Novel evidence for a PIWI-interacting RNA (piRNA) as an oncogenic mediator of disease progression, and a potential prognostic biomarker in colorectal cancer

Abstract

BackgroundEmerging evidence suggests that PIWI-interacting RNAs (piRNAs) may be important epigenetic regulators of gene expression in human cancers; however, their functional and clinical significance in colorectal cancer (CRC) remains unknown.MethodsWe performed piRNA expression profiling in paired cancer and normal tissues through small RNA-sequencing. The clinical significance of candidate piRNAs was investigated, and independently validated in 771 CRC patients from three independent cohorts. The biological function of piRNAs was characterized in cell lines, followed by identification and validation of downstream target genes in CRC tissues.ResultsWe identified piR-1245 as a novel and frequently overexpressed noncoding RNA in CRC, and its expression significantly correlated with advanced and metastatic disease. Patients with high piR-1245 expression experienced significantly shorter overall survival, and multivariate analysis identified its expression to serve as an independent prognostic biomarker in CRC. Functionally, piR-1245 acts as an oncogene and promotes tumor progression, and gene expression profiling results identified a panel of downstream target-genes involved in regulating cell survival pathway. Based upon piRNA:mRNA sequence complementarity, we identified a panel of tumor suppressor genes (ATF3, BTG1, DUSP1, FAS,NFKBIA, UPP1, SESN2, TP53INP1 and MDX1) as direct targets of piR-1245, and successfully validated an inverse correlation between their expression and piR-1245 in CRC.ConclusionsWe for the first time have identified the role for a PIWI-interacting noncoding RNA, piR-1245, as a novel oncogene and a potential prognostic biomarker in colorectal cancer.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0767-3) contains supplementary material, which is available to authorized users.

Tumor suppressive activity of PIWI‐interacting RNA in human fibrosarcoma mediated through repression of RRM2

“…In recent years, small non‐coding RNAs, including miRNAs, siRNAs, and piRNAs has garnered the attention of the researchers in the field of gene regulation and epigenetics . Recent studies have shown that piRNAs, a newly discovered class of ncRNAs are differentially expressed in cancers and regulate several key biological processes revealing their tumorigenic potential (tumor suppressors or oncogenes) . Hence, this class of ncRNAs has the potential to be used as diagnostic and prognostic markers as well as therapeutic interventions for different types of human cancers.…”

“…Recently, our lab has also reported the expression of piRNAs in human brain, and Alzheimer's disease (AD)‐affected brain, epithelial ovarian cancer sub‐types and neuroblastoma . Further, aberrant expression of piRNAs has been documented in cancers such as breast, pancreas, lung, kidney, colorectal, cervical, head, neck, and gastric cancer . However, only a few piRNAs such as piR‐651, piR‐20365, piR‐021285, piR‐932, and piR‐823 have been intensively explored and validated in different cancers to decipher their role in oncogenesis .…”

“…11 Further, aberrant expression of piRNAs has been documented in cancers such as breast, pancreas, lung, kidney, colorectal, cervical, head, neck, and gastric cancer. [24][25][26][27][28][29][30] However, only a few piRNAs such as piR-651, piR-20365, piR-021285, piR-932, and piR-823 have been intensively explored and validated in different cancers to decipher their role in oncogenesis. 8,[31][32][33][34] Cheng et al reported that the expression of piR-823 in gastric cancer tissues was significantly lower compared to non-cancerous tissues and its increased expression inhibited growth of gastric cancer cells.…”

piR‐39980 promotes cell proliferation, migration and invasion, and inhibits apoptosis via repression of SERPINB1 in human osteosarcoma

“…Therefore, the failure of apoptosis leads to cancer cell survival and malignancy [Pileczki et al, 2016]. Numerous studies have shown several piR-NAs are upregulated in cancers and their inhibition leads to induce apoptosis [Weng et al, 2018;Yan et al, 2015;Yao et al, 2016]. Therefore, we assessed the role of piR-39980 in the apoptosis of OS cells by transfecting with its inhibitor.…”

“…Among ncRNAs, Piwi-interacting RNAs (piRNAs) have recently emerged as promising ncR-NAs which are initially reported to maintain genome stability either by post-transcriptional silencing or by histone modification and DNA-methylation of transposons in association with PIWI-proteins [Brennecke et al, 2007;Ku and Lin, 2014;Houwing et al, 2007;Castel and Martienssen, 2013;Watanabe and Lin, 2014]. These are of ß26-36 nucleotides (nts) in length characterised by a 3-terminal 2´-Omethylation and are now reported in somatic and cancer cells regulating differentiation, development, proliferation, apoptosis, invasiveness, angiogenesis, chemo-resistance and so on besides their germline functions [Bahn et al, 2015;Khurana and Theurkauf, 2010;Xiong et al, 2015;Weng et al, 2018;Firmino et al, 2016]. More specifically, only a few piRNAs such as piR-651, piR-20365, piR-021285, piR-932 and piR-823 have been reported to regulate oncogenesis of various cancers such as breast, pancreas, lung, kidney, colorectal, cervical, head, neck and gastric cancer [Zhang et al, 2013;Li et al, 2016;Cordeiro et al, 2016;Fu et al, 2015;Yin et al, 2017].…”