Oncotarget

Research Papers:

The impact of EpCAM expression on response to chemotherapy and clinical outcomes in patients with epithelial ovarian cancer

Shingo Tayama, Takeshi Motohara _, Dashdemberel Narantuya, Chenyan Li, Koichi Fujimoto, Isao Sakaguchi, Hironori Tashiro, Hideyuki Saya, Osamu Nagano and Hidetaka Katabuchi

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Oncotarget. 2017; 8:44312-44325. https://doi.org/10.18632/oncotarget.17871

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Abstract

Shingo Tayama1,*, Takeshi Motohara1,*, Dashdemberel Narantuya1, Chenyan Li1, Koichi Fujimoto1, Isao Sakaguchi1, Hironori Tashiro2, Hideyuki Saya3, Osamu Nagano3 and Hidetaka Katabuchi1

1Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, Chuo-Ku, Kumamoto 860-8556, Japan

2Department of Maternal-Newborn Nursing, Kumamoto University, Chuo-Ku, Kumamoto 860-0976, Japan

3Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-Ku, Tokyo 160-8582, Japan

*These authors contributed equally to this work

Correspondence to:

Takeshi Motohara, email: [email protected]

Keywords: ovarian cancer, cancer stem cell, EpCAM, chemoresistance, prognosis

Received: October 09, 2016     Accepted: April 29, 2017     Published: May 15, 2017

ABSTRACT

Epithelial ovarian cancer is a highly lethal malignancy; moreover, overcoming chemoresistance is the major challenging in treating ovarian cancer patients. The cancer stem cell (CSC) hypothesis considers CSCs to be the main culprits in driving tumor initiation, metastasis, and resistance to conventional therapy. Although growing evidence suggest that CSCs are responsible for chemoresistance, the contribution of CSC marker EpCAM to resistance to chemotherapy remains unresolved.

Here we have demonstrated that ovarian cancers containing high levels of EpCAM have a significantly much lower probability of achieving overall responsive rates after first-line chemotherapy. In addition, multivariate analysis revealed that EpCAM expression is an independent risk factor for chemoresistance, indicating that EpCAM expression is a predictive biomarker of chemotherapeutic response. Consistent with these clinical observations, in vitro assays, we found that the subpopulation of EpCAM-positive ovarian cancer cells shows a significantly higher viability compared with EpCAM-negative cells in response to cisplatin treatment by preventing chemotherapy-induced apoptosis, which is regulated by EpCAM-Bcl-2 axis. Furthermore, in an in vivo mouse model, platinum agents preferentially eliminated EpCAM-negative cells in comparison with EpCAM-positive cells, suggesting that the remaining subpopulation of EpCAM-positive cells contributes to tumor recurrence after chemotherapy. Finally, we also found that an increased expression of EpCAM is associated with poor prognosis in ovarian cancer patients.

Our findings highlight the clinical significance of EpCAM in the resistance to chemotherapy and provide a rationale for EpCAM-targeted therapy to improve chemoresistance. Targeting EpCAM should be a promising approach to effectively extirpate the CSCs as the putative root of ovarian cancer.


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