title: Severe Hepatitis Promotes Hepatocellular Carcinoma Recurrence via NF-κB Pathway-Mediated Epithelial-Mesenchymal Transition after Resection.
abstract: OBJECTIVE
  Surgical resection is considered as a curative treatment modality for hepatocellular carcinoma; however, the incidence of postoperative tumor recurrence is high, leading to worse patient survival. Persistent hepatitis (inflammation) is one of the risk factors of tumor recurrence after surgical resection. The aim of this study is to investigate the underlying mechanisms linking liver inflammation to hepatocellular carcinoma progression.
  
  
  METHODS
  In this study, we used a cytokine array to identify important cytokines whose levels are increased in liver microenvironment with severe hepatitis. We evaluated the morphologic changes, migration and invasion ability, and signal transduction in hepatocellular carcinoma cells with or without inflammatory cytokine in vitro Finally, we analyzed the NF-κB signal pathway in tumor specimens from 232 patients with hepatocellular carcinoma by immunohistochemical staining.
  
  
  RESULTS
  The proinflammatory cytokine TNFα was increased in the peritumoral microenvironment and contributed to tumor recurrence and metastasis. Specifically, TNFα promoted hepatocellular carcinoma cancer cell migration, invasion, and epithelial-mesenchymal transition (EMT) by upregulating the transcriptional regulator, Snail. We identified Snail as a direct target gene downstream of the TNFα-mediated canonical NF-κB activation. In addition, tumor recurrence-free survival of hepatocellular carcinoma patients correlated negatively with high p65 and Snail expression and positively with high E-cadherin expression.
  
  
  CONCLUSIONS
  Our results establish a signaling axis that explains how inflammatory tumor microenvironment promotes hepatocellular carcinoma recurrence and metastasis. These findings suggest that controlling liver inflammation and/or targeting NF-κB-mediated Snail expression may be a potential therapeutic strategy to prevent hepatocellular carcinoma recurrence after hepatectomy.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Division of Liver and Transplantation Surgery, Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University Medical School, Taoyuan, Taiwan.
authors.forename: Ting-Jung
authors.initials: TJ
authors.lastname: Wu
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.
authors.forename: Shih-Shin
authors.initials: SS
authors.lastname: Chang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yi-Hsin
authors.initials: YH
authors.lastname: Hsu
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
authors.forename: Tse-Ching
authors.initials: TC
authors.lastname: Chen
authors.affiliation: Division of Liver and Transplantation Surgery, Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University Medical School, Taoyuan, Taiwan.
authors.forename: Wei-Chen
authors.initials: WC
authors.lastname: Lee
authors.affiliation: Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
authors.forename: Chau-Ting
authors.initials: CT
authors.lastname: Yeh
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas. Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan. Department of Biotechnology, Asia University, Taichung, Taiwan. mhung@mdanderson.org.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D006505:Hepatitis / Q000150:complications* / Q000175:diagnosis; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D016328:NF-kappa B / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local; D012720:Severity of Illness Index; D000071250:Snail Family Transcription Factors / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D000071250:Snail Family Transcription Factors; D051996:Transcription Factor RelA