IL-17 induces AKT-dependent IL-6/JAK2/STAT3 activation and tumor progression in hepatocellular carcinoma

• Main Authors: Gu Fang-Ming, Li Quan-Lin, Gao Qiang, Jiang Jia-Hao, Zhu Kai, Huang Xiao-Yong, Pan Jin-Feng, Yan Jun, Hu Jin-Hui, Wang Zheng, Dai Zhi, Fan Jia, Zhou Jian
• Format: Article
• Language: English
• Published: BMC 2011-12-01
• Series: Molecular Cancer
• Online Access: http://www.molecular-cancer.com/content/10/1/150

<p>Abstract</p> <p>Background</p> <p>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).</p> <p>Methods</p> <p>Effects and underlying molecular mechanisms of IL-17 on human HCC were explored <it>in vitro </it>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.</p> <p>Results</p> <p>Although exogenous IL-17 showed no direct effect on the growth rate of HCC cells <it>in vitro</it>, 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 <it>in vivo</it>. 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.</p> <p>Conclusions</p> <p>IL-17 mediated tumor-promoting role involves a direct effect on HCC cells through IL-6/JAK2/STAT3 induction by activating the AKT pathway.</p>