Role of the transcribed pseudogene RPSAP52 in gene expression regulation in cancer

Abstract

[eng] Most of our genome encodes for RNA that is not translated into proteins in some cell type or at some developmental time-point resulting in non-coding RNA (ncRNA). Long non-coding RNA (lncRNA) emerged as a critical class of ncRNAs participating in a wide range of cellular functions. Although their biological roles are still largely unknown, a growing number of long non-coding RNA display diverse roles in regulating gene expression at both the transcriptional and translational levels involved in tumorigenesis. Among them, a new lncRNA RPSAP52 (Ribosomal protein SA pseudogene 52) has been identified as a functional molecule, reexpressed in several human cancers and promotes tumorigenic features by enhancing HMGA2 transcription and IGF2BP2 function. LncRNA RPSAP52´s role in promoting oncogenic processes in ovarian cancer (OC) has not been fully elucidated. This study investigates the effects of RPSAP52 on OC and explores its potential as a therapeutic target using GapmeR antisense oligonucleotides in orthotopic patient- derived xenograft (PDOX) models. Analysis of RPSAP52 and HMGA2 expression in TCGA datasets, OC PDOX models, and commercial cell lines revealed that RPSAP52 is overexpressed in OC, particularly in early-stage disease, correlating with poorer clinical outcomes. Silencing RPSAP52 via lentiviral-mediated depletion significantly reduced tumor growth in vitro and in vivo. Furthermore, antisense LNA GapmeRs targeting RPSAP52 showed strong antitumor effects in PDOX models without toxicity. These findings suggest that RPSAP52 promotes OC growth and may serve as a valuable therapeutic target and prognostic biomarker for early-stage OC. LncRNA RPSAP52 also plays a pivotal role in both rhabdomyosarcoma (RMS) and myogenesis by modulating key molecular pathways. Our findings indicate that RPSAP52 significantly impacts the expression of HMGA2 and IGF2BP2, two critical regulators of myoblast proliferation and differentiation. Through its interaction with IGF2BP2, RPSAP52 enhances the translation of myogenic mRNAs, including IGF1R and NRAS, thereby promoting cell proliferation and inhibiting differentiation. Notably, RPSAP52 appears to influence miR-29a, a microRNA involved in muscle differentiation and tumorigenesis, by potentially modulating its stability or maturation through IGF2BP2. This regulatory axis between RPSAP52, IGF2BP2, and miR-29a underscores the complex role of lncRNAs in both normal muscle development and RMS pathology, presenting new therapeutic targets for treating RMS and related muscle disorders. In summary, the present work proposes that lncRNA RPSAP52 plays a crucial role in cancer biology by modulating key oncogenic processes and signaling pathways. Its involvement in stabilizing mRNA of oncogenes and interacting with RNA-binding proteins like IGF2BP2 highlights its significance in tumor progression and resistance. Taken together, RPSAP52 has potential as both a therapeutic target and prognostic biomarker in ovarian cancer and

rhabdomyosarcoma, revealing its impact on cell proliferation, differentiation, and tumor growth. Targeting RPSAP52 could offer novel strategies for treating these cancers and improving patient outcomes.