Abstract
Gastric cancer is one of the leading causes of the cancer-related mortality worldwide. The etiology of this disease is complex and involves genetic predisposition and environmental factors, including Helicobacter pylori. Infection of the stomach with H. pylori leads to gastritis and gastric atrophy, which can progress stepwise to gastric cancer. Matrix metalloproteinases (MMPs) actively participate in the pathology development. The further progression of gastric cancer seems to be less dependent on bacteria but of intra-tumor cell dynamics. Bioinformatics data confirmed an important role of the extracellular matrix constituents and specific MMPs in stomach carcinoma invasion and metastasis, and revised their potential as predictors of the disease outcome. In this review, we describe, in detail, the impact of MMPs in H. pylori–associated gastritis and gastric cancer.
Highlights
Normal and pathological proteolysis of the extracellular matrix and the processing of a variety of cell surface molecules are mediated by a big family of zinc-dependent proteases that consists of 24 Matrix metalloproteinases (MMPs), about 35 ADAMs and 19 ADAMTS (ADAMs with thrombospondin domain) [1]
In the cell lines MKN45, AGS and SNU638, as well as in primary gastric cells, infection with cagPAI- and OipA-positive H. pylori led to expression of the MMP-1 gene, as well as genes encoding for its promoter regulators c-Fos, c-Jun and PEA3 in a JNK
In the IL-8-251 AA genotype Koreans, there was a significant correlation between the MMP-9 level and progression from H. pylori infection to chronic atrophic gastritis/intestinal metaplasia and gastric adenocarcinoma [64]
Summary
Normal and pathological proteolysis of the extracellular matrix and the processing of a variety of cell surface molecules are mediated by a big family of zinc-dependent proteases that consists of 24 MMPs (matrix metalloproteinases), about 35 ADAMs (a disintegrin and metalloproteinase) and 19 ADAMTS (ADAMs with thrombospondin domain) [1]. MMPs activity is regulated (i) at the transcriptional level in a cell-type-dependent manner (in response to growth factors and cytokines); (ii) through proteolytic cleavage of their. Among the genetic factors involved in gastric pathology, inherited or somatic mutations in genes encoding cell structure molecules (e.g., E-cadherin and adenomatous polyposis coli protein), as well as SNPs (single nucleotide polymorphisms) in genes encoding pro-inflammatory cytokines, including IL-1β, IL-8, TNF, some MMPs, TIMPs and defensins, have been described [15,16,17]. The immune cells to the and release bigrelease number ofnumber mediators, including MMPs. MMPs from different cells populations activate each other, participate in matrix remodeling, regulate focal adhesion complexes and shed proteins in cellular junctions. MMPs from different cells populations activate each other, participate in matrix remodeling, regulate focal adhesion complexes and shed proteins in cellular junctions It leads to disturbances in the cellular contacts and restructures actin, which impacts the cellular motility.
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