Abstract
Abstract The largest part of the human genome is transcribed into non-coding RNAs (ncRNAs) which are functional transcripts displaying relevant roles in many biological processes, and their dysregulation has been shown to be involved in the development of diseases like cancer. The group of long non-coding RNAs (lncRNAs) has been elucidated to be key regulators of gene expression by acting at different levels, as regulators of epigenetic modifications and chromatin remodelling by acting as structural scaffolds, decoys or guides in the nucleus; as well as post-transcriptional regulators of messenger RNA stability and translation in the cytoplasm. Hence, the knowledge about their mechanisms of action may provide a better understanding of cell biology and likewise, lncRNAs may be used as biomarkers or therapeutical tools. The aim of the current project has been to describe the mechanism of action of a lncRNA called RPSAP52 (Ribosomal Protein SA Pseudogene 52) in ovarian cancer, as well as to study the potential use of RPSAP52 as a tool for therapeutical strategies. Our previous results indicate that RPSAP52, which is an antisense transcript to the well described oncogene HMGA2 (High Mobility Group A2), positively regulates HMGA2 expression through the formation of an R loop structure, and it has been shown that RPSAP52 enhances the oncofetal pathway HMGA2-IGF2BP2-RAS axis through LIN28B-dependent and independent inhibition of let-7 miRNAs in breast cancer and sarcomas. Since the dysregulation of this pathway has been described to be involved in the development of ovarian cancer; which is among the most common types of cancer with poor prognosis, the goal of this project has been to reveal the relevance of RPSAP52 in this system. The oncogenic potential of RPSAP52 has been confirmed by the analysis of a battery of xenograft samples from ovarian cancer patients, in which significant higher levels of RPSAP52 in those samples versus normal ovary have been observed, and it is positively correlated with higher levels of the sense gene HMGA2. Preliminary in vitro studies have shown that the depletion of RPSAP52 with shRNAs is related with a down-regulation of the oncogenic protein LIN28A in SKOV3 cells. Our findings suggest that RPSAP52 may be involved in the pathogenesis of ovarian cancer, and a further analysis of the link between RPSAP52 and LIN28A needs to be performed, together with the study of other candidate protein partners of RPSAP52 revealed by RNA pull down and RAP-MS techniques. Interestingly, the use of the LNA Gapmers as a strategy for the depletion of RPSAP52 also allows us to use them in vivo to confirm in vitro results as well as to study its potential role as a therapeutic target in ovarian cancer. Citation Format: Anaís Sánchez Castillo, Cristina Oliveira Mateos, Marta Soler Riera, Manel Esteller, Sonia Guil. Non-coding RNAs as key players for understanding oncogenic pathways in ovarian cancer: Studying new therapeutic strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1819.
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