TMPRSS4 Drives Angiogenesis in Hepatocellular Carcinoma by Promoting HB-EGF Expression and Proteolytic Cleavage
TMPRSS4 Drives Angiogenesis in Hepatocellular Carcinoma by Promoting HB-EGF Expression and Proteolytic Cleavage
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TMPRSS4 通过促进 HB-EGF 表达和蛋白水解裂解来驱动肝细胞癌中的血管生成。
DOI：
10.1002/hep.31076
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发表时间：
2020-06-30
期刊：
影响因子：
13.5
通讯作者：
Li, Tao
中科院分区：
文献类型：
--
作者：
Dong, Zhao-Ru;Sun, Dong;Li, Tao
背景和目的肝素结合表皮生长因子（HB-EGF）是表皮生长因子家族的成员，在多种恶性肿瘤的进展中发挥着关键作用，但其在肝细胞癌（HCC）中的作用和调节机制尚不清楚。在这里，我们报告，跨膜蛋白酶丝氨酸4（TMPRSS 4）显着增强的表达和蛋白水解切割HB-EGF，以促进血管生成和肝癌的进展。方法和结果一个机制分析表明，TMPRSS 4不仅增加HB-EGF前体的转录和翻译水平，而且通过EGF受体/Akt/哺乳动物雷帕霉素靶/低氧诱导因子1 α信号通路增强基质金属肽酶9的表达，促进其蛋白水解裂解。此外，HB-EGF通过EGF受体/磷酸肌醇3-激酶/Akt信号通路促进HCC增殖和侵袭。HCC患者血清或HCC组织中HB-EGF水平与TMPRSS 4表达和微血管密度呈正相关，并被确定为总生存期和无复发生存期的预后因子，提示HB-EGF可作为HCC潜在的治疗靶点。更重要的是，我们证明了单独使用HB-EGF抑制剂交叉反应物质197或与索拉非尼联合使用可以显著抑制血管生成和HCC进展。结论TMPRSS 4可调控HB-EGF促进HCC的增殖、侵袭和血管生成，HB-EGF抑制剂交叉反应物质197联合索拉非尼可用于HCC的个体化治疗。
Background and Aims Heparin-binding epidermal growth factor (HB-EGF), a member of the epidermal growth factor family, plays a pivotal role in the progression of several malignancies, but its role and regulatory mechanisms in hepatocellular carcinoma (HCC) remain obscure. Here, we report that transmembrane protease serine 4 (TMPRSS4) significantly enhanced the expression and proteolytic cleavage of HB-EGF to promote angiogenesis and HCC progression. Approach and Results A mechanistic analysis revealed that TMPRSS4 not only increased the transcriptional and translational levels of HB-EGF precursor, but also promoted its proteolytic cleavage by enhancing matrix metallopeptidase 9 expression through the EGF receptor/Akt/mammalian target of rapamycin/ hypoxia-inducible factor 1 alpha signaling pathway. In addition, HB-EGF promoted HCC proliferation and invasion by the EGF receptor/phosphoinositide 3-kinase/Akt signaling pathway. The level of HB-EGF in clinical samples of serum or HCC tissues from patients with HCC was positively correlated with the expression of TMPRSS4 and the microvessel density, and was identified as a prognostic factor for overall survival and recurrence-free survival, which suggests that HB-EGF can serve as a potential therapeutic target for HCC. More importantly, we provide a demonstration that treatment with the HB-EGF inhibitor cross-reacting material 197 alone or in combination with sorafenib can significantly suppress angiogenesis and HCC progression. Conclusions HB-EGF can be regulated by TMPRSS4 to promote HCC proliferation, invasion, and angiogenesis, and the combination of the HB-EGF inhibitor cross-reacting material 197 with sorafenib might be used for individualized treatment of HCC.