title: Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3.
abstract: Interleukin-22 (IL-22), one of the cytokines secreted by T helper 17 (Th17) cells, was recently reported to be a novel inflammation driver through STAT3 signaling activation. We aimed to investigate the role of IL-22 expression in hepatocellular carcinoma (HCC). We demonstrated significant up-regulation of IL-22 in human HCC tumor infiltrated leukocytes (TILs) compared to peripheral lymphocytes. Moreover, IL-22 expression was significantly higher in Edmondson Grade III-IV HCC patients versus Grade I-II, confirmed by both real-time polymerase chain reaction and immunohistochemistry. Both IL-22 receptor α and IL-23 were highly expressed in HCC and adjacent cirrhotic tissues compared to normal controls. Enhanced tumor growth and metastasis was found in mice that underwent subrenal transplantation of MHCC-97H cells cotransplanted with IL-22+ TILs cells. STAT3 phosphorylation and up-regulation of downstream genes Bcl-2, Bcl-XL, CyclinD1, and vascular endothelial growth factor (VEGF) promoted tumor growth and metastasis. In vitro studies confirmed the tumor-promoting and antiapoptotic effect of IL-22, as well as IL-6. In the mouse chronic hepatitis and HCC model, sustained and increased IL-22 expression and STAT3 activation were found in liver tissues. A linear correlation was demonstrated between IL-22 expression and hepatic complementary proliferation. An in vivo diethyl-nitrosamine-induced mouse HCC model verified that tumor formation was significantly decreased in IL-22 knockout mice.
  
  
  CONCLUSIONS
  Excessive IL-22 can be found in the HCC microenvironment, leading to tumor growth, inhibition of apoptosis, and promotion of metastasis due to STAT3 activation.
authors.affiliation: Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China.
authors.forename: Runqiu
authors.initials: R
authors.lastname: Jiang
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Tan
authors.forename: Lei
authors.initials: L
authors.lastname: Deng
authors.forename: Yun
authors.initials: Y
authors.lastname: Chen
authors.forename: Yongxiang
authors.initials: Y
authors.lastname: Xia
authors.forename: Yun
authors.initials: Y
authors.lastname: Gao
authors.forename: Xuehao
authors.initials: X
authors.lastname: Wang
authors.forename: Beicheng
authors.initials: B
authors.lastname: Sun
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000473:pathology; D005260:Female; D006801:Humans; D007378:Interleukins / Q000032:analysis / Q000502:physiology*; D008113:Liver Neoplasms / Q000209:etiology* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D050796:STAT3 Transcription Factor / Q000502:physiology*; D059016:Tumor Microenvironment; D000097043:Interleukin-22
chemical_list: D007378:Interleukins; D050796:STAT3 Transcription Factor; D000097043:Interleukin-22; C494086:STAT3 protein, human