Abstract 3895: New potential mechanism of mnx1-as1 in the regulation of the carboplatin chemoresistant phenotype in ovarian cancer cell lines
Authors: Alvarez Tamara Alejandra Viscarra , Mena Kurt Leopoldo Buchegger , Garrido Daniela Inés León , Gangas Carmen Gloria Ili , Zenteno Jorge Sapunar , Flores Marcela Berrios , Pezoa Ramón Silva , Barreto Sindy Paola Cabarca , Mieville Priscilla Brebi 
Published: April 2023

Introduction: Ovarian cancer (OC) is one of the most lethal diseases in the female population worldwide, being considered by 2020 the eighth most common type of cancer and the eighth cause of cancer death in that population. The most widely used chemotherapy treatment is based on the application of platinum based drugs, carboplatin (CBDCA) being one of the most common, in combination with taxanes and cisplatin. Unfortunately, a high percentage of the population relapses shortly after chemotherapy treatment, presenting a drug resistant phenotype. This phenotype reduces overall survival in patients with OC. In this context, various mechanisms have been investigated to understand and study these chemoresistant phenotypes. In the last decade, lncRNAs have been identified in multiple biological processes, including the development of drug-resistant phenotypes in malignant tumors, however, little is known about their role in carboplatin resistance in OC. This study seeks to characterize the effect of lncRNA expression on the chemoresistant phenotype and its potential molecular mechanism involved.

Materials and Methods: Ovarian cancer cell lines corresponding to: A2780-R-CBDCA, A2780-P, UCI-101, OVCAR3 and SKOV3 were used. Drug susceptibility assays were performed using MTT. Relative expression was performed via RTqPCR. RNAseq was performed on a CBDCA resistance model in vitro using the Illumina HiSeq 4000 platform. Gene Ontology (GO) was analyzed using ClueGO. Gene set enrichment analysis (GSEA) was performed to define enriched biological pathways. Triplexator was used to predict the triplex forming oligonucleotides (TFO) and triplex target sites (TTS) that may be involved in the formation of RNA-DNA triplexes.

Results: RNAseq analysis showed 156 differentially expressed protein coding genes (DEGs). The most enriched and deregulated signaling pathway was Wnt/β-catenin. In this context, several regulators of this pathway were found to be altered, including sFRP1, sFRP4, PCDHB6, CTNNA2, DACT1, PCDHB6, WNT3A, and CER1. In addition, 17 lncRNAs involved in CDBCA resistance were found to be deregulated. In this sense, MNX1-AS1 showed high levels of expression in CBDCA resistant cell lines. Interestingly, it has been shown that MNX1-AS1 has the ability to form a triplex with the PCDHB6 gene, which is a tumor suppressor gene and whose expression was found to be decreased in CBDCA resistant cell lines.

Conclusions: Our results indicate that MNX1-AS1 expression could contribute to the modulation of platinum drug resistance through regulation of PCDHB6 expression via triplexes formation in OC. This finding could explain a new mechanism in CBDCA resistance in OC.

Citation Format: Tamara Alejandra Viscarra Alvarez, Kurt Leopoldo Buchegger Mena, Daniela Inés León Garrido, Carmen Gloria Ili Gangas, Jorge Sapunar Zenteno, Marcela Berrios Flores, Ramón Silva Pezoa, Sindy Paola Cabarca Barreto, Priscilla Brebi Mieville. New potential mechanism of mnx1-as1 in the regulation of the carboplatin chemoresistant phenotype in ovarian cancer cell lines. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3895.