title: Significant involvement of herpesvirus entry mediator in human esophageal squamous cell carcinoma.
abstract: BACKGROUND
  Herpesvirus entry mediator (HVEM) is known to regulate immune response and to be expressed in several human malignancies. However, to the authors's knowledge, the precise role of HVEM in human cancer biology remains unknown. The objective of the current study was to clarify the clinical significance of HVEM in human esophageal squamous cell carcinoma as well as its in vivo functions.
  
  
  METHODS
  HVEM expression was evaluated in 103 patients with esophageal squamous cell carcinoma to explore its clinical relevance and prognostic value. The functions of HVEM in tumors were analyzed in vitro and in vivo using the small interfering RNA (siRNA) silencing technique.
  
  
  RESULTS
  HVEM expression was found to be significantly correlated with depth of tumor invasion and lymph node metastasis. Furthermore, it was found to be inversely correlated with tumor-infiltrating CD4(+) , CD8(+) , and CD45RO(+) lymphocytes. It is important to note that HVEM status was identified as an independent prognostic marker. HVEM gene silencing significantly inhibited cancer cell proliferation in vitro and cancer growth in vivo. This antitumor effect was associated with reduced cell proliferation activity. The effect was also correlated with the induction of CD8(+) cells and upregulation of local immune response.
  
  
  CONCLUSIONS
  HVEM plays a critical role in both tumor progression and the evasion of host antitumor immune responses, possibly through direct and indirect mechanisms. Therefore, HVEM may be a promising therapeutic target for human esophageal cancer.
authors.affiliation: Department of Surgery, Nara Medical University, Nara, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Migita
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sho
authors.forename: Keiji
authors.initials: K
authors.lastname: Shimada
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yasuda
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yamato
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Takayama
authors.forename: Sohei
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Kohei
authors.initials: K
authors.lastname: Wakatsuki
authors.forename: Kiyohiko
authors.initials: K
authors.lastname: Hotta
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tanaka
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ito
authors.forename: Noboru
authors.initials: N
authors.lastname: Konishi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Nakajima
mesh_terms: D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000235:genetics*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006801:Humans; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008207:Lymphatic Metastasis; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D034622:RNA Interference; D034741:RNA, Small Interfering; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; D053240:Receptors, Tumor Necrosis Factor, Member 14; D017493:Leukocyte Common Antigens
keywords: esophageal squamous cell carcinoma; herpesvirus entry mediator (HVEM); immunotherapy; prognosis