血管生成
表皮生长因子
癌症研究
肝素结合EGF样生长因子
索拉非尼
蛋白激酶B
PI3K/AKT/mTOR通路
生物
信号转导
肝细胞癌
内科学
医学
受体
细胞生物学
作者
Zhao‐Ru Dong,Dong Sun,Yafei Yang,Wei Zhou,Rui Wu,Xiaowei Wang,Kai Shi,Yu-Chuan Yan,Lun-Jie Yan,Cheng-Yu Yao,Zhiqiang Chen,Xu Zhi,Tao Li
出处
期刊:Hepatology
[Wiley]
日期:2020-06-30
卷期号:72 (3): 923-939
被引量:35
摘要
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 α 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.
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