Long Non-Coding RNA HAND2-AS1 Acts as a Tumor Suppressor in High-Grade Serous Ovarian Carcinoma.

Mariastella Zannini,Priyanka Gokulnath,Ichcha Manipur,Tina Di Palma,Tiziana De Cristofaro,Amata Amy Soriano,Mario Rosario Guarracino

doi:10.3390/ijms21114059

Abstract

Long non-coding RNAs (lncRNAs) are increasingly being identified as crucial regulators in pathologies like cancer. High-grade serous ovarian carcinoma (HGSC) is the most common subtype of ovarian cancer (OC), one of the most lethal gynecological malignancies. LncRNAs, especially in cancers such as HGSC, could play a valuable role in diagnosis and even therapy. From RNA-sequencing analysis performed between an OC cell line, SKOV3, and a Fallopian Tube (FT) cell line, FT194, an important long non-coding RNA, HAND2 Anti sense RNA 1 (HAND2-AS1), was observed to be significantly downregulated in OCs when compared to FT. Its downregulation in HGSC was validated in different datasets and in a panel of HGSC cell lines. Furthermore, this study shows that the downregulation of HAND2-AS1 is caused by promoter hypermethylation in HGSC and behaves as a tumor suppressor in HGSC cell lines. Since therapeutic relevance is of key importance in HGSC research, for the first time, HAND2-AS1 upregulation was demonstrated to be one of the mechanisms through which HDAC inhibitor Panobinostat could be used in a strategy to increase HGSC cells’ sensitivity to chemotherapeutic agents currently used in clinical trials. To unravel the mechanism by which HAND2-AS1 exerts its role, an in silico mRNA network was constructed using mRNAs whose expressions were positively and negatively correlated with this lncRNA in HGSC. Finally, a putative ceRNA network with possible miRNA targets of HAND2-AS1 and their mRNA targets was constructed, and the enriched Gene Ontology (GO) biological processes and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were identified.

Highlights

Long non-coding RNAs are non-translated RNAs, 200–10,000 nucleotides in size, that act as masters of genome regulation [1]
To better understand the mechanisms by which long non-coding RNAs are involved in the development of High-grade serous ovarian cancer (HGSC), an RNA-seq experiment was performed between an ovarian cancer cell line (SKOV3) and a fallopian tube cell line (FT-194)
To further confirm the role of HAND2-AS1 in HGSC originating from the fallopian tube, two other datasets between HGSC and FT were validated

Summary

Introduction

Long non-coding RNAs (lncRNAs) are non-translated RNAs, 200–10,000 nucleotides in size, that act as masters of genome regulation [1]. Research on lncRNAs is a growing field in molecular biology, keeping in mind their vast milieu and their diverse roles in physiology and pathology, especially in cancer [3] They have been attributed a role in bringing about every cancer hallmark and have an important contribution towards almost all regulatory process at a cellular level [4]. High-grade serous ovarian cancer (HGSC) is the most incident and lethal subtype of ovarian cancer (OC) [5], which in turn is the most common cause of mortality in women due to gynecological malignancy [6] This is a very aggressive cancer subtype that is almost always detected after intraperitoneal spread due to the lack of early markers or unique diagnostic symptoms [7]. We add HAND2-AS1 to this growing list of lncRNAs with an important role in HGSC

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