they have no competing interests.
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