title: Prognostic value of peritumoral heat-shock factor-1 in patients receiving resection of hepatocellular carcinoma.
abstract: BACKGROUND
  The cross-talk of hepatocellular carcinoma (HCC) cells and abnormal metabolic signals in peritumoral microenvironment modifies our knowledge of hepatocarcinogenesis. As an indispensable modulator of various stresses, the clinical significance of heat-shock transcription factor-1 (HSF1) in HCC microenvironment has never been defined.
  
  
  METHODS
  Hepatocellular carcinoma and matched peritumoral liver tissues (n=332) were semiquantitatively analysed for HSF1 expression, followed by correlation with clinicopathological parameters (patient outcomes). Moreover, the effects of HSF1 deficiency in L02 on monocarboxylate transporter-4 (MCT4) and HCC cells' colonisation and proliferation were investigated.
  
  
  RESULTS
  High expression of HSF1 in peritumoral tissue but not in HCC tissue was associated with poorer overall survival (OS) and time to recurrence (TTR), especially early recurrence (ER), which was further reconfirmed in validation cohort. Multivariate analysis showed that prognostic performance of peritumoral HSF1 was independent of other clinicopathological factors (hazard ratio for OS=2.60, P=0.002, for TTR=2.52, P<0.001). Notably, downregulation of HSF1 in L02 decreased MCT4 expression significantly. The supernatant from L02-shRNA-HSF1 in hypoxia, NOT normoxia condition, inhibited HCC cell colonisation and proliferation. Moreover, the combination of peritumoral HSF1 and MCT4 was the best predictor for ER and OS.
  
  
  CONCLUSIONS
  High peritumoral HSF1 expression can serve as a sensitive 'readout' for high-risk HCC ER, and could be a potential metabolic intervention target following curative resection.
authors.affiliation: 1] Liver Cancer Institute and Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, China [2] Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, China.
authors.forename: J-B
authors.initials: JB
authors.lastname: Zhang
authors.forename: K
authors.initials: K
authors.lastname: Guo
authors.forename: H-C
authors.initials: HC
authors.lastname: Sun
authors.forename: X-D
authors.initials: XD
authors.lastname: Zhu
authors.forename: B
authors.initials: B
authors.lastname: Zhang
authors.forename: Z-H
authors.initials: ZH
authors.lastname: Lin
authors.forename: B-H
authors.initials: BH
authors.lastname: Zhang
authors.forename: Y-K
authors.initials: YK
authors.lastname: Liu
authors.forename: Z-G
authors.initials: ZG
authors.lastname: Ren
authors.forename: J
authors.initials: J
authors.lastname: Fan
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D015331:Cohort Studies; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism*; D018869:Heat-Shock Response; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology; D011379:Prognosis
chemical_list: D006360:Heat-Shock Proteins