Diagnostic Utility of Selected Matrix Metalloproteinases (MMP-2, MMP-3, MMP-11, MMP-26), HE4, CA125 and ROMA Algorithm in Diagnosis of Ovarian Cancer.

Ovarian cancer (OC) has an unfavorable prognosis. Due to the lack of effective screening tests, new diagnostic methods are being sought to detect OC earlier. The aim of this study was to evaluate the concentration and diagnostic utility of selected matrix metalloproteinases (MMPs) as OC markers in comparison with HE4, CA125 and the ROMA algorithm. The study group consisted of 120 patients with OC; the comparison group consisted of 70 patients with benign lesions and 50 healthy women. MMPs were determined via the ELISA method, HE4 and CA125 by CMIA. Patients with OC had elevated levels of MMP-3 and MMP-11, similar to HE4, CA125 and ROMA values. The highest SE, SP, NPV and PPV values were found for MMP-26, CA125 and ROMA in OC patients. Performing combined analyses of ROMA with selected MMPs increased the values of diagnostic parameters. The topmost diagnostic power of the test was obtained for MMP-26, CA125, HE4 and ROMA and performing combined analyses of MMPs and ROMA enhanced the diagnostic power of the test. The obtained results indicate that the tested MMPs do not show potential as stand-alone OC biomarkers, but can be considered as additional tests to raise the diagnostic utility of the ROMA algorithm.

MMP1, MMP9, MMP11 and MMP13 in melanoma and its metastasis - key points in understanding the mechanisms and celerity of tumor dissemination.

BACKGROUND: Matrix metalloproteinase (MMP)1, MMP9, MMP11, and MMP13 are overexpressed in malignant melanoma (MM), being associated with tumor invasive phase, metastases, and more aggressive neoplastic phenotypes. AIM: The main objective of the current study was to correlate the expression of the MMPs with the evolution of MM toward distant metastasis. PATIENTS, MATERIALS AND METHODS: We designed a retrospective cohort study, including 13 patients with metastatic MM. Data concerning age, sex, localization of the primary lesion and metastasis, and histological and immunohistochemical features (intensity of expression and percent of positive cells for MMPs) were statistically processed. RESULTS: The time between the diagnosis of primitive melanoma and the diagnosis of metastasis ranged between 0 and 73 months, with a mean value of 18.3 months. The metastases rich in MMP1- and MMP9-positive cells occurred earlier than the metastases with low levels of positive cells. The mean period until metastasis was shorter for the MMP1-expressing tumors than the ones without MMP1 expression. MMP13 expression in the tumor and its metastasis was significantly linked with the time until the metastasis occurrence. CONCLUSIONS: This study emphasizes the roles of MMP1, MMP9, and MMP13 in the process of metastasis in melanoma and the opportunity to use them as therapeutic targets and surveillance molecules.

Explore novel molecular mechanisms of FNDC5 in ischemia-reperfusion (I/R) injury by analyzing transcriptome changes in mouse model of skeletal muscle I/R injury with FNDC5 knockout.

BACKGROUND: Irisin, a myokine derived from proteolytic cleavage of the fibronectin type III domain-containing protein 5 (FNDC5) protein, is crucial in protecting tissues and organs from ischemia-reperfusion (I/R) injury. However, the underlying mechanism of its action remains elusive. In this study, we investigated the expression patterns of genes associated with FNDC5 knockout to gain insights into its molecular functions. METHODS: We employed a mouse model of skeletal muscle I/R injury with FNDC5 knockout to examine the transcriptional profiles using RNA sequencing. Differentially expressed genes (DEGs) were identified and subjected to further analyses, including gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, protein-protein interaction (PPI) network analysis, and miRNA-transcription factor network analysis. The bioinformatics findings were validated using qRT-PCR and Western blotting. RESULTS: Comparative analysis of skeletal muscle transcriptomes between wild-type (WT; C57BL/6), WT-I/R, FNDC5 knockout (KO), and KO-I/R mice highlighted the significance of FNDC5 in both physiological conditions and I/R injury. Through PPI network analysis, we identified seven key genes (Col6a2, Acta2, Col4a5, Fap, Enpep, Mmp11, and Fosl1), which facilitated the construction of a TF-hub genes-miRNA regulatory network. Additionally, our results suggested that the PI3K-Akt pathway is predominantly involved in FNDC5 deletion-mediated I/R injury in skeletal muscle. Animal studies revealed reduced FNDC5 expression in skeletal muscle following I/R injury, and the gastrocnemius muscle with FNDC5 knockout exhibited larger infarct size and more severe tissue damage after I/R. Moreover, Western blot analysis confirmed the upregulation of Col6a2, Enpep, and Mmp11 protein levels following I/R, particularly in the KO-I/R group. Furthermore, FNDC5 deletion inhibited the PI3K-Akt signaling pathway. CONCLUSION: This study demonstrates that FNDC5 deletion exacerbates skeletal muscle I/R injury, potentially involving the upregulation of Col6a2, Enpep, and Mmp11. Additionally, the findings suggest the involvement of the PI3K-Akt pathway in FNDC5 deletion-mediated skeletal muscle I/R injury, providing novel insights into the molecular mechanisms underlying FNDC5's role in this pathological process.

Exosomes from Human Umbilical Cord Mesenchymal Stem Cells Facilitates Injured Endometrial Restoring in Early Repair Period through miR-202-3p Mediating Formation of ECM.

Endometrial damage repair disorder is the main reason of intrauterine adhesions (IUA) and thin endometrium (TA), which is caused by curettage or infection. Exosomal miRNAs derived from human umbilical cord mesenchymal stem cells (hucMSCs) were reported to play an important role in damage repair disorder, including endometrial fibrosis. In this study, we aimed to investigate the role of hucMSCs-derived exosomal microRNA-202-3p (miR-202-3p) in endometrial damage repair. We established rat endometrial injury model according to curettage to mimic women curettage abortion operation. The miRNA array analysis indicated that miR-202-3p was increased and matrix metallopeptidase 11 (MMP11) was decreased in the exosomes-treated rat uterine tissues. Bioinformatics analysis suggested that MMP11 is the target gene of miR-202-3p. We observed that the mRNA and protein of MMP11 were significantly decreased in exosome treatment group on day 3, and the components of extracellular matrix (ECM) COL1A1, COL3A1, COLVI and fibronectin (FN) protein were increased. And we found that when the injured human stromal cells were treated with miR-202-3p overexpression exosomes, the COLVI and FN were also upregulated in protein and mRNA expression level. For the first time MMP11 was proved to be the target gene of miR-202-3p by dual luciferase reporter system. At last, we found the state of stromal cells was better in miR-202-3p overexpression exosomes group compared to exosomes group, and miR-202-3p overexpression exosomes markedly upregulated the FN and collagen on day 3 after endometrial injury. We thought that miR-202-3p overexpression exosomes promoted endometrial repair by regulating ECM remodeling in early repair of damaged endometrium. Taken together, these experimental findings may provide a theoretical basis for understanding endometrial repair and an insight into the clinical treatment for IUA. Human umbilical cord mesenchymal stem cells exosomal miR-202-3p could regulate the expression of MMP11 and promote the accumulation of extracellular matrix, such as COL1A1, COL3A1, COLVI, FN, in the early repair period of endometrial injury.

The profiles of miR-4510 expression level in breast cancer.

MicroRNA that is abnormally produced in breast cells can disrupt biological processes, which can lead to cancer. This study aims to screen differentially expressed genes (DEGs) and ncRNAs (DEncRNAs) in the formalin-fixed paraffin-embedded (FFPE) tissues of breast cancer (BC) as compared with the normal adjacent tissues (NAT), and identify miR-4510 as a novel biomarker of BC. This study looked at differentially expressed genes (DEGs) using MACE-Seq and differentially expressed ncRNAs (DEncRNAs) using the small RNA-Seq. Real-time qPCR was used to determine the level of expression of miR-4510. In this study, MACE-Seq results showed that 26,795 genes, with a p-value < 0.05, were differentially expressed in BC paraffin tissues as compared with NAT. Small RNA-Seq results revealed that 1326 ncRNAs, with a p-value < 0.05, were differentially expressed. We confirmed that miR-4510 was significantly down-expressed (p-value = 0.001) by qRT-PCR in the paraffin tissue of 120 BC patients. Based on eleven computational prediction programs, TP53, TP53INP1, MMP11, and COL1A1 for the miR-4510 were identified as miR-4510 targets. The MACE-seq result showed that the gene of TP53 (p-value = 0.001) and TP53INP1 (p-value = 0.02) was significantly down-regulated, but the gene of MMP11 (p-value = 0.004) and COL1A1 (p-value = 0.0001) was significantly over-expressed in 20 paired specimens of the BC and NAT. We discovered that a single SNP inside the miR-4510 binding site occurred only in BC, in which Guanine (G) changed into Adenine (A). Two SNPs outside the miR-4510 binding site occurred, and Guanine (G) in both BC and NAT was changed into Thymine (T), as compared to the reference sequence (RefSeq). Overall, our results suggested that miR-4510 functions as a tumor suppressor in the BC. Mir-4510 may act as a tumor suppressor, however additional experimental data is needed to corroborate these assumptions and can be exploited as a biomarker for BC.

Germline gain-of-function MMP11 variant results in an aggressive form of colorectal cancer.

Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and nonmatrix proteins. Although most MMPs are secreted as inactive proenzymes and are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11's protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.

Quantitative multiplexed analysis of MMP-11 and CD45 in metastatic breast cancer tissues by immunohistochemistry-assisted LA-ICP-MS.

Breast cancer is the leading cause of cancer death in woman and tremendous efforts are undertaken to limit its dissemination and to provide effective treatment. Various histopathological parameters are routinely assessed in breast cancer biopsies to provide valuable diagnostic and prognostic information. MMP-11 and CD45 are tumor-associated antigens and potentially valuable biomarkers for grading aggressiveness and metastatic probability. This paper presents methods for quantitative and multiplexed imaging of MMP-11 and CD45 in breast cancer tissues and investigates their potential for improved cancer characterization and patient stratification. An immunohistochemistry-assisted laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) method was successfully developed and optimized using lanthanide-tagged monoclonal antibodies as proxies to determine spatial distributions and concentrations of the two breast cancer biomarkers. The labeling degree of antibodies was determined via size exclusion-ICP-tandem mass spectrometry (SEC-ICP-MS/MS) employing online calibration via post-column isotope dilution analysis (IDA). The calibration of spatial distributions of labeled lanthanides in tissues was performed by ablating mold-prepared gelatin standards spiked with element standards. Knowledge of labeling degrees enabled the translation of lanthanide concentrations into biomarkers concentrations. The k-means clustering was used to select tissue areas for statistical analysis and mean concentrations were compared for sets of metastatic, non-metastatic and healthy samples. MMP-11 was expressed in stroma surrounding tumor areas, while CD45 was predominantly found inside tumor areas with high cell density. There was no significant correlation between CD45 and metastasis (P = 0.70); however, MMP-11 was significantly up-regulated (202%) in metastatic samples compared to non-metastatic (P = 0.0077) and healthy tissues (P = 0.0087).

An MMP-based risk score strongly distinguishes prognosis in hepatocellular carcinoma after resection.

Aim: To first explore the prognostic value of MMP11 and MMP15 in hepatocellular carcinoma. Methods: MMP11/MMP15 expression was immunohistochemically detected and correlated with clinicopathologic variables and survival and confirmed in publicly available databases. An MMP-based risk score (MMPRS) was established. Results: Tumoral MMP11/MMP15 expression was higher and univariately associated with crucial clinicopathologic parameters, overall survival and disease-free survival in all patients and/or many subsets. Multivariately, MMP11/MMP15 expression remained significant. Their overexpression and prognostic value were confirmed in the Ualcan and Kaplan-Meier plotter databases. Critically, the novel MMPRS integrating MMP11, MMP15 and tumor-node-metastasis stage identified subgroups with the best and worst prognoses, with much higher predictive power. Conclusion: MMP11 and MMP15 served as prognosticators in hepatocellular carcinoma. MMPRS might work more accurately.

MMP11 and MMP15, involved in cancer dissemination, were found to have important biological functions in several cancers. However, their prognostic value in hepatocellular carcinoma (HCC) remains unknown. In the present study, it was found that MMP11 and MMP15 were overexpressed and predictive of the outcome of HCC. Moreover, the novel MMP-based risk score integrating MMP11, MMP15 and tumor­node­metastasis stage had much higher prognostic power. MMP11, MMP15 and especially the MMP-based risk score were identified as promising indicators of prognosis in HCC.

Skin Aging in Long-Lived Naked Mole-Rats Is Accompanied by Increased Expression of Longevity-Associated and Tumor Suppressor Genes.

Naked mole-rats (NMRs) (Heterocephalus glaber) are long-lived mammals that possess a natural resistance to cancer and other age-related pathologies, maintaining a healthy life span >30 years. In this study, using immunohistochemical and RNA-sequencing analyses, we compare skin morphology, cellular composition, and global transcriptome signatures between young and aged (aged 3‒4 vs. 19‒23 years, respectively) NMRs. We show that similar to aging in human skin, aging in NMRs is accompanied by a decrease in epidermal thickness; keratinocyte proliferation; and a decline in the number of Merkel cells, T cells, antigen-presenting cells, and melanocytes. Similar to that in human skin aging, expression levels of dermal collagens are decreased, whereas matrix metalloproteinase 9 and matrix metalloproteinase 11 levels increased in aged versus in young NMR skin. RNA-sequencing analyses reveal that in contrast to human or mouse skin aging, the transcript levels of several longevity-associated (Igfbp3, Igf2bp3, Ing2) and tumor-suppressor (Btg2, Cdkn1a, Cdkn2c, Dnmt3a, Hic1, Socs3, Sfrp1, Sfrp5, Thbs1, Tsc1, Zfp36) genes are increased in aged NMR skin. Overall, these data suggest that specific features in the NMR skin aging transcriptome might contribute to the resistance of NMRs to spontaneous skin carcinogenesis and provide a platform for further investigations of NMRs as a model organism for studying the biology and disease resistance of human skin.

Mechanism of miR-340-5p in laryngeal cancer cell proliferation and invasion through the lncRNA NEAT1/MMP11 axis.

OBJECTIVES: Laryngeal cancer (LC), with a relatively rare diagnosis, is a primary malignancy originating from laryngeal mucosa. This study investigated the mechanisms of microRNA (miR)- 340-5p in LC cell proliferation and invasion. METHODS: The expression patterns of miR-340-5p, long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1), and matrix metallopeptidase 11 (MMP11) in LC cells, tissues, and para-carcinoma tissues, and human bronchial epithelial cells (HBEC) were examined via RT-qPCR. The effects of elevating or silencing miR-340-5p on LC cell proliferation and invasion were examined. The subcellular localization of lncRNA NEAT1 was determined. The binding relations among miR-340-5p, lncRNA NEAT1, and MMP11 were verified. Functional rescue experiments were designed to verify the functions of lncRNA NEAT1 and MMP11 on LC cell proliferation and invasion. Nude-mouse tumor models were established to assess the role of miR-340-5p in LC in vivo. RESULTS: miR-340-5p was under-expressed in LC, and miR-340-5p overexpression repressed LC cell proliferation and invasion. Mechanically, miR-340-5p decreased lncRNA NEAT1 stability via directly binding to lncRNA NEAT1 and thus declined lncRNA NEAT1 expression in LC cells, while lncRNA NEAT1 accelerated MMP11 transcription via binding to heat shock factor 1 (HSF1). Overexpression of lncRNA NEAT1 or MMP11 reversed the repression of miR-340-5p overexpression on LC cell proliferation and invasion. In vivo, miR-340-5p overexpression repressed the tumor growth. CONCLUSION: miR-340-5p overexpression reduced lncRNA NEAT1 stability via binding to lncRNA NEAT1, which declined lncRNA NEAT1 expression and reduced the binding of lncRNA NEAT1 to HSF1 to further inhibit MMP11 transcription, thus repressing LC cell proliferation and invasion.

Single cell transcriptomic landscape of diabetic foot ulcers.

Diabetic foot ulceration (DFU) is a devastating complication of diabetes whose pathogenesis remains incompletely understood. Here, we profile 174,962 single cells from the foot, forearm, and peripheral blood mononuclear cells using single-cell RNA sequencing. Our analysis shows enrichment of a unique population of fibroblasts overexpressing MMP1, MMP3, MMP11, HIF1A, CHI3L1, and TNFAIP6 and increased M1 macrophage polarization in the DFU patients with healing wounds. Further, analysis of spatially separated samples from the same patient and spatial transcriptomics reveal preferential localization of these healing associated fibroblasts toward the wound bed as compared to the wound edge or unwounded skin. Spatial transcriptomics also validates our findings of higher abundance of M1 macrophages in healers and M2 macrophages in non-healers. Our analysis provides deep insights into the wound healing microenvironment, identifying cell types that could be critical in promoting DFU healing, and may inform novel therapeutic approaches for DFU treatment.

Matrix metalloproteinase 11 (MMP11) in macrophages promotes the migration of HER2-positive breast cancer cells and monocyte recruitment through CCL2-CCR2 signaling.

Matrix metalloproteinase 11 (MMP11), a member of the MMP family involved in the degradation of the extracellular matrix, has been implicated in cancer progression. Despite the stromal expression of MMP11 in breast cancer, the prognostic significance and role of MMP11 in immune or stromal cells of breast cancer remain unclear. Based on the immunohistochemical analysis of breast cancer tissues from 497 patients, we demonstrated that MMP11 expression in mononuclear inflammatory cells (predominantly macrophages) is an independent negative prognostic factor in breast cancer, whereas MMP11 expression in tumor cells and fibroblasts is not associated with patient survival. Enforced MMP11 expression in breast cancer cells did not promote cell proliferation and migration. However, MMP11-overexpressing macrophages enhanced the migration of HER2-positive (HER2+) breast cancer cells, recruitment of monocytes, and tube formation of endothelial cells. Furthermore, we found that the chemokine CCL2 secreted from MMP11-overexpressing macrophages activated the MAPK pathway via its receptor CCR2 in breast cancer cells, thereby promoting the migration of HER2+ breast cancer cells through MMP9 upregulation. We also found that MMP11 expression in macrophages was stimulated by MMP11-overepressing HER2+ breast cancer cells. Collectively, our findings provide evidence that MMP11 in macrophages may play a pro-tumoral role in HER2+ breast cancer through interaction with cancer cells, monocytes, and endothelial cells.

The paradoxical role of matrix metalloproteinase-11 in cancer.

The microenvironment surrounding the tumor affects biological processes, such as cell proliferation, angiogenesis, apoptosis, and invasion. Therefore, the ability to change these environments is an important attribute for tumor cells to obtain specific functions necessary for growth and metastasis. Matrix metalloproteinases (MMPs) are zinc-dependent proteolytic metalloenzymes that facilitate protease-dependent tumor progression by degrading extracellular matrix (ECM) proteins, releasing cytokines, growth factors, and other cell surface molecules. As one of the most widely studied MMPs, MMP-11 is an important protease that is expressed in cancer cells, stromal cells, and the adjacent microenvironment. MMP-11 has a dual effect on tumors. On one hand, MMP-11 promotes tumor development by inhibiting apoptosis and promoting the migration and invasion of cancer cells in the early stage. On the other hand, in animal models, MMP-11 has a protective effect on tumor growth and metastasis at an advanced stage. Based on current findings regarding the importance of MMP-11 in altering the tumor microenvironment, there is a need to further understand how stromal cells and the ECM regulate tumor progression, which may result in the re-examination of MMPs as drug targets for cancer and other diseases. In this review, we summarize the dual role of MMP-11 in cancer and its potential clinical significance.

Abnormal expression of FAK and paxillin correlates with oral cancer invasion and metastasis.

Globally, the tenth most common cancer is the oral squamous cell carcinoma (OSCC) and the treatment strategy for improving of OSCC patients survival rate still remains a challenging one. Aberrant regulation of cell to extracellular matrix protein interactions leads to progression of human cancers. The focal adhesion kinase (FAK) and its downstream target paxillin have been implicated in cancer growth, migration, invasion and metastasis of different cancers. However, the clinical significance of FAK and paxillin in OSCC is not well characterized so far. In the present work, we showed that relative mRNA and protein expressions of FAK and paxillin are significantly higher in side population (SP) cells of OSCC cell line SCC-55. Concomitantly, the matrix metalloproteinase-11 (MMP-11) level is also significantly elevated in SP cells. The enhanced expression of paxillin is strongly correlated with increased chemoresistance, proliferation rate, migration and invasion potential of SP cells. In addition, inhibition of paxillin expression by RNAi makes SP cells more sensitive to chemotherapy drugs. Therefore, our results suggest that paxillin over expression might play a significant role in cancer progression, invasion and chemoresistance of OSCC.

MMP11 promotes the proliferation and progression of breast cancer through stabilizing Smad2 protein.

Breast cancer (BC) is one of the most common malignant tumours in women. The matrix metalloproteinase (MMP) enzyme family plays a complex role in the development of BC. There is increasing evidence that MMP11 plays a major role in BC; however, the underlying mechanisms are not clear. The present study confirmed by analysing clinical samples and TCGA data sets, that high expression of MMP11 in clinical samples of BC was strongly associated with a poor prognosis in BC patients. In addition, MTT and colony formation assays indicated that the proliferative capacity of BC was affected when MMP11 expression changed. Furthermore, pathway enrichment analysis was performed and it was revealed that the TGF­ß signalling pathway was a potential downstream target of MMP11. In the TGF­ß signalling pathway, MMP11 could significantly regulate the protein expression levels of Smad2 and Smad3 and inhibit the degradation of Smad2 through the ubiquitin proteasome pathway as determined by western blotting. In vivo, it was further verified that MMP11 knockdown could inhibit tumour proliferation and growth. Collectively, the present results demonstrated that MMP11 inhibited the degradation of Smad2 in the TGF­ß signalling pathway, thereby promoting the development of BC. Thus, MMP11 expression was not only revealed to be an important indicator of BC prognosis but may also be an important therapeutic target for further prevention of BC growth and proliferation. The present study indicated that MMP11­targeted therapy may provide new solutions for BC treatment.

Norepinephrine inhibits migration and invasion of human glioblastoma cell cultures possibly via MMP-11 inhibition.

PURPOSE: Growing evidence has shown that the stress hormones affect tumor progression. Patients with surgery to remove tumor often have increased norepinephrine during the perioperative period. However, the effect of norepinephrine on the progression of glioblastoma has not yet studied. Therefore, the present study aimed at investigating the effects of norepinephrine on the migration and invasion of the human glioblastoma U87 and U251 cell lines and the mechanism for the effects. METHODS: The U87 and U251 cells were treated with 0, 0.1, 1, 5, 10 or 50 µM norepinephrine. A scratch wound healing assay and a transwell invasion assay were used to investigate cell migration and invasion, respectively. The Human Tumor Metastasis RT2 Profiler PCR Array was used to detect the expression of 84 genes known to be involved in metastasis. RESULTS: Following norepinephrine treatment, the ability of the U87 and U251 cells to migrate and invade was significantly decreased. Human Tumor Metastasis RT2 Profiler PCR Array assay showed that matrix metallopeptidase-11 (MMP-11) was decreased following norepinephrine treatment. The ß-adrenergic receptor blocker (AR) propranolol blunted the suppressive effect of norepinephrine on the migration and invasion of U251 cells but did not have such an effect on the invasion of U87 cells. MMP-11 silencing inhibited the migration and invasion of U87 and U251 cells. The Cancer Genome Atlas data showed that patients with higher expression of MMP-11 in the glioblastoma tissues had poorer prognosis. CONCLUSION: Our results indicate that norepinephrine inhibits the migration and invasion of human glioblastoma cells. This effect may be mediated by the decrease of MMP-11. ß-AR may be a regulatory factor for this effect in U251 cells.

Extracellular Matrix Proteins and Transcription of Matrix-Associated Genes in Mesenchymal Stromal Cells during Modeling of the Effects of Microgravity.

We studied the effects of simulated microgravity (10 days) on the production of extracellular matrix proteins and expression of extracellular matrix-associated genes in human mesenchymal stem cells. A decrease in collagen production, reduced expression of TIMP-1, TIMP-3, and MMP-11 genes, and enhanced expression of tenascin and laminin subunit were revealed. The results attest to activation of proteolytic processes in the matrix of mesenchymal stromal cells and weakening of cell adhesion to extracellular matrix under conditions of simulated microgravity.

The prognostic value and potential mechanism of Matrix Metalloproteinases among Prostate Cancer.

Background: Matrix Metalloproteinases (MMPs) play an indispensable role in the initial alteration and development of PCa. We tried to generate an MMP-related prognostic signature (MMPS) in prostate cancer (PCa). Methods: TCGA-PRAD, MSKCC/GSE21032, GSE116918, GSE70769 cohorts were enrolled to assess the prognostic value of MMPs. The least absolute shrinkage and selection operator (LASSO) Cox regression was employed to generate the MMPS signature. The log-rank test and Kaplan-Meier (K-M) survival curve were applied to show the difference RFS, The receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) was plotted to predict the accuracy of signature. CIBERSORT was conducted to analyze the different immune infiltration in MMPS-H and MMPS-L groups. Potential signaling pathways activated in the MMPS-H groups by Metascape. Results: MMP1, MMP7, MMP11, MMP24 and MMP26 were selected by LASSO regression and established the MMPS predict signature. The MMPS showed the high prognostic value in TCGA-PRAD training cohort (AUC=0.714) and validation cohorts (GSE116918: AUC=0.976, GSE70769: AUC=0.738, MSKCC: AUC=0.793). Pid integrin1 pathway, G2M checkpoint, and response to growth factor signaling pathways were activated in MMPS-H group, patients with the high MMPS risk score and low M2 macrophage showed the worst recurrence-free survival (RFS). Conclusion: MMPs involved and played an essential role in the tumorigenesis and biochemical recurrence in PCa patients. The MMPS signature could accurately predict the recurrence of PCa patients and validated in several cohorts.

Matrix Metalloproteinase 11 as a Novel Tumor Promoter and Diagnostic and Prognostic Biomarker for Pancreatic Ductal Adenocarcinoma.

OBJECTIVES: Matrix metalloproteinase 11 (MMP-11) was found to be implicated in tumorigenesis in cancers. However, the significance of MMP-11 in pancreatic ductal adenocarcinoma (PDAC) is unclear. METHODS: In the study, we detected malignant biological behaviors of pancreatic cancer after downregulation of MMP-11. Furthermore, we explored the possible mechanism, and the diagnostic value of serum MMP-11 level was analyzed in 116 patients with pathologically confirmed PDAC. In addition, we explored their prognostic value in PDAC. RESULTS: We observed that MMP-11 could be expressed and activated in the cytoplasm of PDAC cells. Immunohistochemistry staining of PDAC tissues showed that MMP-11 was highly expressed in cancerous ductal epithelium instead of cancer stroma. We found that downregulation of MMP-11 inhibited proliferation of PDAC cell lines. The expression levels of cyclin-dependent kinase 4 and cyclin D1 were downregulated after MMP-11 knockdown. As for its clinical value, the serum level of MMP-11 was shown to be a potent promising diagnostic marker for PDAC. CONCLUSIONS: Matrix metalloproteinase 11 may act as a tumor promoter, playing a positive role in PDAC development. Serum MMP-11 also has great potential to be a promising diagnostic marker for PDAC.

MicroRNA-125b as a tumor suppressor by targeting MMP11 in breast cancer.

BACKGROUND: Breast cancer is a common type of tumor in women worldwide. MicroRNAs have been identified as regulators in many human cancers. The aim of this study was therefore to investigate the functional role of miR-125b in regulating breast cancer progression. METHODS: We used the StarBase database to investigate the expression of miRNA-125b in breast cancer and adjacent normal tissues. MMP11 3'-UTR construct and luciferase reporter assays was performed for target genes. Cell proliferation was evaluated by CCK-8 and colony formation assay. The migration and invasion were assessed by transwell assay. RESULTS: Luciferase reporter assays showed miRNA-125b directly targeted MMP11. miRNA-125b by transfection with its mimic in breast cancer cells significantly suppressed breast cancer cell proliferation and migration. Western blot revealed that overexpression of miRNA-125b substantially reduced MMP11 protein expression. We used the UALCAN database to investigate the expression of MMP11 in human breast cancer and adjacent normal tissues. In addition, we found that miRNA-125b spoiled MMP11 induced breast cancer cell proliferation and migration promotion effect. CONCLUSIONS: miRNA-125b mimic inhibited proliferation, migration, and invasion of breast cancer cells through targeting MMP11 protein.