Abstract
Piwi-interacting RNAs (piRNAs), whose role in germline maintenance has been established, are now also being classified as post-transcriptional regulators of gene expression in somatic cells. PIWI proteins, central to piRNA biogenesis, have been identified as genetic and epigenetic regulators of gene expression. piRNAs/PIWIs have emerged as potential biomarkers for cancer but their relevance to breast cancer has not been comprehensively studied. piRNAs and mRNAs were profiled from normal and breast tumor tissues using next generation sequencing and Agilent platforms, respectively. Gene targets for differentially expressed piRNAs were identified from mRNA expression dataset. piRNAs and PIWI genes were independently assessed for their prognostic significance (outcomes: Overall Survival, OS and Recurrence Free Survival, RFS). We discovered eight piRNAs as novel independent prognostic markers and their association with OS was confirmed in an external dataset (The Cancer Genome Atlas). Further, PIWIL3 and PIWIL4 genes showed prognostic relevance. 306 gene targets exhibited reciprocal relationship with piRNA expression. Cancer cell pathways such as apoptosis and cell signaling were the key Gene Ontology terms associated with the regulated gene targets. Overall, we have captured the entire cascade of events in a dysregulated piRNA pathway and have identified novel markers for breast cancer prognostication.
Highlights
Piwi-interacting RNAs belong to a class of small regulatory RNAs that include microRNAs and small interfering RNAs [1]
We have identified eight non-redundant Piwi-interacting RNAs (piRNAs) as novel prognostic markers for breast cancer
Four and six piRNAs were found to be associated with OS and RFS, respectively, among which two piRNAs were common for OS and RFS
Summary
Piwi-interacting RNAs (piRNAs, 24 – 32 nt in length) belong to a class of small regulatory RNAs that include microRNAs (miRNAs) and small interfering RNAs (siRNAs) [1]. Mature forms of these RNAs associate with biogenesis pathway proteins such as Argonaute (AGO) class of proteins: miRNAs and siRNAs with AGO proteins and piRNAs with PIWI proteins [2,3,4,5] to guide target specific gene regulation [6, 7]. It is known that PIWI proteins, which are guided by piRNAs bind to specific targets (based on sequence specific complementarity) and recruit chromatin modifiers to enable transcriptional repression [13]. Given the diverse functions of piRNAs and PIWI proteins, it is evident that these molecules may contribute to tumorigenesis [9]
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