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.
Highlights
Emerging evidence suggests that PIWI-interacting RNAs may be important epigenetic regulators of gene expression in human cancers; their functional and clinical significance in colorectal cancer (CRC) remains unknown
Our results revealed that 3 PIWI-interacting RNAs (piRNAs) were upregulated, while piR-26,525 was down-regulated in cancer tissues
In order to account for patient cohort differences and tumor heterogeneity, we validated the expression of these two piRNAs in two independent patient cohorts (Shanghai and Okayama cohorts)
Summary
Emerging evidence suggests that PIWI-interacting RNAs (piRNAs) may be important epigenetic regulators of gene expression in human cancers; their functional and clinical significance in colorectal cancer (CRC) remains unknown. Current guidelines for risk stratification of patients predominantly rely on the clinicopathological factors, which are inadequate and often result in under or over-treatment for CRC patients [4, 5]. In view of this clinical challenge, identification of novel molecular targets that more robustly typify and represent disease biology would be of great value in improving prognosis and allowing precision therapeutic targeting in CRC patients
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