Fibroblast Growth Factor 19–Mediated Up‐regulation of SYR‐Related High‐Mobility Group Box 18 Promotes Hepatocellular Carcinoma Metastasis by Transactivating Fibroblast Growth Factor Receptor 4 and Fms‐Related Tyrosine Kinase 4

Background and Aims The poor prognosis of patients with hepatocellular carcinoma (HCC) is mainly attributed to its high rate of metastasis and recurrence. However, the molecular mechanisms underlying HCC metastasis need to be elucidated. The SRY‐related high‐mobility group box (SOX) family proteins, which are a group of highly conserved transcription factors, play important roles in cancer initiation and progression. Here, we report on a role of SOX18, a member of the SOX family, in promoting HCC invasion and metastasis. Approach and Results The elevated expression of SOX18 was positively correlated with poor tumor differentiation, higher tumor‐node‐metastasis (TNM) stage, and poor prognosis. Overexpression of SOX18 promoted HCC metastasis by up‐regulating metastasis‐related genes, including fibroblast growth factor receptor 4 (FGFR4) and fms‐related tyrosine kinase 4 (FLT4). Knockdown of both FGFR4 and FLT4 significantly decreased SOX18‐mediated HCC invasion and metastasis, whereas the stable overexpression of FGFR4 and FLT4 reversed the decrease in cell invasion and metastasis that was induced by inhibition of SOX18. Fibroblast growth factor 19 (FGF19), which is the ligand of FGFR4, up‐regulated SOX18 expression. A mechanistic investigation indicated that the up‐regulation of SOX18 that was mediated by the FGF19‐FGFR4 pathway relied on the phosphorylated (p)‐fibroblast growth factor receptor substrate 2/p‐glycogen synthase kinase 3 beta/β‐catenin pathway. SOX18 knockdown significantly reduced FGF19‐enhanced HCC invasion and metastasis. Furthermore, BLU9931, a specific FGFR4 inhibitor, significantly reduced SOX18‐mediated HCC invasion and metastasis. In human HCC tissues, SOX18 expression was positively correlated with FGF19, FGFR4, and FLT4 expression, and patients that coexpressed FGF19/SOX18, SOX18/FGFR4, or SOX18/FLT4 had the worst prognosis. Conclusions We defined a FGF19‐SOX18‐FGFR4 positive feedback loop that played a pivotal role in HCC metastasis, and targeting this pathway may be a promising therapeutic option for the clinical management of HCC.