A double-negative feedback loop between Wnt-β-catenin signaling and HNF4α regulates epithelial-mesenchymal transition in hepatocellular carcinoma

• Published in: Journal of cell science Vol. 126; no. Pt 24; pp. 5692 - 5703
• Main Authors: Yang, Meng, Li, Sheng-Nan, Anjum, Khalid M, Gui, Long-Xin, Zhu, Shan-Shan, Liu, Jun, Chen, Jia-Kun, Liu, Qing-Feng, Ye, Guo-Dong, Wang, Wen-Jie, Wu, Jia-Fa, Cai, Wang-Yu, Sun, Guang-Bin, Liu, Yun-Jia, Liu, Rong-Fu, Zhang, Zhi-Ming, Li, Bo-An
• Format: Journal Article
• Language: English
• Published: England 15.12.2013
• Subjects: Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; beta Catenin - metabolism; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition; Feedback, Physiological; Gene Expression Regulation, Neoplastic; HEK293 Cells; Hepatocyte Nuclear Factor 4 - metabolism; Humans; Liver Neoplasms, Experimental - metabolism; Liver Neoplasms, Experimental - pathology; Male; Protein Binding; Rats; Rats, Wistar; Snail Family Transcription Factors; Transcription Factor 4; Transcription Factors - metabolism; Wnt Signaling Pathway; Epithelial-mesenchymal transition; Hepatocellular carcinoma; HNF4α; Wnt–β-catenin signaling
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.135053

Wnt-β-catenin signaling participates in the epithelial-mesenchymal transition (EMT) in a variety of cancers; however, its involvement in hepatocellular carcinoma (HCC) and downstream molecular events is largely undefined. HNF4α is the most prominent and specific factor maintaining the differentiation of hepatic lineage cells and a potential EMT regulator in HCC cells. However, the molecular mechanisms by which HNF4α maintains the differentiated liver epithelium and inhibits EMT have not been completely defined. In this study, we systematically explored the relationship between Wnt-β-catenin signaling and HNF4α in the EMT process of HCC cells. Our results indicated that HNF4α expression was negatively regulated during Wnt-β-catenin signaling-induced EMT through Snail and Slug in HCC cells. In contrast, HNF4α was found to directly associate with TCF4 to compete with β-catenin but facilitate transcription co-repressor activities, thus inhibiting expression of EMT-related Wnt-β-catenin targets. Moreover, HNF4α may control the switch between the transcriptional and adhesion functions of β-catenin. Overexpression of HNF4α was found to completely compromise the Wnt-β-catenin-signaling-induced EMT phenotype. Finally, we determined the regulation pattern between Wnt-β-catenin signaling and HNF4α in rat tumor models. Our studies have identified a double-negative feedback mechanism controlling Wnt-β-catenin signaling and HNF4α expression in vitro and in vivo, which sheds new light on the regulation of EMT in HCC. The modulation of these molecular processes may be a method of inhibiting HCC invasion by blocking Wnt-β-catenin signaling or restoring HNF4α expression to prevent EMT.