OncoTargets and Therapy (Oct 2019)
Hypoxia-Induced Cleavage Of Soluble ephrinA1 From Cancer Cells Is Mediated By MMP-2 And Associates With Angiogenesis In Oral Squamous Cell Carcinoma
Abstract
Ting-Ting Ma,1,* Lin Wang,2,* Jun-Lin Wang,1 Yan-Jie Liu,1 Yu-Cong Chen,1 Hu-Jie He,1 Yong Song1 1Department of Stomatology, Liuzhou People’s Hospital, Guangxi, People’s Republic of China; 2Department of Oral and Maxillofacial-Head and Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yong SongDepartment of Stomatology, Liuzhou People’s Hospital, 8 Wenchang Road, Liuzhou 545006, People’s Republic of ChinaTel +86 0772 2662705Email [email protected]: ephrinA1 plays important roles in tumor angiogenesis. Matrix metalloproteases (MMPs) can cleave ephrinA1 from the cell membrane into extracellular environment. However, how soluble ephrinA1 is modulated by hypoxia and whether MMPs participate in this hypoxic process remains to be investigated in detail.Methods: Thirty-seven patients with oral squamous cell carcinoma (OSCC) were included in the present study for HIF-1α, MMP-2, MMP-9 and ephrinA1 detection by immunohistochemistry. Serum samples from 35 patients were collected both preoperatively and postoperatively to confirm the existence of soluble ephrinA1 by ELISA. Block assay and Western blot analysis were further carried out to elucidate the proteolysis mechanism of ephrinA1 under hypoxic condition in vitro.Results: Our data demonstrated that HIF-1α, MMP-2, MMP-9 and ephrinA1 expressed positively, and correlated with microvessel density in OSCCs, except for MMP-9. The serum expression level of ephrinA1 in OSCC patients decreased significantly after surgical removal of the solid tumors. In vitro experiments indicated that GM6001, a MMP-specific inhibitor, could reduce hypoxia-induced soluble ephrinA1 secretion from SCC cells. Further Western blot analysis confirmed that both HIF-1α and MMP-2 were up-regulated by hypoxia in a similar time-dependent manner, with the MMP-9 expression unchanged during this course.Conclusion: These results suggested a possible novel mechanism that ephrinA1 secretion is mediated by HIF-1α/MMP-2 signaling cascade which may play pivotal roles in OSCC neovascularization in a paracrine manner.Keywords: soluble ephrinA1, matrix metalloproteases, hypoxia, angiogenesis, oral squamous cell carcinoma
