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
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
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DOI：
10.1002/hep.30951
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发表时间：
2020-02-10
期刊：
影响因子：
13.5
通讯作者：
Xia, Limin
中科院分区：
文献类型：
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作者：
Chen, Jie;Du, Feng;Xia, Limin
背景和目的肝细胞癌（HCC）患者预后差的主要原因是其高转移率和高复发率。然而，肝癌转移的分子机制需要阐明。SRY相关的高迁移率族蛋白家族（SOX）是一类高度保守的转录因子，在肿瘤的发生、发展中起着重要作用。在这里，我们报告的作用SOX 18，SOX家族的成员，在促进HCC的侵袭和transferation.Approach和结果SOX 18的表达升高与肿瘤分化差，较高的肿瘤淋巴结转移（TNM）阶段，预后不良呈正相关。SOX 18的过表达通过上调转移相关基因，包括成纤维细胞生长因子受体4（FGFR 4）和fms相关酪氨酸激酶4（FLT 4），促进HCC转移。FGFR 4和FLT 4的敲低显著降低了SOX 18介导的HCC侵袭和转移，而FGFR 4和FLT 4的稳定过表达逆转了由抑制SOX 18诱导的细胞侵袭和转移的降低。成纤维细胞生长因子19（FGF 19）是FGFR 4的配体，上调SOX 18的表达。一项机制研究表明，由FGF 19-FGFR 4途径介导的SOX 18的上调依赖于磷酸化的（β）-成纤维细胞生长因子受体底物2/β-糖原合成酶激酶3 β/β-连环蛋白途径。SOX 18敲除显着降低了FGF 19增强的HCC侵袭和转移。此外，特异性FGFR 4抑制剂BLU 9931显著降低了SOX 18介导的HCC侵袭和转移。在人肝癌组织中，SOX 18表达与FGF 19、FGFR 4和FLT 4表达呈正相关，并且共表达FGF 19/SOX 18、SOX 18/FGFR 4或SOX 18/FLT 4的患者预后最差。靶向该通路可能是HCC临床治疗的一个有前景的治疗选择。
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/beta-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.