The Long Non-Coding RNA SNHG12 as a Mediator of Carboplatin Resistance in Ovarian Cancer via Epigenetic Mechanisms

Cecilie Abildgaard, Luisa Matos Do Canto, Cláudia Aparecida Rainho, Fabio Albuquerque Marchi, Naiade Calanca, Marianne Waldstrøm, Karina Dahl Steffensen, Silvia Regina Rogatto*

*Kontaktforfatter

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Abstract

Genetic and epigenetic changes contribute to intratumor heterogeneity and chemotherapy resistance in several tumor types. LncRNAs have been implicated, directly or indirectly, in the epigenetic regulation of gene expression. We investigated lncRNAs that potentially mediate carboplatin-resistance of cell subpopulations, influencing the progression of ovarian cancer (OC). Four carboplatin-sensitive OC cell lines (IGROV1, OVCAR3, OVCAR4, and OVCAR5), their derivative resistant cells, and two inherently carboplatin-resistant cell lines (OVCAR8 and Ovc316) were subjected to RNA sequencing and global DNA methylation analysis. Integrative and cross-validation analyses were performed using external (The Cancer Genome Atlas, TCGA dataset, n = 111 OC samples) and internal datasets (n = 39 OC samples) to identify lncRNA candidates. A total of 4255 differentially expressed genes (DEGs) and 14529 differentially methylated CpG positions (DMPs) were identified comparing sensitive and resistant OC cell lines. The comparison of DEGs between OC cell lines and TCGA-OC dataset revealed 570 genes, including 50 lncRNAs, associated with carboplatin resistance. Eleven lncRNAs showed DMPs, including the SNHG12. Knockdown of SNHG12 in Ovc316 and OVCAR8 cells increased their sensitivity to carboplatin. The results suggest that the lncRNA SNHG12 contributes to carboplatin resistance in OC and is a potential therapeutic target. We demonstrated that SNHG12 is functionally related to epigenetic mechanisms.

OriginalsprogEngelsk
Artikelnummer1664
TidsskriftCancers
Vol/bind14
Udgave nummer7
Antal sider18
ISSN2072-6694
DOI
StatusUdgivet - 1. apr. 2022

Bibliografisk note

Funding Information:
Funding: This study was supported by grants from the Region of Southern Denmark Research Fund (J.nr.: 18/17869 and J.nr.: 20/14277), Denmark. C.A.R. and N.C. were granted with scholarships from the Brazilian Federal Agency for Support and Evaluation of Graduate Education (CAPES), in the scope of the Program CAPES-PrInt (process number 88887.310463/2018-00), mobility numbers 88887.374335/2019-00 and 88887.570391/2020-00, respectively.

Funding Information:
This study was supported by grants from the Region of Southern Denmark Research Fund (J.nr.: 18/17869 and J.nr.: 20/14277), Denmark. C.A.R. and N.C. were granted with scholarships from the Brazilian Federal Agency for Support and Evaluation of Graduate Education (CAPES), in the scope of the Program CAPES-PrInt (process number 88887.310463/2018-00), mobility numbers 88887.374335/2019-00 and 88887.570391/2020-00, respectively.

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

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