Tg737 regulates epithelial–mesenchymal transition and cancer stem cell properties via a negative feedback circuit between Snail and HNF4α during liver stem cell malignant transformation. (28th August 2017)

• Record Type: Journal Article
• Authors: Huang, Qike; Pu, Meng; Zhao, Ge; Dai, Bin; Bian, Zhenyuan; Tang, Haili; Chen, Chong; Liu, Wei; Qu, Xuan; Shen, Liangliang; Tao, Kaishan
• Is Part Of: Cancer letters. Volume 402(2017)
• Page Start: 52
• Page End: 60
• Publication Date: 2017-08-28
• Subjects: Tg737 -- Epithelial–mesenchymal transition -- Snail -- HNF4α -- Liver stem cells; ALB albumin -- AFP alpha-fetoprotein -- CSCs cancer stem cells -- DEN diethyl nitrosamine -- EMT epithelial–mesenchymal transition -- FCM flow cytometry -- FLSPCs fetal liver stem/progenitor cells -- HCC hepatocellular carcinoma -- HNF4α hepatocyte nuclear factor 4-alpha -- HOCs hepatic oval cells -- IFT88 intraflagellar transport 88 -- LSCs liver stem cells -- LCSCs liver cancer stem cells -- WB WB-F344 cells -- TSS transcriptional start site; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2017.05.005
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Determining the origin of liver cancer stem cells is important for treating hepatocellular carcinoma. Tg737 deficiency plays an important role in the malignant transformation of liver stem cells, but the underlying mechanism remains unclear. Here we established a chemical-induced mouse hepatoma model and found that Tg737 and hepatocyte nuclear factor 4-alpha (HNF4α) expression decreased and epithelial–mesenchymal transition (EMT)-related marker expression increased during liver cancer development. To investigate the underlying mechanism, we knocked down Tg737 in WB-F344 (WB) rat hepatic oval cells. Loss of Tg737 resulted in nuclear β-catenin accumulation and activation of the Wnt/β-catenin pathway, which further promoted EMT and the malignant phenotype. XAV939, a β-catenin inhibitor, attenuated WB cell malignant transformation due to Tg737 knockdown. To clarify the relationships of Tg737, the β-catenin pathway, and HNF4α, we inhibited Snail and overexpressed HNF4α after Tg737 knockdown in WB cells and found that Snail and HNF4α comprise a negative feedback circuit. Taken together, the results showed that Tg737 regulates a Wnt/β-catenin/Snail-HNF4α negative feedback circuit, thereby blocking EMT and the malignant transformation of liver stem cells to liver cancer stem cells. Highlights: Tg737 and HNF4α are lowly expressed in the chemical-induced mouse hepatoma tissue and associated with EMT-related markers. Loss of Tg737 promotes liver cancer stem cell properties of WB cells. Tg737 blocks the activation of Wnt/β-catenin pathway, and consequently abolished Snail expression and EMT phenotype. Wnt/β-catenin/Snail and HNF4α forms a negative feedback circuit, which is regulated by Tg737 during liver stem cell malignant transformation.