Inhibition of ZEB1 leads to inversion of metastatic characteristics and restoration of paclitaxel sensitivity of chronic chemoresistant ovarian carcinoma cells

Jun Sakata,Kiyosumi Shibata,Eiko Yamamoto,Takeshi Senga,Fumi Utsumi,Shiro Suzuki,Hiroaki Kajiyama,Kaoru Niimi,Fumitaka Kikkawa

doi:10.18632/oncotarget.20107

Jun Sakata, Kiyosumi Shibata + Show 7 more

Open Access

https://doi.org/10.18632/oncotarget.20107

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Journal: Oncotarget	Publication Date: Aug 10, 2017
Citations: 35	License type: cc-by

Affiliation: Fujita Health University, Nagoya University

Abstract

ZEB1, a member of the zinc-finger E-box binding homeobox family, is considered to play a crucial role in cancer progression and metastasis. In the current study, we investigated the role of ZEB1 in metastasis and chronic chemoresistance of epithelial ovarian carcinoma (EOC) cells. Using several EOC and acquired paclitaxel (PTX)-resistant EOC cell lines, we investigated whether silencing ZEB1 led to a reversal of the chemoresistance and metastatic potential in vitro and in vivo. Subsequently, the expression of ZEB1 in EOC tissues and its association with the oncologic outcome were investigated. According to the immunohistochemical staining of EOC tissues, as the positivity of ZEB1 expression was increased, the overall survival of EOC patients became poorer (P = 0.0022 for trend). Additionally, cell migration and invasion were significantly decreased by ZEB1 silencing in both PTX-sensitive and PTX- resistant cells. Although PTX-sensitivity was not changed by silencing ZEB1 in parental EOC cells, the depletion of ZEB1 made the PTX-resistant EOC cells more sensitive to PTX treatment. In an animal model, mice injected with ZEB1-silencing PTX-resistant cells survived for longer than the control cell-injected mice. Although the intravenous injection of PTX did not affect the tumor weight of shCtrl cells, the tumor weight of shZEB1 cells was significantly reduced by PTX treatment. The current data indicate the possible involvement of ZEB1 in the metastasis and paclitaxel resistance of EOC, and suggest that targeting this molecule may reverse the malignant potential and improve the oncologic outcome for EOC patients.

Highlights

Epithelial ovarian carcinoma (EOC) is a major cause of mortality among all gynecological malignancies [1]
We investigated the role of ZEB1 in metastasis and chronic chemoresistance of epithelial ovarian carcinoma (EOC) cells
Most EOC patients with peritoneal dissemination are asymptomatic until the late stage, tumor dissemination throughout the peritoneal cavity gradually spreads underneath the surface

Summary

Introduction

Epithelial ovarian carcinoma (EOC) is a major cause of mortality among all gynecological malignancies [1]. The prognosis of patients with EOC is most likely related to the degree of peritoneal dissemination [3,4,5]. Since EOC often remains silent in clinical situations, the majority of patients show aggressive peritoneal dissemination at the time of diagnosis [6]. Reflecting the cell biology of EOC, despite the fact that complete clinical remission can be achieved in approximately 80% of these patients owing to cytoreductive surgery, followed by systematic front-line chemotherapy, the majority of those clinical complete responders develop recurrent disease [7]. If all EOC tumor cells have sufficient sensitivity to conventional chemotherapy, they will disappear in due course. Since the sensitivity of tumors www.impactjournals.com/oncotarget is heterogeneous, recurrence will eventually develop due to the remaining resistant tumor cells.

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