Hepatology (Baltimore, Md.), 2020-09, Vol.72 (3), p.923-939
2020
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- Autor(en) / Beteiligte
- Titel
- TMPRSS4 Drives Angiogenesis in Hepatocellular Carcinoma by Promoting HB‐EGF Expression and Proteolytic Cleavage
- Ist Teil von
- Hepatology (Baltimore, Md.), 2020-09, Vol.72 (3), p.923-939
- Ort / Verlag
- United States: Wiley Subscription Services, Inc
- Erscheinungsjahr
- 2020
- Quelle
- Wiley Online Library Journals Frontfile Complete
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0270-9139eISSN: 1527-3350DOI: 10.1002/hep.31076Titel-ID: cdi_proquest_journals_2446708748
- Format
- –
- Schlagworte
- AKT protein, Angiogenesis, Angiogenesis Inhibitors - pharmacology, Bacterial Proteins - pharmacology, Carcinoma, Hepatocellular - drug therapy, Carcinoma, Hepatocellular - metabolism, Carcinoma, Hepatocellular - pathology, Cell Line, Tumor, Cell Proliferation - drug effects, Epidermal growth factor, ErbB Receptors - metabolism, Heparin, Heparin-binding EGF-like Growth Factor - metabolism, Hepatocellular carcinoma, Hepatology, Humans, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit - metabolism, Liver cancer, Liver Neoplasms - drug therapy, Liver Neoplasms - metabolism, Liver Neoplasms - pathology, Matrix Metalloproteinase 9 - metabolism, Membrane Proteins - metabolism, Metalloproteinase, Neovascularization, Pathologic - metabolism, Neovascularization, Pathologic - prevention & control, Phosphatidylinositol 3-Kinases - metabolism, Prognosis, Proteolysis, Rapamycin, Serine, Serine Endopeptidases - metabolism, Signal Transduction, Sorafenib - pharmacology, Survival, TOR protein, Transcription