Abstract
Ovarian clear cell carcinoma (OCCC) is a histological subtype of epithelial ovarian cancer and exhibits dismal prognosis due to chemoresistance. Moreover, only few effective therapeutic options exist for patients with recurrent OCCC, and an understanding of its molecular characteristics is essential for the development of novel therapeutic approaches. In the present study, we investigated unique MicroRNAs (miRNA) profiles in recurrent/metastatic OCCC and the role of miRNAs in cisplatin resistance. Comprehensive miRNA sequencing revealed that expression of several miRNAs, including miR-508-3p, miR-509-3p, miR-509-3-5p, and miR-514a-3p was remarkably less in recurrent cancer tissues when compared with that in paired primary cancer tissues. These miRNAs are located in the chrXq27.3 region on the genome. Moreover, its expression was negative in omental metastases in two patients with advanced OCCC. In vitro analyses revealed that overexpression of miR-509-3p and miR-509-3-5p reversed cisplatin resistance and yes-associated protein 1 (YAP1) was partially responsible for the resistance. Immunohistochemistry revealed that YAP1 expression was inversely correlated with the chrXq27.3 miRNA cluster expression. In conclusion, these findings suggest that alteration of the chrXq27.3 miRNA cluster could play a critical role in chemoresistance and miRNAs in the cluster and their target genes can be potential therapeutic targets.
Highlights
Epithelial ovarian cancer (EOC) remains one of the leading causes of cancer death among females worldwide, being
There are 22 miRNAs located in the chrXq27.3 miRNA cluster, but its detailed functions in EOC remain unclear
We revealed the status of the chrXq27.3 miRNA cluster in Ovarian clear cell carcinoma (OCCC) and its function in cisplatin sensitivity (Fig. 7)
Summary
Epithelial ovarian cancer (EOC) remains one of the leading causes of cancer death among females worldwide, being. All 22 miRNA genes in the chrXq27.3 cluster are oriented in the same transcriptional direction, and there are no annotated protein-coding genes interrupting the miRNA genes in the cluster [12] These miRNAs are considered to be under the control of a common regulatory unit and co-expressed [7, 14]. In EOC, several reports indicated an association between the status of the miRNA cluster and clinical outcomes [20,21,22]. These reports mostly included patients with HGSOC, whereas few patients with OCCC were enrolled. In vitro analyses demonstrated that miR-509-3p and miR-509-3-5p, two members of the chrXq27.3 cluster, are associated with cisplatin resistance via yes-associated protein 1 (YAP1) and the Hippo signaling pathway
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