HMGB proteins, lncRNAs, and their interaction in epithelial ovarian cancer

Resumen

Ovarian cancer is one of the most lethal gynecological malignancies worldwide due to the lack of early diagnostic methods. In this regard, HMGB family members, HMGB1 and HMGB2, as well as long non-coding RNAs (lncRNAs), participate in the malignant transformation by regulating gene expression and, therefore, their study represents an opportunity to progress towards a better understanding of the disease and the development of novel clinical strategies. The main objective of this work was to identify lncRNAs in epithelial ovarian cancer that are deregulated and/or associated with HMGB1 and/or HMGB2 because of their potential value as novel diagnostic biomarkers and therapeutic targets. The determination of new RNA interactions of these proteins would allow a better understanding of their mechanism of action and their role in ovarian cancer pathology. We performed a meta-analysis on transcriptomic profiling expression data from epithelial ovarian cancer patients that are publicly available. By this approach, we identified several lncRNAs previously unrelated to epithelial ovarian cancer, with diagnostic and prognostic values, and associated with metastasis, chemoresistance, or histological subtype. Then, the RNA interactome of HMGB1 and HMGB2 was determined by applying in silico binding predictions, as well as two immunoprecipitation-based techniques, RIP-Seq and eCLIP in a high-grade serous epithelial ovarian cancer cell line, PEO1. The identified lncRNAs and messenger RNAs (mRNAs) are related to previous information present in scientific literature and gene ontologies regarding biological processes, respectively. Finally, HMGB1 and HMGB2 silencing was carried out using an siRNA-based approach and their effects on PEO1 transcriptome were analyzed. Their role in signaling pathways and biological processes in addition to the HMGB-regulated lncRNAs were assessed.