Hypoxia-Induced Cleavage Of Soluble ephrinA1 From Cancer Cells Is Mediated By MMP-2 And Associates With Angiogenesis In Oral Squamous Cell Carcinoma
Hypoxia-Induced Cleavage Of Soluble ephrinA1 From Cancer Cells Is Mediated By MMP-2 And Associates With Angiogenesis In Oral Squamous Cell Carcinoma
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缺氧诱导癌细胞中可溶性 ephrinA1 的裂解由 MMP-2 介导，并与口腔鳞状细胞癌中的血管生成相关
DOI：
10.2147/ott.s213252
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发表时间：
2019-01-01
影响因子：
4
通讯作者：
Song, Yong
中科院分区：
文献类型：
--
作者：
Ma, Ting-Ting;Wang, Lin;Song, Yong
前言ephrinA 1在肿瘤血管生成中起重要作用。基质金属蛋白酶（MMP）可将ephrinA 1从细胞膜切割到细胞外环境。然而，如何可溶性ephrinA 1是由缺氧和MMPs是否参与这一缺氧过程的调制仍有待详细研究。方法采用免疫组化法检测37例口腔鳞癌组织中HIF-1α、MMP-2、MMP-9和ephrinA 1的表达。收集35例患者术前和术后的血清样本，通过ELISA确认可溶性ephrinA 1的存在。通过阻断实验和Western blot分析进一步阐明ephrinA 1在体外缺氧条件下的蛋白水解机制。结果HIF-1α、MMP-2、MMP-9和ephrinA 1在OSCC中均呈阳性表达，除MMP-9外，其余均与微血管密度相关。OSCC患者手术切除实体瘤后血清ephrinA 1表达水平明显下降。体外实验表明，MMP特异性抑制剂GM 6001可减少缺氧诱导的SCC细胞分泌可溶性ephrinA 1。进一步的Western blot分析证实HIF-1α和MMP-2在缺氧过程中以类似的时间依赖性方式上调，而MMP-9的表达在此过程中没有变化。结论HIF-1α/MMP-2信号通路介导ephrinA 1的分泌，可能是OSCC新生血管形成的重要机制。
Introduction 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.