Research Papers:

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

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

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Oncotarget. 2017; 8:99482-99494. https://doi.org/10.18632/oncotarget.20107

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Jun Sakata1, Fumi Utsumi1, Shiro Suzuki1, Kaoru Niimi1, Eiko Yamamoto2, Kiyosumi Shibata3, Takeshi Senga4, Fumitaka Kikkawa1 and Hiroaki Kajiyama1

1Department of Obstetrics and Gynecology, Graduate School of Medicine, Nagoya University, Nagoya, Japan

2Department of Healthcare Administration, Graduate School of Medicine, Nagoya University, Nagoya, Japan

3Department of Obstetrics and Gynecology, Banbuntane Hotokukai, Fujita Health University, Fujita, Japan

4Division of Tumor Biology, Graduate School of Medicine, Nagoya University, Nagoya, Japan

Correspondence to:

Hiroaki Kajiyama, email: [email protected]

Keywords: epithelial ovarian carcinoma, epithelial-mesenchymal transition, ZEB1, chemoresistance, metastasis

Received: June 07, 2017     Accepted: July 25, 2017     Published: August 10, 2017


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.

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