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

ABSTRACT: Great progress has been achieved in the study of the role of TGF-? signaling in triggering epithelial-mesenchymal transition (EMT) in a variety of cancers; however, the regulation of TGF-? 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-? 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-? 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-? 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.

SUBMITTER: Wu RS

PROVIDER: S-EPMC5503621 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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

Wu Rong-Si RS Hong Jing-Jing JJ Wu Jia-Fa JF Yan Shen S Wu Di D Liu Na N Liu Qing-Feng QF Wu Qiu-Wan QW Xie Yuan-Yuan YY Liu Yun-Jia YJ Zheng Zhong-Zheng ZZ Chan Err-Cheng EC Zhang Zhi-Ming ZM Li Bo-An BA

Oncotarget 20170601 24

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 ...[more]

PMID: 28455959

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Project description:Rationale: Metastasis is the leading cause of disease-related death among patients with nasopharyngeal carcinoma (NPC). Mounting evidence suggest that epithelial-mesenchymal transition (EMT) is crucial for cancer cells to acquire metastatic ability. In this study, we aim to clarify the extent to which EMT is involved in various cancer properties and identify novel markers for predicting the prognosis of NPC patients. Methods: Two cellular models derived from the same NPC cell line with distinct metastasis ability were used for microarray analysis to identify key transcriptional factors that drive metastasis. Cell migration and invasion were analyzed by wound healing and Transwell analysis. Lung metatasis was determined by tail vein injection assay. Cancer stemness was analyzed using colony formation and xenograft assay. The EMT extent was evaluated using immunoblotting, RT-qPCR and immunofluorescence of EMT markers. The value of OVOL2 in prognosis was determined by immunohistochemistry in NPC biopsies. Results: OVOL2 was the most significantly down-regulated EMT transcription factor (EMT-TF) in cellular models of NPC metatasis. Low levels of OVOL2 were associated with poor overall survival of NPC patients and the reduced expression is partly due to promoter methylation and epithelial dedifferentiation. Knockout of OVOL2 in epithelial-like NPC cells partially activates EMT program and significantly promotes cancer stemness and metastatic phenotypes. Conversely, ectopically expression of OVOL2 in mesenchymal-like cells leads to a partial transition to an epithelial phenotype and reduced malignancy. Reversing EMT by depleting ZEB1, a major target of OVOL2, does not eliminate the stemness advantage of OVOL2-deficient cells but does reduce their invasion capacity. A comparison of subpopulations at different stages of EMT revealed that the extent of EMT is positively correlated with metastasis and drug resistance; however, only the intermediate EMT state is associated with cancer stemness. Conclusion: Distinct from other canonical EMT-TFs, OVOL2 only exhibits modest effect on EMT but has a strong impact on both metastasis and tumorigenesis. Therefore, OVOL2 could serve as a prognostic indicator for cancer patients.

Dataset Information

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

Publications

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

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