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Matrix metalloproteinases
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
S. McDonnell, A. O’Connor, D. Murray, C. C. Lynch
The degradation of the ECM is a multi-step process in which members of the MMP family are inextricably linked. Each MMP has a unique yet slightly overlapping substrate specificity (Table 1). MMP-7, which has thus far been the only MMP family member to be classified in the minimal domain category, has the broadest substrate activity of all MMPs, with an ability to degrade collagens, proteoglycans and glycoproteins10. The hemopexin domain is comprised of several members including MMP-1, MMP-8 and MMP-13, which are capable of degrading fibrillar collagens that include types I, II, III, VII and X. MMP-3, MMP-10, MMP-11 and MMP-12 are capable of cleaving many ECM components including proteoglycans, fibronectin, collagens and gelatins, but have no proteolytic activity for native collagen type I. MMP-11 is a weak proteinase in comparison with other members of this subclass, but has been shown to cleave laminin and fibronectin11. MMP-12 not only degrades elastin but also collagen type IV, fibronectin and laminin. The fibronectin domain contains MMP-2 and MMP-9, which degrade denatured collagens (gelatins) and are specific for the degradation of type IV basement membrane collagen. The transmembrane-type metalloproteinases domain currently contains six family members. The first member of this family, MT1-MMP, was isolated by Sato and colleagues12, and has been shown to induce specific activation of MMP-2 on the cell surface in vitro. The substrate specificities of the remaining members of the MT-MMP group remain unclear.
Molecular basis and biomarkers of disease activity
Published in Seema Chopra, Endometriosis, 2020
Several previous studies in the literature have evaluated expression in the endometrial cells among patients with endometriosis. Researchers have shown at least 72 dysregulated genes in women with endometriosis by sequencing mRNA from the secretory phase endometrial samples. Of these, 4 upregulated proteins including MMP-11, Fos proto-oncogene, dual specificity phosphatase and serpin family E member 1, and adenosine deaminase 2 were validated using quantitative polymerase chain reaction (PCR). Similarly, several acyl carnitines were found to be elevated while trimethylamine-N-oxide was decreased in the cases of endometriosis using mass spectrometry methods. Studies using nuclear magnetic resonance spectrometry have revealed that metabolites containing valine, fucose, and choline, amino acids lysine/arginine, and lipoproteins were upregulated, while creatinine was downregulated in patients with late stages of the disease [41].
Cell and Extracellular Matrix Interactions in a Dynamic Biomechanical Environment:
Published in Michel R. Labrosse, Cardiovascular Mechanics, 2018
In healthy tissues, matrix-degrading enzymes such as matrix metalloproteinases (MMPs) are involved in homeostatic renewal of the ECM as well as in degrading the ECM to facilitate cell migration and proliferation. More than 20 MMPs have been identified, which share three common domains: the prodomain, which is removed to activate the enzyme; the catalytic domain, which contains the active site that degrades the ECM target; and a hemopexin domain, which confers substrate specificity and can also bind inhibitors (Visse and Nagase 2003, Peng et al. 2012). Matrix metalloproteinases are grouped into families based on which ECM protein they can degrade; they include collagenases (MMP-1, MMP-8, MMP-13, and MMP-18), gelatinases (MMP-2 and MMP-9), and stromelysins (MMP-3, MMP-10, and MMP-11). Most MMPs are secreted into the ECM, but some types remain membrane-bound to the cell (Visse and Nagase 2003).
Bone morphogenetic protein signaling in breast cancer progression
Published in Growth Factors, 2019
Lap Hing Chi, Allan D. Burrows, Robin L. Anderson
The ability of cancer cells to invade the stroma is frequently measured by migration and invasion assays in vitro (Table 1). BMPs have been reported to regulate this process through various mechanisms. For instance, the level and activity of matrix metalloproteinases (MMPs) that promote tumor invasion and dissemination are regulated by BMP signaling. BMP2 upregulates the expression of MMP11 (Huang et al. 2017), while BMP4 stimulates the expression or activity of MMP1, MMP2 and MMP9, and promotes the invasion of cancer cells. This invasive phenotype is reversed by the MMP inhibitor Batimastat or the BMP antagonists Chrdl1, Noggin and Gremlin (Ampuja et al. 2013; Cyr-Depauw et al. 2016; Guo, Huang, and Gong 2012). Contrary to these reports, BMP4 downregulates the expression of MMP9 induced by PMA (a protein kinase C ligand) in MDA-MB-231, SKBR3 and the SMAD4-null MDA-MB-468 cells, although the mechanism is unclear (Laulan and St-Pierre 2015). Also, BMP6 downregulates MMP1 and MMP9, potentially through canonical signaling that mediates the suppression of p38/AP-1, and inhibits invasion (Hu et al. 2016; C. Wang et al. 2011). BMP9 overexpression leads to reduced production of MMP9, where a concomitant reduction of p-AKT is observed (S. Li et al. 2018).
Serum, plasma and saliva biomarkers for head and neck cancer
Published in Expert Review of Molecular Diagnostics, 2018
Lidia Maria Rebolho Batista Arantes, Ana Carolina De Carvalho, Matias Eliseo Melendez, André Lopes Carvalho
Several matrix metalloproteinase were also studied to analyze their prognostic behavior in OSCC tumors. In this way, Hsin and colleagues showed that plasma levels of endopeptidase MMP-11 were significantly higher in OSCC patients with advanced T status, lymph node metastasis, and higher TNM stages [130]. In addition, the authors called attention to the fact that, although the levels of MMP-11 were significantly higher in patients with N2 (16.96 ± 9.93 ng/mL), when compared with patients without nodal metastasis, patients with N1 (17.12 ± 10.05 ng/mL) were not different to N0 patients [130]. Similarly, Patel and colleagues analyzed MMP-2 and MMP-9 plasma expression level in 38 OSCC patients, where 12 of them were also sampled before initiation of anticancer therapy [131]. Results indicated that plasma MMP-9 levels were significantly lower in responders compared with pretreatment levels, while the MMP-9 levels were comparable between pretreatment patients and nonresponders [131].
Comprehensive analysis of matrix metalloproteinases and their inhibitors in head and neck squamous cell carcinoma
Published in Acta Oncologica, 2022
Mingyuan Zou, Chen Zhang, Yan Sun, Huina Wu, Feng Xiao, Wei Gao, Fengfeng Zhao, Xiaobo Fan, Guoqiu Wu
In this study, we comprehensively analyzed the differential expression of MMPs/TIMPs in HNSCC tumor and adjacent normal tissues, the correlation between MMP/TIMP expression and clinicopathological stage, and the impact of MMP/TIMP mRNA expression on survival in patients with HNSCC. To provide more intuitive insight into the effect of MMPs/TIMPs on the clinical features of patients with HNSCC, a Sankey diagram (Figure 5(A)) was constructed to summarize our main findings. Tumor-overexpressed genes are often associated with the development and progression of cancer and are correlated with poor prognosis. However, in our study, we found that although the expression of most MMPs was upregulated in tumor tissues, only MMP11 and MMP23B were significantly and positively correlated with pathological stage. For tumor lower expression genes, MMP27 and TIMP4, MMP27 expression was negatively correlated with clinical stage, but not with overall survival. However, TIMP4 expression was negatively correlated with overall survival, but not with clinical stage. Although MMP25 was highly expressed in tumor tissues compared to that in adjacent normal tissues, the expression of MMP25 was negatively associated with tumor grade, and high MMP25 expression predicted a good prognosis for patients with HNSCC. The above results indicated that the gene expression profiles of a single gene of MMPs/TIMPs may not be a good predictor of the progression and prognosis of HNSCC. The construction of the PPI network (Figure 5(B)) revealed that the MMP and TIMP components form a complex interaction network. It has been suggested that TIMPs are coregulated with MMPs, and high MMP activity would induce high TIMP activity [54]. TIMPs are also required for MMP activation; TIMP2 and MMP14 form an activation complex for MMP2 [55]. The positive regulation of MMP activity are presumably more complicated [56–59]. Nyberg et al. [56] reported that various human cancer cells express tumor-associated trypsinogen-2, which can efficiently activate MMPs in vitro. Rather unexpectedly, Nieminen et al. [57] indicated that Oral microbes, for example Treponema denticola (Td), are also participate in the regulation of MMPs activity. One of the key virulence factors of Td is a cell surface-bound chymotrypsin-like proteinase (CTLP), which was found to convert pro MMP-8 and −9 into their active forms. In addition, Td-CTLP was able to degrade the proteinase inhibitors TIMP-1, TIMP-2.