Matrix metalloproteinase-10 regulates stemness of ovarian cancer stem-like cells by activation of canonical Wnt signaling and can be a target of chemotherapy-resistant ovarian cancer

// Tasuku Mariya 1, 2 , Yoshihiko Hirohashi 1 , Toshihiko Torigoe 1 , Yuta Tabuchi 1, 2 , Takuya Asano 1, 2 , Hiroshi Saijo 1, 3 , Takafumi Kuroda 1, 2 , Kazuyo Yasuda 1 , Masahito Mizuuchi 1, 2 , Tsuyoshi Saito 2 , Noriyuki Sato 1 1 Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan 2 Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan 3 Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan Correspondence to: Yoshihiko Hirohashi, e-mail: hirohash@sapmed.ac.jp Toshihiko Torigoe, e-mail: torigoe@sapmed.ac.jp Keywords: ovarian cancer, cancer stem cell, MMP10, chemoresistance Received: August 26, 2015      Accepted: March 2, 2016      Published: April 08, 2016 ABSTRACT Epithelial ovarian cancer (EOC) is one of the most lethal cancers in females. Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) have been reported to be origin of primary and recurrent cancers and to be resistant to several treatments. In this study, we identified matrix metalloproteinase-10 (MMP10) is expressed in CSCs/CICs of EOC. An immunohistochemical study revealed that a high expression level of MMP10 is a marker for poor prognosis and platinum resistance in multivariate analysis. MMP10 gene overexpression experiments and MMP10 gene knockdown experiments using siRNAs revealed that MMP10 has a role in the maintenance of CSCs/CICs in EOC and resistance to platinum reagent. Furthermore, MMP10 activate canonical Wnt signaling by inhibiting noncanonical Wnt signaling ligand Wnt5a. Therefore, MMP10 is a novel marker for CSCs/CICs in EOC and that targeting MMP10 is a novel promising approach for chemotherapy-resistant CSCs/CICs in EOC.