کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5525218 | 1546667 | 2017 | 9 صفحه PDF | دانلود رایگان |
- 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.
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.
Journal: Cancer Letters - Volume 402, 28 August 2017, Pages 52-60