Interleukin‐22 promotes human hepatocellular carcinoma by activation of STAT3

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. (HEPATOLOGY 2011;)

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