title: Clinical impact of herpesvirus entry mediator expression in human hepatocellular carcinoma.
abstract: BACKGROUND
  Herpes virus entry mediator (HVEM), also known as tumour necrosis factor receptor (TNFR) superfamily 14, regulates a variety of physiological and pathological responses in both innate and acquired immunity. Although HVEM is also suggested to be a critical regulator in tumours, actual roles in human cancer are largely unknown. This study aimed to clarify clinical importance of HVEM in human hepatocellular carcinoma (HCC).
  
  
  METHODS
  We studied HVEM expression in 150 HCC patients to explore its clinical relevance, and we examined tumour infiltrating T cells and local immune status of them.
  
  
  RESULTS
  HVEM was expressed in HCC cells, while no or only limited expression was observed in normal tissues in the liver. Tumour HVEM expression was significantly correlated with age, serum protein induced by vitamin K absence or antagonist-II (PIVKA-II) level, vascular invasion and tumour node metastasis (TNM) stage. Furthermore, tumour HVEM expression significantly correlated with postoperative recurrence and survival. Importantly, multivariate analysis indicated that the HVEM status had an independent prognostic value. Furthermore, HVEM status was inversely correlated with tumour-infiltrating CD4(+), CD8(+) and CD45RO(+) lymphocytes. In addition, it was also associated with reduced expression of perforin, granzyme B and interferon-γ (IFN-γ). Taken together, tumour-expressing HVEM plays a functionally important role in HCC.
  
  
  CONCLUSIONS
  Tumour-expressing HVEM plays a critical role in human HCC, possibly through regulating immune evasion. Therefore, targeting HVEM may be a novel promising therapeutic strategy for HCC.
authors.affiliation: Department of Surgery, Nara Medical University, Nara 6348522, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hokuto
authors.affiliation: Department of Surgery, Nara Medical University, Nara 6348522, Japan. Electronic address: m-sho@naramed-u.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sho
authors.affiliation: Department of Surgery, Nara Medical University, Nara 6348522, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yamato
authors.affiliation: Department of Surgery, Nara Medical University, Nara 6348522, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yasuda
authors.affiliation: Department of Surgery, Nara Medical University, Nara 6348522, Japan.
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Obara
authors.affiliation: Department of Surgery, Nara Medical University, Nara 6348522, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Nomi
authors.affiliation: Department of Surgery, Nara Medical University, Nara 6348522, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Nakajima
mesh_terms: D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D053804:Granzymes / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008207:Lymphatic Metastasis; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism; D008297:Male; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D054353:Perforin / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D053240:Receptors, Tumor Necrosis Factor, Member 14; C506028:TNFRSF14 protein, human; D054353:Perforin; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens; D053804:Granzymes
keywords: HCC; HVEM; Prognosis; TIL; TNFRSF14; Tumour immunity