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FoxM1 overexpression promotes epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma.
World J Gastroenterol. 2015 Jan 07; 21(1):196-213.WJ

Abstract

AIM

To investigate the expression of forkhead box protein M1 (FoxM1) in the process of epithelial mesenchymal transition in hepatocellular carcinoma (HCC) and its role in metastasis.

METHODS

FoxM1 and E-cadherin expression in HCC tissue microarray specimens was evaluated by immunohistochemical staining, and statistical methods were applied to analyze the correlation between FoxM1 and epithelial-mesenchymal transition (EMT). Kaplan-Meier analysis of the correlation between the FoxM1 expression level and recurrence or overall survival of HCC patients was performed. The expression of FoxM1, E-cadherin and snail homologue 1 (SNAI1) in HCC cell lines was evaluated by real-time reverse transcription-polymerase chain reaction and Western blot. Hepatocyte growth factor (HGF) was used to induce EMT and stimulate cell migration in HCC cells. The expression of FoxM1 and SNAI1 was regulated by transfection with plasmids pcDNA3.1 and siRNAs in vitro. The occurrence of EMT was evaluated by Transwell assay, morphologic analysis and detection of the expression of EMT markers (E-cadherin and vimentin). Luciferase and chromatin immunoprecipitation assays were used to evaluate whether SNAI1 is a direct transcriptional target of FoxM1.

RESULTS

FoxM1 expression was increased significantly in HCC compared with para-carcinoma (10.7 ± 0.9 vs 8.2 ± 0.7, P < 0.05) and normal hepatic (10.7 ± 0.9 vs 2.7 ± 0.4, P < 0.05) tissues. Overexpression of FoxM1 was correlated with HCC tumor size, tumor number, macrovascular invasion and higher TNM stage, but was negatively correlated with E-cadherin expression in microarray specimens and in cell lines. FoxM1 overexpression was correlated significantly with HCC metastasis and EMT. In vitro, we found that FoxM1 plays a key role in HGF-induced EMT, and overexpression of FoxM1 could suppress E-cadherin expression and induce EMT changes, which were associated with increased HCC cell invasiveness. Next, we confirmed that FOXM1 directly binds to and activates the SNAI1 promoter, and we identified SNAI1 as a direct transcriptional target of FOXM1. Moreover, inhibiting the expression of SNAI1 significantly inhibited FoxM1-mediated EMT.

CONCLUSION

FoxM1 overexpression promotes EMT and metastasis of HCC, and SNAI1 plays a critical role in FoxM1-mediated EMT.

Authors+Show Affiliations

Fan-Di Meng, Ji-Chao Wei, Kai Qu, Zhi-Xin Wang, Ming-Hui Tai, Hao-Chen Liu, Rui-Yao Zhang, Chang Liu, Department of Hepatobiliary Surgery, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.Fan-Di Meng, Ji-Chao Wei, Kai Qu, Zhi-Xin Wang, Ming-Hui Tai, Hao-Chen Liu, Rui-Yao Zhang, Chang Liu, Department of Hepatobiliary Surgery, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.Fan-Di Meng, Ji-Chao Wei, Kai Qu, Zhi-Xin Wang, Ming-Hui Tai, Hao-Chen Liu, Rui-Yao Zhang, Chang Liu, Department of Hepatobiliary Surgery, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.Fan-Di Meng, Ji-Chao Wei, Kai Qu, Zhi-Xin Wang, Ming-Hui Tai, Hao-Chen Liu, Rui-Yao Zhang, Chang Liu, Department of Hepatobiliary Surgery, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.Fan-Di Meng, Ji-Chao Wei, Kai Qu, Zhi-Xin Wang, Ming-Hui Tai, Hao-Chen Liu, Rui-Yao Zhang, Chang Liu, Department of Hepatobiliary Surgery, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.Fan-Di Meng, Ji-Chao Wei, Kai Qu, Zhi-Xin Wang, Ming-Hui Tai, Hao-Chen Liu, Rui-Yao Zhang, Chang Liu, Department of Hepatobiliary Surgery, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.Fan-Di Meng, Ji-Chao Wei, Kai Qu, Zhi-Xin Wang, Ming-Hui Tai, Hao-Chen Liu, Rui-Yao Zhang, Chang Liu, Department of Hepatobiliary Surgery, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.Fan-Di Meng, Ji-Chao Wei, Kai Qu, Zhi-Xin Wang, Ming-Hui Tai, Hao-Chen Liu, Rui-Yao Zhang, Chang Liu, Department of Hepatobiliary Surgery, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.Fan-Di Meng, Ji-Chao Wei, Kai Qu, Zhi-Xin Wang, Ming-Hui Tai, Hao-Chen Liu, Rui-Yao Zhang, Chang Liu, Department of Hepatobiliary Surgery, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25574092

Citation

Meng, Fan-Di, et al. "FoxM1 Overexpression Promotes Epithelial-mesenchymal Transition and Metastasis of Hepatocellular Carcinoma." World Journal of Gastroenterology, vol. 21, no. 1, 2015, pp. 196-213.
Meng FD, Wei JC, Qu K, et al. FoxM1 overexpression promotes epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma. World J Gastroenterol. 2015;21(1):196-213.
Meng, F. D., Wei, J. C., Qu, K., Wang, Z. X., Wu, Q. F., Tai, M. H., Liu, H. C., Zhang, R. Y., & Liu, C. (2015). FoxM1 overexpression promotes epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma. World Journal of Gastroenterology, 21(1), 196-213. https://doi.org/10.3748/wjg.v21.i1.196
Meng FD, et al. FoxM1 Overexpression Promotes Epithelial-mesenchymal Transition and Metastasis of Hepatocellular Carcinoma. World J Gastroenterol. 2015 Jan 7;21(1):196-213. PubMed PMID: 25574092.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - FoxM1 overexpression promotes epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma. AU - Meng,Fan-Di, AU - Wei,Ji-Chao, AU - Qu,Kai, AU - Wang,Zhi-Xin, AU - Wu,Qi-Fei, AU - Tai,Ming-Hui, AU - Liu,Hao-Chen, AU - Zhang,Rui-Yao, AU - Liu,Chang, PY - 2014/07/02/received PY - 2014/08/19/revised PY - 2014/10/15/accepted PY - 2015/1/10/entrez PY - 2015/1/13/pubmed PY - 2015/9/15/medline KW - E-cadherin KW - Epithelial-mesenchymal transition KW - Forkhead box protein M1 KW - Hepatocellular carcinoma KW - Snail homolog 1 SP - 196 EP - 213 JF - World journal of gastroenterology JO - World J Gastroenterol VL - 21 IS - 1 N2 - AIM: To investigate the expression of forkhead box protein M1 (FoxM1) in the process of epithelial mesenchymal transition in hepatocellular carcinoma (HCC) and its role in metastasis. METHODS: FoxM1 and E-cadherin expression in HCC tissue microarray specimens was evaluated by immunohistochemical staining, and statistical methods were applied to analyze the correlation between FoxM1 and epithelial-mesenchymal transition (EMT). Kaplan-Meier analysis of the correlation between the FoxM1 expression level and recurrence or overall survival of HCC patients was performed. The expression of FoxM1, E-cadherin and snail homologue 1 (SNAI1) in HCC cell lines was evaluated by real-time reverse transcription-polymerase chain reaction and Western blot. Hepatocyte growth factor (HGF) was used to induce EMT and stimulate cell migration in HCC cells. The expression of FoxM1 and SNAI1 was regulated by transfection with plasmids pcDNA3.1 and siRNAs in vitro. The occurrence of EMT was evaluated by Transwell assay, morphologic analysis and detection of the expression of EMT markers (E-cadherin and vimentin). Luciferase and chromatin immunoprecipitation assays were used to evaluate whether SNAI1 is a direct transcriptional target of FoxM1. RESULTS: FoxM1 expression was increased significantly in HCC compared with para-carcinoma (10.7 ± 0.9 vs 8.2 ± 0.7, P < 0.05) and normal hepatic (10.7 ± 0.9 vs 2.7 ± 0.4, P < 0.05) tissues. Overexpression of FoxM1 was correlated with HCC tumor size, tumor number, macrovascular invasion and higher TNM stage, but was negatively correlated with E-cadherin expression in microarray specimens and in cell lines. FoxM1 overexpression was correlated significantly with HCC metastasis and EMT. In vitro, we found that FoxM1 plays a key role in HGF-induced EMT, and overexpression of FoxM1 could suppress E-cadherin expression and induce EMT changes, which were associated with increased HCC cell invasiveness. Next, we confirmed that FOXM1 directly binds to and activates the SNAI1 promoter, and we identified SNAI1 as a direct transcriptional target of FOXM1. Moreover, inhibiting the expression of SNAI1 significantly inhibited FoxM1-mediated EMT. CONCLUSION: FoxM1 overexpression promotes EMT and metastasis of HCC, and SNAI1 plays a critical role in FoxM1-mediated EMT. SN - 2219-2840 UR - https://www.unboundmedicine.com/medline/citation/25574092/FoxM1_overexpression_promotes_epithelial_mesenchymal_transition_and_metastasis_of_hepatocellular_carcinoma_ L2 - https://www.wjgnet.com/1007-9327/full/v21/i1/196.htm DB - PRIME DP - Unbound Medicine ER -