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

Autor: Zhenyuan Bian, Ge Zhao, Qike Huang, Liangliang Shen, Xuan Qu, Bin Dai, Meng Pu, Haili Tang, Kaishan Tao, Chong Chen, Wei Liu
Rok vydání: 2017
Předmět:
0301 basic medicine
Male
Cancer Research
Pathology
medicine.medical_specialty
Carcinoma
Hepatocellular
Epithelial-Mesenchymal Transition
Time Factors
Cell
Liver Stem Cell
Apoptosis
Biology
Transfection
Malignant transformation
Cell Line
03 medical and health sciences
Cancer stem cell
medicine
Animals
Diethylnitrosamine
Epithelial–mesenchymal transition
Wnt Signaling Pathway
Cell Proliferation
Feedback
Physiological
Mice
Inbred BALB C
Tumor Suppressor Proteins
Liver Neoplasms
Wnt signaling pathway
medicine.disease
Rats
Inbred F344
Gene Expression Regulation
Neoplastic
030104 developmental biology
medicine.anatomical_structure
Cell Transformation
Neoplastic
Phenotype
Oncology
Hepatocyte Nuclear Factor 4
Liver
Cancer research
Neoplastic Stem Cells
RNA Interference
Snail Family Transcription Factors
Stem cell
Liver cancer
Zdroj: Cancer letters. 402
ISSN: 1872-7980
Popis: 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.
Databáze: OpenAIRE
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