P18/Stathmin1 is regulated by miR-31 in ovarian cancer in response to taxane
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https://doi.org/10.18632/oncoscience.143
Mohamed Kamel Hassan1,2,3, Hidemichi Watari1, Takashi Mitamura1, Zainab Mohamed1, Sherif F. EL-khamisy3,4, Yusuke Ohba5, Noriaki Sakuragi1
1 Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine, Sapporo, JAPAN
2 Bitechnology Program, Zoology Department, Faculty of Science, Port Said University, Port Said, EGYPT
3 Center of Genomics, Hemly Institute for Medical Sciences, Zewail City for Science and Technology, Giza, EGYPT
4 Krebs Institute, Department of Molecular Biology and Biotechnology, University of Sheffield, UK
5 Department of Cell Physiology, Hokkaido University Graduate School of Medicine, Sapporo, JAPAN
Correspondence:
Mohamed Hassan, email:
Hidemichi Watari, email:
Keywords: ovarian cancer, chemoresistance, miR-31, taxane, Stathmin 1
Received: January 6, 2015 Accepted: March 16, 2015 Published: March 23, 2015
Abstract
MicroRNAs (miRNAs) have been reported to regulate the development of chemoresistance in many tumors. Stathmin 1 (STMN1) is a microtubule-depolymerizing molecule, involved in chemo-response; however, the mechanism of its regulation is unknown. Herein, the immunohistochemical study indicated significant upregulation of the STMN1 in the ovarian cancer tissues defined as resistant tumors compared with those defined as responsive tumors. STMN1 level elevated in the chemoresistant ovarian cancer cells, KF-TX, compared with the parental, KF, ones. Targeting STMN1 by siRNA restored taxane-sensitivity of KF-TX cells. Screening miRNA profiles from KF/KF-TX cellular set followed by bioinformatics-based prediction, revealed that miR-31 could be a possible regulator of STMN1. Down-modulation of miR-31 was verified by quantitative RT-PCR in the cellular set used. Overexpression of miR-31 in KF-TX cells (KF-TX-miR-31) significantly restored chemo-response and reduced STMN1 expression as well. STMN1 reduction-associated cellular characteristics such as enhanced microtubule polymerization and stability, as indicated by acetylated tubulin quantification, confocal visualization, and G2 phase delay, were observed in KF-TX-miR-31 cells, indicating the functional reduction of STMN1. miR-31 suppressed the luciferase activity in reporter construct containing the STMN1 3’-untranslated region (3’-UTR), confirming that miR-31 directly target STMN1. miR-31 has therapeutic potency when introduced into ovarian cancer, in combination with taxane.
