title: IL-17 induces AKT-dependent IL-6/JAK2/STAT3 activation and tumor progression in hepatocellular carcinoma.
abstract: BACKGROUND
  The Th17 subset and IL-17 have been found in increased frequencies within certain tumors. However, their relevance in cancer biology remains controversial. This study aimed to clarify the biological action of IL-17 on hepatocellular carcinoma (HCC).
  
  
  METHODS
  Effects and underlying molecular mechanisms of IL-17 on human HCC were explored in vitro using exogenous IL-17 stimulation and in nude mice by implanting IL-17 overexpressed HCC cells. The clinical significance of IL-17 was investigated in tissue microarrays containing HCC tissues from 323 patients following hepatectomy using immunohistochemistry.
  
  
  RESULTS
  Although exogenous IL-17 showed no direct effect on the growth rate of HCC cells in vitro, PCR and ELISA showed that IL-17 selectively augmented the secretion of diverse proinvasive factors and transwell showed a direct promotion of invasion of HCC cells by IL-17. Furthermore, transfection of IL-17 into HCC cells significantly promoted neoangiogenesis, neutrophil recruitment and tumor growth in vivo. Using siRNA mediated knockdown of AKT and STAT3, we suggested that the effects of IL-17 were operated through activation of the AKT signaling in HCC, which resulted in IL-6 production. Then, IL-6 in turn activated JAK2/STAT3 signaling and subsequently up-regulated its downstream targets IL-8, MMP2, and VEGF. Supporting these findings, in human HCC tissues, immunostaining indicated that IL-17 expression was significantly and positively associated with STAT3 phosphorylation, neutrophil infiltration and increased tumor vascularity. The clinical significance of IL-17 was authenticated by revealing that the combination of intratumoral IL-17+ cells and phospho-STAT3 served as a better prognosticator for postoperative tumor recurrence than either marker alone.
  
  
  CONCLUSIONS
  IL-17 mediated tumor-promoting role involves a direct effect on HCC cells through IL-6/JAK2/STAT3 induction by activating the AKT pathway.
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.
authors.forename: Fang-Ming
authors.initials: FM
authors.lastname: Gu
authors.forename: Quan-Lin
authors.initials: QL
authors.lastname: Li
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gao
authors.forename: Jia-Hao
authors.initials: JH
authors.lastname: Jiang
authors.forename: Kai
authors.initials: K
authors.lastname: Zhu
authors.forename: Xiao-Yong
authors.initials: XY
authors.lastname: Huang
authors.forename: Jin-Feng
authors.initials: JF
authors.lastname: Pan
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.forename: Jin-Hui
authors.initials: JH
authors.lastname: Hu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Zhi
authors.initials: Z
authors.lastname: Dai
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D016009:Chi-Square Distribution; D018450:Disease Progression; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism* / Q000494:pharmacology; D015850:Interleukin-6 / Q000032:analysis / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000032:analysis / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020381:Interleukin-17; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D053614:Janus Kinase 2; D051057:Proto-Oncogene Proteins c-akt