Interleukin-22 Promotes Human Hepatocellular Carcinoma by Activation of STAT3
Interleukin-22 Promotes Human Hepatocellular Carcinoma by Activation of STAT3
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DOI：
10.1002/hep.24486
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发表时间：
2011-09-01
期刊：
影响因子：
13.5
通讯作者：
Sun, Beicheng
中科院分区：
文献类型：
--
作者：
Jiang, Runqiu;Tan, Zhongming;Sun, Beicheng
白细胞介素22(IL-22)是辅助性T细胞(Th17)分泌的一种细胞因子，最近被报道通过STAT3信号激活而成为一种新的炎症驱动因子。本研究旨在探讨IL-22的表达在肝细胞癌中的作用。我们发现，与外周淋巴细胞相比，人肝细胞癌肿瘤浸润性白细胞(TIL)中IL-22的表达显著上调。此外，实时聚合酶链式反应和免疫组织化学均证实，在Edmondson分级的肝细胞癌患者中，IL-22的表达明显高于I-II级。与正常对照组相比，IL-22受体a和IL-23在肝细胞癌及癌旁肝组织中均有高表达。小鼠肾下移植MHCC-97H细胞与IL-22+TILs细胞共移植后，肿瘤生长和转移能力增强。STAT3的磷酸化和下游基因Bcl2、Bclxl、Cycld1和血管内皮生长因子(VEGI)的上调促进了肿瘤的生长和转移。体外研究证实了IL-22和IL-6的促肿瘤和抗凋亡作用。在小鼠慢性肝炎和肝细胞癌模型中，肝组织中IL-22的表达和STAT3的激活持续增加。IL-22的表达与肝组织的互补增殖呈线性相关。体内二乙基亚硝胺诱导的小鼠肝癌模型证实，IL-22基因敲除小鼠的肿瘤形成显著减少。结论：肝细胞癌微环境中存在过量的IL-22，通过激活STAT3，导致肿瘤生长，抑制细胞凋亡，促进转移。(《肝病》2011；54：900-909)
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 HCC patients versus Grade I-II, confirmed by both real-time polymerase chain reaction and immunohistochemistry. Both IL-22 receptor a 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 (VEGI) 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;54:900-909)