IL-17在原发性肝癌上皮-间质转化中的作用和机制研究

Recent researches on tumor-host interactions collectively reveal that the bidirectional and dynamic interactions between the tumors and their microenvironments co-evolve during tumor initiation and progression. As an important part of tumor microenvironment, an inflammatory and immune immune microenvironment has a critical role in careinogenesis, metastatic invasion and dissemination. Intratumor IL-17+ cells are important tumor stromal cells. In early study，we have foud that IL-17 induced AKT-dependent IL-6/JAK2/STAT3 activation and tumor progression in hepatocellular carcinoma. In recent study, we found that the clinical relevance and prognostic significance of the number of tumor-infiltrating IL-17+ cells and the expression of E-cadherin in human HCC. IL-17-treated cells appeared to have more of an mesenchymal spindle-like morphology than the epithelial cobblestone-like morphology characteristic. IL-17 induced epithelial- mesenchymal transition (EMT) -related molecular changes, charaeterized by the loss of epithelial molecule E-cadherin as well as upregulation of N-cadherin, as the mesenehymal marker. Also the EMT-related transcription factors, such as snail, were increased in IL-17-treated cell lines. IL-17 induced a pronounced increase in intracellular translocation of β-catenin in cells. Furthermore, We will try to elucidate the exact role and associated molecular mechanism of IL-17 on EMT in hepatocellular carcinoma in vivo and vitro.?This study will also provide foundation for further study of Th17.

炎症免疫环境作为肿瘤微环境的重要组成部分，与肿瘤的发生发展、复发转移有着密切的关系。免疫炎症细胞IL-17阳性（IL-17+）细胞是肿瘤微环境中的重要间质细胞。前期我们发现IL-17(IL-17A)可通过AKT上调IL-6/JAK2/STAT3促进肝癌侵袭演进。 近期我们又发现在肝癌组织中IL-17阳性(IL-17+)细胞数目还与上皮-间质转化（EMT）中的关键分子E-cadherin表达水平呈明显负相关，细胞实验亦提示IL-17可使肝癌细胞出现类似EMT的形态学变化, 并可下调肝癌E-cadherin，上调N-cadherin、snail, 促进β-catenin核移位。由此拟深入探讨IL-17在肝癌EMT中的作用和机制, 进而阐明肿瘤微环境中IL-17促进肝癌侵袭转移的新机制，同时丰富EMT网络调控机制,并为以后重点研究Th17奠定实验基础。

我们以前证明白细胞介素-17A（IL-17A）与肝细胞癌（HCC）的进展明显相关。然而，其在HCC的侵袭-转移级联中的作用以及IL-17A靶向治疗剂在HCC中的功效仍然很大程度上未知。在这项研究中，我们发现IL-17A在原位植入肿瘤动物模型中促进HCC细胞的肝内和肺转移。此外，我们的结果显示IL-17A诱导上皮-间质转化（EMT）并在体外和体内促进HCC细胞定植，并且IL-17A在侵袭-转移中的作用依赖于AKT途径的激活。值得注意的是，与索拉菲尼单药治疗相比，使用苏金单抗（一种IL-17A的抗体）和索拉菲尼的联合治疗对肿瘤生长和转移具有更好的抑制作用。此外，肿瘤内IL-17A阳性细胞联合E-钙粘蛋白可以通过基于组织芯片及免疫组化方面预测早期HCC患者在肝切除术后的预后。总之，我们的研究表明，IL-17A通过激活AKT信号诱导早期EMT并促进HCC转移的晚期定植。 苏金单抗是一种有前景的临床开发候选药物，它可与索拉非尼联合用于治疗HCC。