TMPRSS4 Drives Angiogenesis in Hepatocellular Carcinoma by Promoting HB-EGF Expression and Proteolytic Cleavage
| Autor: | Ya-Fei Yang, Zhao-Ru Dong, Xiao-Wei Wang, Xu-Ting Zhi, Wei Zhou, Cheng-Yu Yao, Yu-Chuan Yan, Lun-Jie Yan, Tao Li, Kai Shi, Dong Sun, Rui Wu, Zhi-Qiang Chen |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Sorafenib Carcinoma Hepatocellular Angiogenesis Angiogenesis Inhibitors 03 medical and health sciences Phosphatidylinositol 3-Kinases 0302 clinical medicine Bacterial Proteins Epidermal growth factor Cell Line Tumor medicine Humans Receptor Protein kinase B Cell Proliferation Hepatology Neovascularization Pathologic Akt/PKB signaling pathway Chemistry Liver Neoplasms Serine Endopeptidases Membrane Proteins medicine.disease Hypoxia-Inducible Factor 1 alpha Subunit Prognosis digestive system diseases ErbB Receptors 030104 developmental biology Matrix Metalloproteinase 9 Hepatocellular carcinoma Cancer research 030211 gastroenterology & hepatology Signal transduction medicine.drug Heparin-binding EGF-like Growth Factor Signal Transduction |
| Zdroj: | Hepatology (Baltimore, Md.)References. 72(3) |
| ISSN: | 1527-3350 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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