Matrix metalloproteinase (MMP)-7 in Barrett's esophagus and esophageal adenocarcinoma: expression, metabolism, and functional significance.

Hanan M Garalla,Zita Reisz,Andrea Varro,Nantaporn Lertkowit,Alec Simpson,Rob Beynon,Tibor Wittman,Laszlo Tiszlavicz,David Mark Pritchard,András I Rosztóczy,Deborah Simpson,Andrew R Moore,Jothi Dinesh Kumar,Akos Varga,Chris Holmberg,Graham J Dockray,Steven Dodd

doi:10.14814/phy2.13683

Hanan M Garalla, Zita Reisz + Show 15 more

Open Access

https://doi.org/10.14814/phy2.13683

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Abstract

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.

Highlights

The gastrointestinal epithelium undergoes continuous remodeling to maintain tissue architecture both in the face of normal cell proliferation and differentiation, and as part of the adaptive responses following infection or injury
This study shows expression of Matrix metalloproteinase (MMP)‐7 is associated with the progressive epithelial changes that characterize the transformation of normal squamous epithelium through the preneoplastic condition of Barrett’s esophagus (BE) to esophageal adenocarcinoma (EAC)
Gastrin regulates MMP-7 expression in stomach and CCK2 receptors are expressed in BE, we found no evidence that gastrin is associated with increased MMP-7 in the progression to EAC

Summary

Introduction

The gastrointestinal epithelium undergoes continuous remodeling to maintain tissue architecture both in the face of normal cell proliferation and differentiation, and as part of the adaptive responses following infection or injury. The matrix metalloproteinases (MMPs) are zincdependent proteases that constitute one class of extracellular matrix (ECM) proteolytic enzyme that, collectively, are involved in maintaining and remodeling the ECM, and the cell attachments to it (Sternlicht and Werb 2001). These events are crucial for the orderly cell a 2018 The Authors. MMP-7 and Esophageal Adenocarcinoma migration and invasion that underpin the maintenance of epithelial organization They are disrupted in the progression to major epithelial diseases including cancer where they participate in events central to the process of metastasis (Egeblad and Werb 2002; Gialeli et al 2011)

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