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

Rong-Si Wu,Jia-Fa Wu,Err-Cheng Chan,Zhong-Zheng Zheng,Na Liu,Shen Yan,Qiu-Wan Wu,Bo-An Li,Yun-Jia Liu,Qing-Feng Liu,Di Wu,Yuan-Yuan Xie,Jing-Jing Hong,Zhi-Ming Zhang

doi:10.18632/oncotarget.17031

Rong-Si Wu, Jia-Fa Wu + Show 12 more

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https://doi.org/10.18632/oncotarget.17031

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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.

Highlights

Tumor invasion and metastasis are the result of a complex process that involves local invasion, intravasation, transport, extravasation, micro-metastasis formation, and colonization [1, 2]
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; the regulation of TGF-β signaling during EMT in mammary tumor metastasis has not been completely defined
We further found that forced OVOL2 expression inhibited the TGF-β-induced upregulation of numerous EMT-related transcription factors and mesenchymal genes, such as Zeb1, Zeb2, Twist1, Twist2, Snai2, Fibronectin and Vimentin (Figure 1D), whereas knockdown of OVOL2 further enhanced TGFβ-induced upregulation of these genes (Supplementary Figure 1B)

Summary

Introduction

Tumor invasion and metastasis are the result of a complex process that involves local invasion, intravasation, transport, extravasation, micro-metastasis formation, and colonization [1, 2]. Due to the complex and dynamic nature of EMT and MET, multiple signaling pathways that are important for both normal development and cancer development, including TGF-β, Wnt/β-catenin, Notch, EGF, HGF, FGF, and HIF, have been implicated in the regulation of these processes [6, 8, 12]. These signaling pathways directly or indirectly activate many EMT-related transcription factors, such as SNAIL (SNAIL1), SLUG (SNAIL2), TWIST1/2, EF1/ ZEB1, SIP1/ZEB2, and E47, which subsequently inhibit E-cadherin production [6]

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