IL‐17A promotes the invasion–metastasis cascade via the AKT pathway in hepatocellular carcinoma

Abstract

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.

Keywords

• colonization
• epithelial–mesenchymal transition
• hepatocellular carcinoma
• interleukin‐17A
• secukinumab