Hypoxia-Induced Cleavage Of Soluble ephrinAI From Cancer Cells Is Mediated By MMP-2 And Associates With Angiogenesis In Oral Squamous Cell Carcinoma

Introduction: ephrinAI plays important roles in tumor angiogenesis. Matrix metallopro-teases (MMPs) can cleave ephrinAI 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 inve...

Full description

Saved in:
Bibliographic Details
Published in:OncoTargets and therapy 2019-10, p.8491
Main Authors: Ma, Ting-Ting, Wang, Lin, Wang, Jun-Lin, Liu, Yan-Jie, Chen, Yu-Cong, He, Hu-Jie, Song, Yong
Format: Article
Language:English
Subjects:
Analysis
Cancer
Cancer cells
Carcinoma
Cell membranes
Enzyme-linked immunosorbent assay
Immunohistochemistry
Neovascularization
Novels
Proteases
Proteolysis
Squamous cell carcinoma
Tumor removal
Tumors
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Introduction: ephrinAI plays important roles in tumor angiogenesis. Matrix metallopro-teases (MMPs) can cleave ephrinAI 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-1[alpha], 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-1[alpha], 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-1[alpha] 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-1[alpha]/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
ISSN:1178-6930
1178-6930
DOI:10.2147/OTT.S213252