Hepatocyte nuclear factor 6 suppresses the migration and invasive growth of lung cancer cells through p53 and the inhibition of epithelial-mesenchymal transition.

Abstract

Epithelial-mesenchymal transition plays an important role in many patho-physiological processes, including cancer invasion and metastatic progression. Hepatocyte nuclear factor 6 (HNF6) has been known to be an important factor for both physiological and pathological functions in liver and pancreas. However, its role in EMT and lung cancer progression remains unidentified. We observed that HNF6 level can be down-regulated by TGF-β1 in human lung cancer cells. Knockdown of HNF6 induced EMT and increased cell migration. In contrast, ectopically expression of HNF6 inhibited cell migration and attenuated TGF-β1-induced EMT. The data suggest that HNF6 plays a role in maintaining epithelial phenotype, which suppresses EMT. HNF6 also inhibits both colony formation and proliferation of lung cancer cells. It pronouncedly reduced the formation of tumor xenografts in nude mice. In addition, HNF6 can activate the promoter activity of p53 by directly binding to a specific region of its promoter and therefore increase the protein level of tumor suppressor p53. p53 knockdown induced EMT and increased cell migration, whereas the opposite effect was generated by p53 overexpression. p53 knockdown also inhibited the effect of HNF6 on EMT and cell migration, indicating that p53 is required for the functions of HNF6 herein. Moreover, there is a high positive correlation among the expression levels of HNF6, p53, and E-cadherin in human lung cancer cells and tissues. The data suggest that HNF6 inhibits EMT, cell migration, and invasive growth through a mechanism involving the transcriptional activation of p53.

• Authors: Xin-Wang Yuan, Dong-Mei Wang, Ying Hu, Yun-Neng Tang, Wei-Wei Shi, Xiao-Jie Guo, Jian-Guo Song
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 43 Pg. 31206-16 (Oct 25 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 24022481 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cadherins
• Hepatocyte Nuclear Factor 6
• TP53 protein, human
• Transforming Growth Factor beta1
• Tumor Suppressor Protein p53

Topics

• Adenocarcinoma (genetics, metabolism, pathology, therapy)
• Animals
• Cadherins (genetics, metabolism)
• Cell Line, Tumor
• Cell Movement
• Epithelial-Mesenchymal Transition
• Gene Expression Regulation, Neoplastic (genetics)
• Gene Knockdown Techniques
• Hepatocyte Nuclear Factor 6 (genetics, metabolism)
• Heterografts
• Humans
• Lung Neoplasms (genetics, metabolism, pathology, therapy)
• Mice
• Neoplasm Invasiveness
• Neoplasm Transplantation
• Transcriptional Activation (genetics)
• Transforming Growth Factor beta1 (genetics, metabolism)
• Tumor Suppressor Protein p53