Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that are involved in the degradation of various proteins in the extracellular matrix (ECM). Typically, MMPs have a propeptide sequence, a catalytic metalloproteinase domain with catalytic zinc, a hinge region or linker peptide, and a hemopexin domain. MMPs are commonly classified on the basis of their substrates and the organization of their structural domains into collagenases, gelatinases, stromelysins, matrilysins, membrane-type (MT)-MMPs, and other MMPs. MMPs are secreted by many cells including fibroblasts, vascular smooth muscle (VSM), and leukocytes. MMPs are regulated at the level of mRNA expression and by activation of their latent zymogen form. MMPs are often secreted as inactive pro-MMP form which is cleaved to the active form by various proteinases including other MMPs. MMPs cause degradation of ECM proteins such as collagen and elastin, but could influence endothelial cell function as well as VSM cell migration, proliferation, Ca2+ signaling, and contraction. MMPs play a role in tissue remodeling during various physiological processes such as angiogenesis, embryogenesis, morphogenesis, and wound repair, as well as in pathological conditions such as myocardial infarction, fibrotic disorders, osteoarthritis, and cancer. Increases in specific MMPs could play a role in arterial remodeling, aneurysm formation, venous dilation, and lower extremity venous disorders. MMPs also play a major role in leukocyte infiltration and tissue inflammation. MMPs have been detected in cancer, and elevated MMP levels have been associated with tumor progression and invasiveness. MMPs can be regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs), and the MMP/TIMP ratio often determines the extent of ECM protein degradation and tissue remodeling. MMPs have been proposed as biomarkers for numerous pathological conditions and are being examined as potential therapeutic targets in various cardiovascular and musculoskeletal disorders as well as cancer.

/pdf/biochemical-and-biological-attributes-of-matrix-541keac0a1.pdf

Biochemical and Biological Attributes of Matrix Metalloproteinases.

Evolution provides the unifying framework with which to understand biology. The coherent investigation of genic and genomic data often requires comparative genomics analyses based on whole-genome alignments, sets of homologous genes and other relevant datasets in order to evaluate and answer evolutionary-related questions. However, the complexity and computational requirements of producing such data are substantial: this has led to only a small number of reference resources that are used for most comparative analyses. The Ensembl comparative genomics resources are one such reference set that facilitates comprehensive and reproducible analysis of chordate genome data. Ensembl computes pairwise and multiple whole-genome alignments from which large-scale synteny, per-base conservation scores and constrained elements are obtained. Gene alignments are used to define Ensembl Protein Families, GeneTrees and homologies for both protein-coding and non-coding RNA genes. These resources are updated frequently and have a consistent informatics infrastructure and data presentation across all supported species. Specialized web-based visualizations are also available including synteny displays, collapsible gene tree plots, a gene family locator and different alignment views. The Ensembl comparative genomics infrastructure is extensively reused for the analysis of non-vertebrate species by other projects including Ensembl Genomes and Gramene and much of the information here is relevant to these projects. The consistency of the annotation across species and the focus on vertebrates makes Ensembl an ideal system to perform and support vertebrate comparative genomic analyses. We use robust software and pipelines to produce reference comparative data and make it freely available.Database URL: http://www.ensembl.org.

Database: The Journal of Biological Databases and Curation

Tumors often show, compared to normal tissues, a markedly decreased extracellular pH resulting from anaerobic or aerobic glycolysis in combination with a reduced removal of acidic metabolites. Several studies indicate that acidosis induces (independently from hypoxia) hematogenous and lymphatic spread of tumor cells worsening the long-term prognosis of tumor patients. This review gives an overview on the impact of low pH on different steps of metastasis including (a) local tumor cell invasion and angiogenesis, (b) intravasation of tumor cells and detachment into the circulation, and (c) adherence of circulating tumor cells, transmigration and invasion in the new host tissue. The review describes pH-dependent cellular mechanisms fostering these steps such as epithelial-to-mesenchymal transition (EMT), activation of cell migration, degradation of the extracellular matrix, or angiogenesis. The review discusses mechanisms of tumor cells for proton sensing including acid-sensitive ion channels (ASICs, TRPs) or ion transporters (NHE1) and G protein coupled H+-sensors. Finally, the review describes several intracellular signaling cascades activated by H+ sensing mechanisms leading to transcriptional, post-transcriptional, or functional changes in the cell relevant for the metastatic spread. From these studies, different therapeutical approaches are described to overcome tumor acidosis or to interfere with the signaling cascades to reduce the metastatic potential of tumors.

Tumor pH and metastasis: a malignant process beyond hypoxia

Matrix metalloproteinases (MMPs) are a diverse group of proteolytic enzymes and play an important role in the degradation and remodeling of the extracellular matrix (ECM). In normal physiological conditions, MMPs are usually minimally expressed. Despite their low expression, MMPs have been implicated in many cellular processes ranging from embryological development to apoptosis. The activity of MMPs is controlled at three different stages: (1) transcription; (2) zymogen activation; and (3) inhibition of active forms by tissue inhibitor metalloproteinases (TIMPs). They can collectively degrade any component of ECM and basement membrane, and their excessive activity has been linked to numerous pathologies mainly including, but not limited to, tumor invasion and metastasis. The lack of information about several MMPs and the steady stream of new discoveries suggest that there is much more to be studied in this field. In particular, there is a need for controlling their expression in disease states. Various studies over the past 30 years have found that each MMP has a specific mode of activation, action, and inhibition. Drugs specifically targeting individual MMPs could revolutionize the treatment of a great number of health conditions and tremendously reduce their burden. In this review article, we have summarized the recent advances in understanding the role of MMPs in physiological and pathological conditions. J. Cell. Physiol. 231: 2599-2621, 2016. © 2016 Wiley Periodicals, Inc.

Intricate functions of matrix metalloproteinases in physiological and pathological conditions

Objective: To identify candidate biomarkers correlated with clinical prognosis of patients with bladder cancer (BC). Methods: Weighted gene co-expression network analysis was applied to build a co-expression network to identify hub genes correlated with tumor node metastasis (TNM) staging of BC patients. Functional enrichment analysis was conducted to functionally annotate the hub genes. Protein-protein interaction network analysis of hub genes was performed to identify the interactions among the hub genes. Survival analyses were conducted to characterize the role of hub genes on the survival of BC patients. Gene set enrichment analyses were conducted to find the potential mechanisms involved in the tumor proliferation promoted by hub genes. Results: Based on the results of topological overlap measure based clustering and the inclusion criteria, top 50 hub genes were identified. Hub genes were enriched in cell proliferation associated gene ontology terms (mitotic sister chromatid segregation, mitotic cell cycle and cell cycle, etc) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways (cell cycle, Oocyte meiosis, etc). 17 hub genes were found to interact with ≥ 5 of the hub genes. Survival analysis of hub genes suggested that lower expression of MMP11, COL5A2, CDC25B, TOP2A, CENPF, CDCA3, TK1, TPX2, CDCA8, AEBP1, and FOXM1were associated with better overall survival of BC patients. BC samples with higher expression of hub genes were enriched in gene sets associated with P53 pathway, apical junction, mitotic spindle, G2M checkpoint, and myogenesis,etc. Conclusions: We identified several candidate biomarkers correlated with the TNM staging and overall survival of BC patients. Accordingly, they might be used as potential diagnostic biomarkers and therapeutic targets with clinical utility.

/pdf/identification-of-biomarkers-correlated-with-the-tnm-staging-2oerntxale.pdf

Identification of Biomarkers Correlated with the TNM Staging and Overall Survival of Patients with Bladder Cancer.

Squamous cell carcinoma of the head and neck (SCCHN) is an aggressive disease with poor survival and is the sixth most common cancer worldwide. Gastroesophageal reflux is a common event in SCCHN patients. GPR4 is a proton-sensing G-protein coupled receptor, which can be activated by acidosis. The objective of this study was to explore the role of GPR4 in acid exposure and tumor angiogenesis in SCCHN. In this study, we confirmed that overexpressing GPR4 in SCCHN cells could increase the expression and secretion of IL6, IL8 and VEGFA at pH 5.9. This effect could be inhibited by SB203580 (a p38 inhibitor). Western blot analysis indicated that phosphorylation of p38 increased in GPR4 infected cells at pH 5.9, which could be inhibited by SB203580. In tube formation assay, HMEC-1 cells were incubated with conditioned medium (CM, pH 5.9, 6.5, 7.4) derived from control and GPR4 infected SCCHN cells. Tube length was significantly increased in HMEC-1 cells incubated with CM from GPR4 infected cells compared with control cells at pH5.9, which indicated the pro-angiogenic effect of GPR4 in acidic pH. The neutralizing antibodies of IL6, IL8 and VEGFA could inhibit tube formation of HMEC-1 cells. In vivo, the effect of GPR4 on angiogenesis was investigated with the chick chorioallantoic membrane (CAM) model. Control and GPR4 infected SCCHN cells were seeded onto the upper CAM surface (n = 5 in each group) and 5 μL DMEM/F12 (pH 5.9, 6.5, 7.4) was added to the surface of the cell every 24 h. Four days later, the upper CAM were harvested and the ratio of the vascular area to the CAM area was quantified using Image-Pro Plus 6.0 software. GPR4 infected cells could recruit more vascular than control cells at pH5.9. In conclusion, we suggested that GPR4 induces angiogenesis via GPR4-induced p38-mediated IL6, IL8 and VEGFA secretion at acidic extracellular pH in SCCHN.

https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0152789&type=printable

The Proton-Sensing G-Protein Coupled Receptor GPR4 Promotes Angiogenesis in Head and Neck Cancer

BACKGROUND To evaluate the association of MMP11 and P14(ARF) expression in laryngeal squamous cell carcinoma (LSCC) with clinical pathological characteristics and survival. METHODS The mRNA and protein levels for both genes were determined in 65 LSCC patients. A log-rank test and Cox models were used to compare survival among different groups. RESULTS The mRNA expressions of MMP11 and P14(ARF) were significantly different between LSCC and their corresponding adjacent tissues (All P < 0.001). The expressions of MMP11 and P14(ARF) were correlated with several clinical characteristics (All P < 0.05). Patients with low MMP11 and high P14(ARF) expression had significantly better survival compared with those with high MMP11 and low P14(ARF) expression, respectively (All P < 0.05). The patients with surgery only had significantly better survival than those with chemoradiotherapy (log rank: P = 0.016), particularly in patients with low MMP11 and high P14(ARF) expression (log rank: P = 0.006). Furthermore, multivariable analysis showed that patients with low MMP11 and high P14(ARF) expression alone had a significantly reduced risk of death compared with those with high MMP11 and low P14(ARF) expression. The reduced risk for overall death was pronounced for patients with low and high expression of both genes (HR, 0.2; 95% CI, 0.1-0.5) compared with any other co-expression status of both genes, particularly for patients with surgery only (HR, 0.1; 95% CI, 0.0-0.9). CONCLUSION These results suggest that altered expression of MMP11 and P14(ARF) in tumors may individually, or in combination, predict poor prognosis of LSCC, particularly for patients with surgery only.

Significance of MMP11 and P14(ARF) expressions in clinical outcomes of patients with laryngeal cancer.

OBJECTIVE
To evaluate whether neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR) and monocyte-to-white blood cell ratio (MWR) can be used as diagnostic and prognostic markers for laryngeal carcinoma (LC).


METHODS
In this retrospective study, 50 patients with LC treated in the Department of Otolaryngology, Head and Neck Surgery of Beijing Tongren Hospital from August 2014 to August 2015 were enrolled in research group. In addition, 40 healthy volunteers from the same period were selected as control group. The counts of white blood cells, neutrophils, lymphocytes, monocytes and platelets in the peripheral blood of participants were measured with a blood counting instrument (Sysmex XE-2100, Sysmex Corporation, Japan), and the NLR, PLR, LMR and MWR were calculated. After that, the survival rate of patients was observed through a 5-year follow-up. The prognostic value of the above four indexes and their combination was discussed in patients with different clinical characteristics.


RESULTS
Compared with the control group, the NLR, PLR and MWR were higher and the LMR was lower in the research group. In terms of survival, patients with higher NLR, PLR and MWR and lower LMR showed a higher 5-year mortality than those with lower NLR, PLR and MWR and higher LMR, indicating that NLR, PLR and MWR were higher and LMR was lower in the survival group than in the death group. Subsequent analysis identified that NLR, PLR, LMR and MWR were closely correlated with age, alcohol drinking, smoking, clinical staging and T-staging. Clinical staging, T-staging, NLR, PLR, LMR, and MWR were confirmed as influencing factors for LC.


CONCLUSIONS
NLR, PLR, LMR, and MWR can be used as diagnostic and prognostic markers for LC and their combination has a superior diagnostic performance.

NLR, PLR, LMR and MWR as diagnostic and prognostic markers for laryngeal carcinoma.

Background: The lack of standardized treatment is problematic in laser surgery for laryngeal cancer, and may result in an increased recurrence rate. This study analyzed the prognosis of early laryn...

Variation in prognosis of early laryngeal carcinoma after different types of cordectomy with transoral laser microsurgery

Background Although poorly differentiated is rare in head and neck squamous cell carcinoma (HNSCC), its prognosis are worse with high rate of local recurrence and distant metastasis (DS). Therefore, this study hopes to carry out prospective clinical research on different treatment options for poorly differentiated patients and explore the treatment scheme more suitable for these patients. Methods This study is a prospective cohort study. We selected patients with poorly differentiated carcinoma in larynx or hypopharynx (stage I–IV, T1–4a, N0–2, M0). The intervention treatment methods for stage I–II patients are as follows: surgery, induction chemotherapy (IC) + surgery, surgery + adjuvant therapy; The intervention treatment methods for stage III–IV patients are as follows: surgery, IC + surgery + adjuvant therapy, surgery + adjuvant therapy. The patients were followed up for at least 1 year, and the disease progression and survival were counted. Results From September 2016 to October 2020, 62 patients were included (29 patients in stage I/II and 33 patients in stage III/IV). We found that there was no significant difference in survival between treatment groups in stage I/II patients [overall survival (OS): P=0.447; progression free survival (PFS): P=0.504], but the surgery + adjuvant treatment group had a significant advantage in 3-year OS (100%). In stage III/IV patients, there were significant differences in DS, OS and PFS between different treatment groups (DS: P=0.013; OS: P=0.021; PFS: P=0.020). Among them, the survival rate of IC + surgery + adjuvant treatment group was the best, with 3-year OS of 78%. Conclusions Our study found that postoperative radiotherapy may improve the OS rate of patients with early (stage I/II) poorly differentiated HNSCC; For advanced patients (stage III/IV), surgery combined with IC and postoperative adjuvant radiotherapy may better control DS and improve the survival rate. However, our study draws the above conclusions based on small sample data, and we will continue to summarize and expand the sample size for verification.

/pdf/clinical-study-of-poorly-differentiated-head-and-neck-7rtequcu.pdf

Clinical study of poorly differentiated head and neck squamous cell carcinoma: a prospective cohort study in China

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