miR-363 confers taxane resistance in ovarian cancer by targeting the Hippo pathway member, LATS2
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Zeinab Mohamed1,2,*, Mohamed Kamel Hassan2,3,4,*, Safwat Okasha1, Takashi Mitamura2, Sarah Keshk3,4, Yusuke Konno2, Tatsuya Kato2, Sherif F. EL-Khamisy4,5, Yusuke Ohba6 and Hidemichi Watari2
1Zoology Department, Faculty of Science, Aswan University, Aswan, Egypt
2Department of Obstetrics and Gynaecology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
3Bitechnology Program, Zoology Department, Faculty of Science, Port Said University, Port Said, Egypt
4Centre for Genomics, HelmyInstitute for Medical Sciences, Zewail City for Science and Technology, Giza, Egypt
5Krebs and Sheffield Institute for Nucleic Acids, University of Sheffield, Sheffield, UK
6Department of Cell Physiology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
*These authors have contributed equally to this work
Mohamed Kamel Hassan, email: [email protected]
Hidemichi Watari, email: [email protected]
Keywords: ovarian cancer; chemoresistance; miR-363; taxane; LATS2
Received: November 21, 2017 Accepted: June 04, 2018 Published: July 10, 2018
Ovarian cancer is the most aggressive female reproductive tract tumours. Taxane (paclitaxel; TX) is widely used for ovarian cancer treatment. However, ovarian cancers often acquire chemoresistance. MicroRNAs (miR) have been reported to mediate many tumours’chemoresistance. We investigated the role of miR-363 in the chemoresistance of the ovarian cancer cell line, KF, and its TX-resistant derivative (KF-TX) cells. QRT-PCR indicated that miR-363 was upregulated in KF-TX cells, and introduction of miR-363 into sensitive ovarian cancer cells confers TX-resistance and significantly inhibited the expression of the Hippo member, LATS2, as indicated by viability, clonogenic assay and expression analysis. Furthermore, we validated the role of LATS2 in TX-response by sh-based silencing, which also confers TX-resistance to the ovarian cancer cells. On the other hand, specific inhibitor against miR-363 restored the response to TX in the resistant cells. In addition, miR-363 was found to bind to the 3′-UTR of LATS2 mRNA, confirming that miR-363 directly targets LATS2 as indicated by dual luciferase assay. RT-PCR-based evaluation of miR-363 in a panel of human ovarian tumours revealed its upregulation in most of the tumour tissues identified as resistant while it was downregulated in most of the tissues identified as sensitive ones. Moreover, higher levels of miR-363 in human ovarian cancer specimens were significantly correlated with TX chemoresistance. Taken together, our study reveals the involvement of miR-363 in chemoresistance by targeting LATS2 in ovarian cancers, raising the possibility that combination therapy with a miR-363 inhibitor and TX may increase TX efficacy and reduce the chance of TX-resistance.
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