title: Upregulated FoxM1 expression induced by hepatitis B virus X protein promotes tumor metastasis and indicates poor prognosis in hepatitis B virus-related hepatocellular carcinoma.
abstract: OBJECTIVE
  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.affiliation: 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.
authors.forename: Limin
authors.initials: L
authors.lastname: Xia
authors.forename: Wenjie
authors.initials: W
authors.lastname: Huang
authors.forename: Dean
authors.initials: D
authors.lastname: Tian
authors.forename: Hongwu
authors.initials: H
authors.lastname: Zhu
authors.forename: Yongguo
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.forename: Daiming
authors.initials: D
authors.lastname: Fan
authors.forename: Yongzhan
authors.initials: Y
authors.lastname: Nie
authors.forename: Kaichun
authors.initials: K
authors.lastname: Wu
mesh_terms: D000328:Adult; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000556:secondary* / Q000821:virology; D045744:Cell Line, Tumor; D002465:Cell Movement; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006515:Hepatitis B virus / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000821:virology; D008175:Lung Neoplasms / Q000556:secondary*; D020935:MAP Kinase Signaling System; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D015534:Trans-Activators / Q000378:metabolism*; D015854:Up-Regulation; D054334:Viral Regulatory and Accessory Proteins; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D000075024:rhoC GTP-Binding Protein
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D054460:rho-Associated Kinases; D020783:Matrix Metalloproteinase 7; C066690:RHOC protein, human; D020741:rho GTP-Binding Proteins; D000075024:rhoC GTP-Binding Protein