title: IL-6, through p-STAT3 rather than p-STAT1, activates hepatocarcinogenesis and affects survival of hepatocellular carcinoma patients: a cohort study.
abstract: BACKGROUND
  Biologic activities of functional mediators activate downstream transducers regulating inflammation and carcinogenesis. Correlation among mediators (IL-6, IL-27, TNF-α, and VEGF) with STAT proteins at diverse clinical-pathologic stages of hepatocellular carcinoma (HCC) remains limited.
  
  
  METHODS
  Serum mediators assayed from 147 untreated HCC cases (HCC-total group) included 70 HBV-infected (HCC-HBV group), 64 HCV-infected (HCC-HCV group), and 13 without HBV-/HCV-infection (HCC-NBNC group). Another 156 non-HCC individuals comprised 54 healthy individuals (HG) and 102 chronic hepatitis patients (CH-total group) as control group. To correlate with serum mediators, 86-paired liver tissues (CH: 52 and HCC: 34 cases) served for p-STATs proteins immunostain.
  
  
  RESULTS
  Although four mediators (IL-6, IL-27, TNF-α, and VEGF) significantly over-expressed, IL-6 presented the strongest correlation in HCC-total versus CH-total or HG groups (HCC-total versus CH-total: P < 0.001; HCC-total versus HG: P < 0.001). Over-expressed IL-6 concentration linked with poor liver function (Albumin: r = -0.383, P < 0.001; Bilirubin: r = 0.280, P = 0.001; INR: r = 0.299, P < 0.001; AST: 0.212, P = 0.016), tumor progression (TNM system: r = 0.370; P < 0.001), clinical condition severity (BCLC system: r = 0.471; P < 0.001; terminal- versus early-stage HCC, P = 0.001; advanced- versus early-stage HCC, P = 0.007; terminal- versus intermediate- stage HCC P = 0.003; advanced- versus intermediate-stage HCC P = 0.019), and 6-month mortality (P = 0.024). Likewise, serum IL-6 (r = 0.501, P = 0.003) as compared to IL-27 (r = 0.052, P = 0.770), TNF-α (r = 0.019, P = 0.917), and VEGF (r = 0.096, P = 0.595) expression reflected positive correlation with activation of tissues p-STAT3 rather than p-STAT1.
  
  
  CONCLUSIONS
  Serum IL-6, through p-STAT3 rather than p-STAT1 signal pathway, affected hepatic function, tumor progression, and determine HCC patient survival.
authors.affiliation: School of Medicine, China Medical University, Taichung, Taiwan. garrydarkao@gmail.com.|Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan. garrydarkao@gmail.com.|Department of Internal Medicine, Division of Hepato-Gastroenterology, China Medical University Hospital, Taichung, Taiwan. garrydarkao@gmail.com.
authors.forename: Jung-Ta
authors.initials: JT
authors.lastname: Kao
authors.affiliation: Department of Internal Medicine, Division of Hepato-Gastroenterology, China Medical University Hospital, Taichung, Taiwan. D6604@mail.cmuh.org.tw.
authors.forename: Chun-Lung
authors.initials: CL
authors.lastname: Feng
authors.affiliation: Department of Internal Medicine, Division of Hepato-Gastroenterology, China Medical University Hospital, Taichung, Taiwan. D10295@mail.cmuh.org.tw.
authors.forename: Cheng-Ju
authors.initials: CJ
authors.lastname: Yu
authors.affiliation: Graduate Institute of Clinical Medical Science, Chang Gung University, Tao-Yuan, Taiwan. shuamy1116@gmail.com.
authors.forename: Shu-Mei
authors.initials: SM
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan. jinglin@ntu.edu.tw.
authors.forename: Ping-Ning
authors.initials: PN
authors.lastname: Hsu
authors.affiliation: School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. 31560@cch.org.tw.|Department of General Surgery, Changhua Christian Hospital, Changhua, Taiwan. 31560@cch.org.tw.
authors.forename: Yao-Li
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan. yyw@mail.cmu.edu.tw.|Department of Medical Laboratory Science and Biotechnology, China Medical University, No. 91, Hsueh-Shih Rd., Taichung, 404, Taiwan. yyw@mail.cmu.edu.tw.
authors.forename: Yi-Ying
authors.initials: YY
authors.lastname: Wu
mesh_terms: D000328:Adult; D000368:Aged; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000737:chemistry / Q000401:mortality / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D019694:Hepatitis B, Chronic / Q000097:blood / Q000150:complications; D019698:Hepatitis C, Chronic / Q000097:blood / Q000150:complications; D006801:Humans; D064094:Interleukin-27 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood*; D008113:Liver Neoplasms / Q000097:blood / Q000737:chemistry / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000032:analysis; D050796:STAT3 Transcription Factor / Q000032:analysis; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D064094:Interleukin-27; D015850:Interleukin-6; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A