Matrix metalloproteinase (MMP)-7 in Barrett's esophagus and esophageal adenocarcinoma: expression, metabolism, and functional significance.
Matrix metalloproteinase (MMP)-7 in Barrett's esophagus and esophageal adenocarcinoma: expression, metabolism, and functional significance.
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DOI：
10.14814/phy2.13683
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发表时间：
2018-05
影响因子：
2.5
通讯作者：
Varro A
中科院分区：
文献类型：
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作者：
Garalla HM;Lertkowit N;Tiszlavicz L;Reisz Z;Holmberg C;Beynon R;Simpson D;Varga A;Kumar JD;Dodd S;Pritchard DM;Moore AR;Rosztóczy AI;Wittman T;Simpson A;Dockray GJ;Varro A
基质金属蛋白酶（MMP）-7，与许多MMP不同，通常在上皮细胞中表达。它与上皮细胞对感染、损伤和组织重塑的反应有关，包括许多癌症的进展。我们现在已经研究了MMP-7表达在食管腺癌（EAC）进展中的变化，并研究了调节其表达的机制及其功能意义。免疫组化显示，MMP-7在EAC附近的正常鳞状上皮中弱表达，但在Barrett食管和EAC的癌前病变的上皮细胞中表达丰富，特别是在浸润前沿。在间质中，假定的表达MMP-7的肌成纤维细胞在浸润前沿丰富，但在邻近组织中很少或不存在。Western blot和ELISA显示EAC细胞系（OE 33）中proMMP-7的高组成性分泌，其被磷脂酰肌醇（PI）3-激酶抑制剂LY 294002抑制，但不被蛋白激酶C或MAP激酶激活的抑制剂抑制。在培养的食管肌成纤维细胞中可检测到proMMP-7，但在培养基中检测不到。通过蛋白质组学分析研究的肌成纤维细胞对MMP-7的可能代谢表明通过广泛的内肽酶降解，然后是氨基肽酶和羧肽酶裂解。肌成纤维细胞表现出对来自OE 33细胞的条件培养基的响应增加的迁移和侵袭，所述条件培养基通过MMP-7敲低和免疫中和而减少。因此，MMP-7表达在EAC的浸润前沿增加，这可能部分归因于PI 3-激酶的激活。分泌的MMP-7可以通过刺激基质细胞迁移和侵袭来改变肿瘤微环境。
Matrix metalloproteinase (MMP)‐7, unlike many MMPs, is typically expressed in epithelial cells. It has been linked to epithelial responses to infection, injury, and tissue remodeling including the progression of a number of cancers. We have now examined how MMP‐7 expression changes in the progression to esophageal adenocarcinoma (EAC), and have studied mechanisms regulating its expression and its functional significance. Immunohistochemistry revealed that MMP‐7 was weakly expressed in normal squamous epithelium adjacent to EAC but was abundant in epithelial cells in both preneoplastic lesions of Barrett's esophagus and EAC particularly at the invasive front. In the stroma, putative myofibroblasts expressing MMP‐7 were abundant at the invasive front but were scarce or absent in adjacent tissue. Western blot and ELISA revealed high constitutive secretion of proMMP‐7 in an EAC cell line (OE33) that was inhibited by the phosphatidylinositol (PI) 3‐kinase inhibitor LY294002 but not by inhibitors of protein kinase C, or MAP kinase activation. There was detectable proMMP‐7 in cultured esophageal myofibroblasts but it was undetectable in media. Possible metabolism of MMP‐7 by myofibroblasts studied by proteomic analysis indicated degradation via extensive endopeptidase, followed by amino‐ and carboxpeptidase, cleavages. Myofibroblasts exhibited increased migration and invasion in response to conditioned media from OE33 cells that was reduced by MMP‐7 knockdown and immunoneutralization. Thus, MMP‑7 expression increases at the invasive front in EAC which may be partly attributable to activation of PI 3‐kinase. Secreted MMP‐7 may modify the tumor microenvironment by stimulating stromal cell migration and invasion.