The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai, China.
Mol Oncol. 2018 Jun;12(6):936-952. doi: 10.1002/1878-0261.12306. Epub 2018 Apr 26.
We previously demonstrated that interleukin-17A (IL-17A) is associated with the progression of hepatocellular carcinoma (HCC). However, its role in the invasion-metastasis cascade of HCC and the efficacy of IL-17A-targeting therapeutics in HCC remain largely unknown. In this study, we found that IL-17A promoted intrahepatic and pulmonary metastasesis of HCC cells in an orthotopic implant model. Moreover, our results showed that IL-17A induced epithelial-mesenchymal transition (EMT) and promoted HCC cell colonization in vitro and in vivo, and the role of IL-17A in invasion-metastasis was dependent on activation of the AKT pathway. Remarkably, combined therapy using both secukinumab and sorafenib has better inhibition on tumour growth and metastasis compared to sorafenib monotherapy. Additionally, the combination of intratumoral IL-17A+ cells and E-cadherin predicted the outcome of patients with HCC at an early stage after hepatectomy based on tissue microarray and immunohistochemistry. In conclusion, our studies reveal that IL-17A induces early EMT and promotes late colonization of HCC metastasis by activating AKT signalling. Secukinumab is a promising candidate for clinical development in combination with sorafenib for the management of HCC.
我们之前的研究表明白细胞介素-17A（IL-17A）与肝细胞癌（HCC）的进展有关。然而，IL-17A 在 HCC 侵袭转移级联中的作用及其在 HCC 中的治疗效果仍然知之甚少。在这项研究中，我们发现 IL-17A 促进了 HCC 细胞在原位种植模型中的肝内和肺转移。此外，我们的结果表明，IL-17A 诱导上皮-间充质转化（EMT），并促进 HCC 细胞在体外和体内的定植，而 IL-17A 在侵袭转移中的作用依赖于 AKT 通路的激活。值得注意的是，与索拉非尼单药治疗相比，使用 secukinumab 和索拉非尼联合治疗对肿瘤生长和转移具有更好的抑制作用。此外，基于组织微阵列和免疫组织化学，肿瘤内 IL-17A+细胞和 E-钙黏蛋白的联合预测了肝癌患者肝切除术后早期的预后。总之，我们的研究表明，IL-17A 通过激活 AKT 信号通路诱导早期 EMT，并促进 HCC 转移的晚期定植。Secukinumab 是与索拉非尼联合用于 HCC 管理的有前途的临床开发候选药物。
