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Regulation and Function of Matrix Metalloproteinase-13 in Cancer Progression and Metastasis.

ABSTRACT: Matrix metalloproteinase-13 (MMP-13) is a member of the Matrix metalloproteinases (MMPs) family of endopeptidases. MMP-13 is produced in low amounts and is well-regulated during normal physiological conditions. Its expression and secretion are, however, increased in various cancers, where it plays multiple roles in tumour progression and metastasis. As an interstitial collagenase, MMP-13 can proteolytically cleave not only collagens I, II and III, but also a range of extracellular matrix proteins (ECMs). Its action causes ECM remodelling and often leads to the release of various sequestered growth and angiogenetic factors that promote tumour cell growth, invasion and angiogenesis. This review summarizes our current understanding of the regulation of MMP-13 expression and secretion and discusses the actions of MMP-13 in cancer progression and metastasis.

SUBMITTER: Li S

PROVIDER: S-EPMC9265061 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Regulation and Function of Matrix Metalloproteinase-13 in Cancer Progression and Metastasis.

Li Shun S Pritchard David Mark DM Yu Lu-Gang LG

Cancers 20220703 13

Matrix metalloproteinase-13 (MMP-13) is a member of the Matrix metalloproteinases (MMPs) family of endopeptidases. MMP-13 is produced in low amounts and is well-regulated during normal physiological conditions. Its expression and secretion are, however, increased in various cancers, where it plays multiple roles in tumour progression and metastasis. As an interstitial collagenase, MMP-13 can proteolytically cleave not only collagens I, II and III, but also a range of extracellular matrix protein ...[more]

PMID: 35805035

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Project description:Background: Tyrosine kinase with immunoglobulin and EGF-like domains 1 (TIE1) is known as an orphan receptor prominently expressed in endothelial cells and participates in angiogenesis by regulating TIE2 activity. Our previous study demonstrated elevated TIE1 expression in cervical cancer cells. However, the role of TIE1 in cervical cancer progression, metastasis and treatment remains elusive. Methods: Immunohistochemistry staining for TIE1 and Basigin was performed in 135 human cervical cancer tissues. Overexpressing vectors and siRNAs were used to manipulate gene expression in tumor cells. Colony formation, wound healing, and transwell assays were used to assess cervical cancer cell proliferation and migration in vitro. Subcutaneous xenograft tumor and lung metastasis mouse models were established to examine tumor growth and metastasis. Co-Immunoprecipitation and Mass Spectrometry were applied to explore the proteins binding to TIE1. Immunoprecipitation and immunofluorescence staining were used to verify the interaction between TIE1 and Basigin. Cycloheximide chase assay and MG132 treatment were conducted to analyze protein stability. Results: High TIE1 expression was associated with poor survival in cervical cancer patients. TIE1 overexpression promoted the proliferation, migration and invasion of cervical cancer cells in vitro, as well as tumor growth and metastasis in vivo. In addition, Basigin, a transmembrane glycoprotein, was identified as a TIE1 binding protein, suggesting a pivotal role in matrix metalloproteinase regulation, angiogenesis, cell adhesion, and immune responses. Knockdown of Basigin or treatment with the Basigin inhibitor AC-73 reversed the tumor-promoting effect of TIE1 in vitro and in vivo. Furthermore, we found that TIE1 was able to interact with and stabilize the Basigin protein and stimulate the Basigin-matrix metalloproteinase axis. Conclusion: TIE1 expression in cervical cells exerts a tumor-promoting effect, which is at least in part dependent on its interaction with Basigin. These findings have revealed a TIE2-independent mechanism of TIE1, which may provide a new biomarker for cervical cancer progression, and a potential therapeutic target for the treatment of cervical cancer patients.

Project description:BackgroundFibrostenotic disease is a common complication in Crohn's disease (CD) patients hallmarked by transmural extracellular matrix (ECM) accumulation in the intestinal wall. The prevention and medical therapy of fibrostenotic CD is an unmet high clinical need. Although targeting IL36R signaling is a promising therapy option, downstream mediators of IL36 during inflammation and fibrosis have been incompletely understood. Candidate molecules include matrix metalloproteinases which mediate ECM turnover and are thereby potential targets for anti-fibrotic treatment. Here, we have focused on understanding the role of MMP13 during intestinal fibrosis.MethodsWe performed bulk RNA sequencing of paired colon biopsies taken from non-stenotic and stenotic areas of patients with CD. Corresponding tissue samples from healthy controls and CD patients with stenosis were used for immunofluorescent (IF) staining. MMP13 gene expression was analyzed in cDNA of intestinal biopsies from healthy controls and in subpopulations of patients with CD in the IBDome cohort. In addition, gene regulation on RNA and protein level was studied in colon tissue and primary intestinal fibroblasts from mice upon IL36R activation or blockade. Finally, in vivo studies were performed with MMP13 deficient mice and littermate controls in an experimental model of intestinal fibrosis. Ex vivo tissue analysis included Masson's Trichrome and Sirius Red staining as well as evaluation of immune cells, fibroblasts and collagen VI by IF analysis.ResultsBulk RNA sequencing revealed high upregulation of MMP13 in colon biopsies from stenotic areas, as compared to non-stenotic regions of patients with CD. IF analysis confirmed higher levels of MMP13 in stenotic tissue sections of CD patients and demonstrated αSMA+ and Pdpn+ fibroblasts as a major source. Mechanistic experiments demonstrated that MMP13 expression was regulated by IL36R signaling. Finally, MMP13 deficient mice, as compared to littermate controls, developed less fibrosis in the chronic DSS model and showed reduced numbers of αSMA+ fibroblasts. These findings are consistent with a model suggesting a molecular axis involving IL36R activation in gut resident fibroblasts and MMP13 expression during the pathogenesis of intestinal fibrosis.ConclusionTargeting IL36R-inducible MMP13 could evolve as a promising approach to interfere with the development and progression of intestinal fibrosis.

Dataset Information

Regulation and Function of Matrix Metalloproteinase-13 in Cancer Progression and Metastasis.

Publications

Regulation and Function of Matrix Metalloproteinase-13 in Cancer Progression and Metastasis.

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