Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3

Hepatology. 2011 Sep 2;54(3):900-9. doi: 10.1002/hep.24486. Epub 2011 Aug 8.

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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Apoptosis
  • Carcinoma, Hepatocellular / etiology*
  • Carcinoma, Hepatocellular / pathology
  • Female
  • Humans
  • Interleukins / analysis
  • Interleukins / physiology*
  • Liver Neoplasms / etiology*
  • Liver Neoplasms / pathology
  • Male
  • Mice
  • Middle Aged
  • Neoplasm Metastasis
  • STAT3 Transcription Factor / physiology*
  • Tumor Microenvironment

Substances

  • Interleukins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • interleukin-22