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Upregulated FoxM1 expression induced by hepatitis B virus X protein promotes tumor metastasis and indicates poor prognosis in hepatitis B virus-related hepatocellular carcinoma.
J Hepatol. 2012 Sep; 57(3):600-12.JH

Abstract

BACKGROUND & AIMS

Forkhead box M1 (FoxM1) is a master regulator of tumor metastasis that plays an important role in the development of hepatocellular carcinoma (HCC). However, whether or not FoxM1 contributes to the progression of HBV-associated HCC (HBV-HCC) remains unknown. Therefore, we aimed at investigating the clinicopathologic significance of FoxM1 in HBV-HCC and the potential role of FoxM1 in hepatitis B virus X (HBx)-mediated invasiveness and metastasis.

METHODS

The expression of FoxM1 and its functional targets matrix metalloproteinase-7 (MMP-7), RhoC, and Rho-kinase 1 (ROCK1) in human HBV-HCC tissues was detected by immunohistochemistry. Luciferase reporter, chromatin immunoprecipitation, and electrophoretic mobility shift assays were used to measure the transcriptional regulation of FoxM1 promoter by HBx. The effect of FoxM1 on HBx-mediated invasiveness and metastasis was analyzed by transwell assays and an orthotopic metastatic model.

RESULTS

FoxM1 overexpression correlated with multiple malignant characteristics and indicated poor prognosis of HBV-HCC patients. FoxM1 expression was an independent factor affecting the recurrence and survival of patients with HBV-HCC after surgical resection. FoxM1 promoted hepatoma cell invasion and metastasis by promoting MMP-7, RhoC, and ROCK1 expression, while FoxM1 overexpression was associated with elevated expressions of these proteins in HBV-HCC tissues. HBx upregulated FoxM1 expression through the ERK/CREB pathway, and FoxM1 inhibition significantly decreased HBx-enhanced hepatoma cell invasion in vitro and lung metastasis in vivo.

CONCLUSIONS

We report a new molecular mechanism for HBV-associated hepatocarcinogenesis that involves the activation of FoxM1 expression by HBx through the ERK/CREB pathway, thereby leading to invasion and metastasis of hepatoma cells.

Authors+Show Affiliations

State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, People's Republic of China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

22613004

Citation

Xia, Limin, et al. "Upregulated FoxM1 Expression Induced By Hepatitis B Virus X Protein Promotes Tumor Metastasis and Indicates Poor Prognosis in Hepatitis B Virus-related Hepatocellular Carcinoma." Journal of Hepatology, vol. 57, no. 3, 2012, pp. 600-12.
Xia L, Huang W, Tian D, et al. Upregulated FoxM1 expression induced by hepatitis B virus X protein promotes tumor metastasis and indicates poor prognosis in hepatitis B virus-related hepatocellular carcinoma. J Hepatol. 2012;57(3):600-12.
Xia, L., Huang, W., Tian, D., Zhu, H., Zhang, Y., Hu, H., Fan, D., Nie, Y., & Wu, K. (2012). Upregulated FoxM1 expression induced by hepatitis B virus X protein promotes tumor metastasis and indicates poor prognosis in hepatitis B virus-related hepatocellular carcinoma. Journal of Hepatology, 57(3), 600-12. https://doi.org/10.1016/j.jhep.2012.04.020
Xia L, et al. Upregulated FoxM1 Expression Induced By Hepatitis B Virus X Protein Promotes Tumor Metastasis and Indicates Poor Prognosis in Hepatitis B Virus-related Hepatocellular Carcinoma. J Hepatol. 2012;57(3):600-12. PubMed PMID: 22613004.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Upregulated FoxM1 expression induced by hepatitis B virus X protein promotes tumor metastasis and indicates poor prognosis in hepatitis B virus-related hepatocellular carcinoma. AU - Xia,Limin, AU - Huang,Wenjie, AU - Tian,Dean, AU - Zhu,Hongwu, AU - Zhang,Yongguo, AU - Hu,Hao, AU - Fan,Daiming, AU - Nie,Yongzhan, AU - Wu,Kaichun, Y1 - 2012/05/18/ PY - 2011/10/05/received PY - 2012/04/04/revised PY - 2012/04/06/accepted PY - 2012/5/23/entrez PY - 2012/5/23/pubmed PY - 2013/2/28/medline SP - 600 EP - 12 JF - Journal of hepatology JO - J. Hepatol. VL - 57 IS - 3 N2 - BACKGROUND & AIMS: Forkhead box M1 (FoxM1) is a master regulator of tumor metastasis that plays an important role in the development of hepatocellular carcinoma (HCC). However, whether or not FoxM1 contributes to the progression of HBV-associated HCC (HBV-HCC) remains unknown. Therefore, we aimed at investigating the clinicopathologic significance of FoxM1 in HBV-HCC and the potential role of FoxM1 in hepatitis B virus X (HBx)-mediated invasiveness and metastasis. METHODS: The expression of FoxM1 and its functional targets matrix metalloproteinase-7 (MMP-7), RhoC, and Rho-kinase 1 (ROCK1) in human HBV-HCC tissues was detected by immunohistochemistry. Luciferase reporter, chromatin immunoprecipitation, and electrophoretic mobility shift assays were used to measure the transcriptional regulation of FoxM1 promoter by HBx. The effect of FoxM1 on HBx-mediated invasiveness and metastasis was analyzed by transwell assays and an orthotopic metastatic model. RESULTS: FoxM1 overexpression correlated with multiple malignant characteristics and indicated poor prognosis of HBV-HCC patients. FoxM1 expression was an independent factor affecting the recurrence and survival of patients with HBV-HCC after surgical resection. FoxM1 promoted hepatoma cell invasion and metastasis by promoting MMP-7, RhoC, and ROCK1 expression, while FoxM1 overexpression was associated with elevated expressions of these proteins in HBV-HCC tissues. HBx upregulated FoxM1 expression through the ERK/CREB pathway, and FoxM1 inhibition significantly decreased HBx-enhanced hepatoma cell invasion in vitro and lung metastasis in vivo. CONCLUSIONS: We report a new molecular mechanism for HBV-associated hepatocarcinogenesis that involves the activation of FoxM1 expression by HBx through the ERK/CREB pathway, thereby leading to invasion and metastasis of hepatoma cells. SN - 1600-0641 UR - https://www.unboundmedicine.com/medline/citation/22613004/Upregulated_FoxM1_expression_induced_by_hepatitis_B_virus_X_protein_promotes_tumor_metastasis_and_indicates_poor_prognosis_in_hepatitis_B_virus_related_hepatocellular_carcinoma_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0168-8278(12)00342-X DB - PRIME DP - Unbound Medicine ER -