OVOL2 antagonizes TGF-β signaling to regulate epithelial to mesenchymal transition during mammary tumor metastasis.

// Rong-Si Wu 1, 3, * , Jing-Jing Hong 1, 3, * , Jia-Fa Wu 1, 4, * , Shen Yan 1, 3, * , Di Wu 1, 3 , Na Liu 2 , Qing-Feng Liu 1, 3 , Qiu-Wan Wu 2 , Yuan-Yuan Xie 1, 3 , Yun-Jia Liu 1, 3 , Zhong-Zheng Zheng 1, 3 , Err-Cheng Chan 5 , Zhi-Ming Zhang 2 and Bo-An Li 1, 3 1 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China 2 The First Affiliated Hospital, Xiamen University, Xiamen, Fujian, China 3 Engineering Research Center of Molecular Diagnostics, Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, China 4 College of Food and Bioengineering, Henan University of Science and Technology, Luoyang, China 5 Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, Taiwan * These authors have contributed equally to this work Correspondence to: Bo-An Li, email: bali@xmu.edu.cn Zhi-Ming Zhang, email: zhangzhiming164@yahoo.cn Err-Cheng Chan, email: chanec@mail.cgu.edu.tw Keywords: mammary tumor, EMT, OVOL2, TGF-β signaling, Smad4 Received: August 23, 2016      Accepted: March 09, 2017      Published: April 11, 2017 ABSTRACT Great progress has been achieved in the study of the role of TGF-β signaling in triggering epithelial-mesenchymal transition (EMT) in a variety of cancers; however, the regulation of TGF-β signaling during EMT in mammary tumor metastasis has not been completely defined. In the present study, we demonstrated that OVOL2, a zinc finger transcription factor, inhibits TGF-β signaling-induced EMT in mouse and human mammary tumor cells, as well as in mouse tumor models. Data from the Oncomine databases indicated a strong negative relationship between OVOL2 expression and breast cancer progression. Moreover, our experiments revealed that OVOL2 inhibits TGF-β signaling at multiple levels, including inhibiting Smad4 mRNA expression and inducing Smad7 mRNA expression, blocking the binding between Smad4 and target DNA, and interfering with complex formation between Smad4 and Smad2/3. These findings reveal a novel mechanism that controls the TGF-β signaling output level in vitro and in vivo . The modulation of these molecular processes may represent a strategy for inhibiting breast cancer invasion by restoring OVOL2 expression.