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Background: The pressing need for reliable biomarkers in colorectal cancer (CRC) diagnosis and prognosis is a major global health concern. Current diagnostic methods rely heavily on invasive procedures like colonoscopy, and existing biomarkers such as Carbohydrate Antigen 19-9 (CA19-9) and Carcinoembryonic Antigen (CEA) exhibit limitations in accuracy and specificity., Aims: This study aims to identify and validate novel biomarkers that can enhance the early detection and diagnostic precision of CRC while overcoming the shortcomings of conventional biomarkers., Materials and Methods: Leveraging advancements in genomic and proteomic technologies, gene expression datasets were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). We identified differentially expressed genes (DEGs) and conducted further analyses, including Gene Ontology (GO) enrichment and Protein-Protein Interaction (PPI) network construction. Five promising biomarkers-INHBA, MMP7, PSAT1, SLC7A5, and TGFBI-were selected based on their robust performance in Receiver Operating Characteristic (ROC) curve analysis. Serum concentrations of these biomarkers were measured in 200 CRC patients and 100 healthy controls., Results: The study revealed significantly elevated expression levels of the selected biomarkers in CRC tissues compared to normal tissues. Additionally, serum concentrations of INHBA, MMP7, PSAT1, SLC7A5, and TGFBI were notably higher in CRC patients than in healthy individuals, with Area Under the Curve (AUC) values ranging from 0.8361 to 0.9869 indicating high diagnostic accuracy. Optimal cutoff values for diagnosis ranged from 38.9 pg/mL to 280.7 pg/mL, yielding sensitivity and specificity values between 74.5% and 92.9%., Discussion: The findings underscore the potential of INHBA, MMP7, PSAT1, SLC7A5, and TGFBI as effective non-invasive biomarkers for CRC detection. Their elevated serum concentrations and robust discriminatory abilities highlight their promise in improving diagnostic accuracy and patient outcomes compared to traditional biomarkers., Conclusion: The identification and validation of these novel biomarkers represent a significant advancement in CRC diagnosis and management. Further studies are required to validate their clinical applicability in larger cohorts and to elucidate their functional roles in CRC pathogenesis, ultimately enhancing diagnostic strategies and personalized treatment approaches., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives: Peri-implantitis (PI) is the most common biological issue surrounding dental implants. According to current knowledge, the aforementioned complication is not equally distributed across different populations, and gene polymorphisms might be one contributing factor. The current study aimed to examine the association between gene polymorphisms of matrix metalloproteinase- (MMP-) 1, -2, -3, -7, and -13 with PI in an Iranian demographic., Material and Methods: The study's sample included 50 subjects suffering from PI and 89 healthy controls. From each participant, a venous blood sample of 5 cc was obtained, and DNA was extracted. Gene polymorphisms were investigated using restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) combined with electrophoresis. Statistical analyses were done using the Pearson chi-square test, odds ratio, and t-test via SPSS version 28., Results: The MMP-3 (-1171 5A/6A) and MMP-7 (-181 A/G) gene polymorphisms were significantly different between the patients with PI and healthy controls (PV < 0.001 and =0.025, respectively). MMP-1 (-1607 1G/2G), MMP-2 (-1306 C/T), and MMP-13 (-77 A/G) gene polymorphisms did not, however, differ in terms of prevalence between the two groups (PV > 0.05). Moreover, the presence of the 6 A allele in the MMP-3 (-1171 5A/6A) genotype resulted in a significant decrease in PI risk (PV < 0.001)., Conclusions: Gene polymorphisms in the genotypes of MMP-3 (-1171 5A/6A) and MMP-7 (-181 A/G) were differential when comparing PI patients and healthy controls of the studied population., (© 2024 The Author(s). Clinical and Experimental Dental Research published by John Wiley & Sons Ltd.)

Renal cell carcinoma (RCC) ranks as a prevalent malignant neoplasm, with clear cell renal cell carcinoma (ccRCC, also known as KIRC) accounting for approximately 75% of all RCC cases. The farnesoid X receptor (FXR, encoded by NR1H4), functioning as a nuclear receptor, plays a crucial role in regulating gene transcription. Although the involvement of FXR in tumors of the digestive system and in acute kidney injury has been extensively studied, its specific role in the pathogenesis of ccRCC has yet to be thoroughly investigated. Consequently, the objective of our current investigation is to uncover the functional roles of FXR in ccRCC. In this study, plasmids for the overexpression of FXR were constructed, and small interfering RNA (siRNA) constructs were designed. Dual-luciferase reporter assays confirmed a direct binding interaction between FXR and the promoter of the matrix metalloproteinase 7 (MMP-7) gene. Additionally, a mouse xenograft model elucidated the regulatory effect of FXR on MMP-7 in the context of tumor growth. This study elucidates how FXR regulates the promotion of ccRCC through the MMP-7-mediated EMT pathway. Interestingly, FXR is typically regarded as a tumor suppressor gene that affects gastrointestinal tumors, providing a potential new therapeutic direction for ccRCC., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: All experimental protocols were approved by the Ethics Committee of Wuhan University People’s Hospital and strictly followed the recommendations of the National Institutes of Health Guide for the Care and Use of Laboratory Animals. The study is reported in accordance with the ARRIVE guidelines., (© 2024. The Author(s).)

Objectives: To investigate the effects of propranolol on the proliferation, apoptosis, migration, and tube formation ability of human umbilical vein endothelial cells (HUVEC), as well as its impact on the expression of sex-determining region Y-box 18 (SOX18), matrix metalloproteinase-7 (MMP-7), and vascular endothelial growth factor A (VEGFA)., Methods: HUVEC were treated with different concentrations of propranolol, and cell viability was assessed using the CCK-8 method to determine the optimal concentration and treatment duration. The experiment consisted of a control group and groups treated with different concentrations of propranolol (50, 100, 150 μmol/L). Apoptosis, migration, and tube formation of HUVEC were observed using flow cytometry, wound healing assays, and tube formation assays. Western blot and real-time quantitative PCR were used to detect the expression levels of SOX18, MMP-7, and VEGFA proteins and mRNA., Results: Compared to the control group, the apoptosis rate in the propranolol treatment groups increased significantly ( P <0.05), and it rose significantly with increasing drug concentration ( P <0.05). The wound healing rate decreased in the propranolol treatment groups, and both the number of tube formation nodes and total tube length were reduced ( P <0.05). The expression levels of SOX18, MMP-7, and VEGFA proteins and mRNA were downregulated in the propranolol treatment groups ( P <0.05)., Conclusions: Propranolol can inhibit the proliferation, migration, and tube formation ability of HUVEC and promote cell apoptosis, resulting in decreased expression levels of SOX18, MMP-7, and VEGFA.

Tissue transglutaminase 2 (TGM2) and matrix metalloproteinase 7 (MMP7) are suggested to be involved in cancer development and progression, however, their specific role in colon cancer remains elusive. The present study investigated whether TGM2 and MMP7 influence epithelial-mesenchymal-transition (EMT) processes of colon cancer cells. TGM2 was either overexpressed or knocked down in SW480 and HCT-116 cells, and MMP7 expression and activity analyzed. Conversely, MMP7 was silenced and its correlation with TGM2 expression and activity examined. Co-immunoprecipitation served to evaluate TGM2-MMP7-interaction. TGM2 and MMP7 expression were correlated with invasion, migration, EMT marker expression (E-cadherin, N-cadherin, Slug, Snail), and ERK/MEK signaling. TGM2 overexpression enhanced MMP7 expression and activity, promoted cell invasion, migration and EMT, characterized by increased N-cadherin and Snail/Slug expression. TGM2 knockdown resulted in the opposite effects. Knocking down MMP7 was associated with reduced TGM2 protein expression, cell invasion and migration. Down-regulation of MMP7 diminished ERK/MEK signaling, whereas its up-regulation activated this pathway. The ERK-inhibitor GDC-0994 blocked phosphorylation of MEK/ERK and suppressed TGM2 and MMP7. TGM2 communicates with MMP7 in colon cancer cells forces cell migration and invasion by the MEK/ERK signaling pathway and triggers EMT. Inhibiting TGM2 could thus offer new therapeutic options to treat patients with colon cancer, particularly to prevent metastatic progression., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The alveolar epithelium is protected by a heparan sulfate-rich, glycosaminoglycan layer called the epithelial glycocalyx. It is cleaved in patients with acute respiratory distress syndrome (ARDS) and in murine models of influenza A (IAV) infection, shedding fragments into the airspace from the cell surface. Glycocalyx shedding results in increased permeability of the alveolar-capillary barrier, amplifying acute lung injury. The mechanisms underlying alveolar epithelial glycocalyx shedding in IAV infection are unknown. We hypothesized that induction of host sheddases such as matrix metalloproteinases (MMPs) during IAV infection results in glycocalyx shedding and increased lung injury., Materials and Methods: We measured glycocalyx shedding and lung injury during IAV infection with and without treatment with the pan-MMP inhibitor Ilomastat (ILO) and in an MMP-7 knock out (MMP-7KO) mouse. C57BL/6 or MMP-7KO male and female mice were given IAV A/PR/8/34 (H1N1) at 30,000 PFU/mouse or PBS intratracheally. For some experiments, C56BL/6 mice were infected in the presence of ILO (100mg/kg) or vehicle given daily by IP injection. Bronchoalveolar lavage (BAL) and lung tissue were collected on day 1, 3, and 7 for analysis of glycocalyx shedding (BAL Syndecan-1) and lung injury (histology, BAL protein, BAL cytokines, BAL immune cell infiltrates, BAL RAGE). Expression and localization of the sheddase MMP-7 and its inhibitor TIMP-1 was examined by RNAScope. For in vitro experiments, MLE-12 mouse lung epithelial cells were cultured and treated with active or heat-inactivated heparinase (2.5 U/mL) prior to infection with IAV (MOI 1) and viral load and MMP-7 and TIMP-1 expression analyzed., Results: IAV infection caused shedding of the epithelial glycocalyx into the BAL. Inhibition of MMPs with ILO reduced glycocalyx shedding by 36% (p = 0.0051) and reduced lung epithelial injury by 40% (p = 0.0404). ILO also reduced viral load by 68% (p = 0.027), despite having no significant effect on lung cytokine production. Both MMP-7 and its inhibitor TIMP-1 were upregulated in IAV infected mice: MMP-7 colocalized with IAV, while TIMP-1 was limited to cells adjacent to infection. However, MMP-7KO mice had similar glycocalyx shedding, epithelial injury, and viral load compared to WT littermates, suggesting redundancy in MMP sheddase function in the lung. In vitro, heparinase treatment before infection led to a 52% increase in viral load (p = 0.0038) without altering MMP-7 or TIMP-1 protein levels., Conclusions: Glycocalyx shedding and MMPs play key roles in IAV-induced epithelial injury, with significant impact on IAV viral load. Further studies are needed to understand which specific MMPs regulate lung epithelial glycocalyx shedding., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Schaaf et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To investigate the expression of inositol polyphosphate 4-phosphatase type Ⅱ B (INPP4B) in colorectal cancer (CRC) and the relevant clinical significance, to determine the relationship between INPP4B and matrix metallopeptidase 7 (MMP7) in CRC cells, and to make preliminary exploration of the effects of INPP4B on the proliferation and migration of CRC cells and mechanisms involved., Methods: The TIMER2.0 and GEPIA2 databases were used to analyze the differences in INPP4B expression between cancer and para-cancerous tissues and the effects of such differences on the prognosis of CRC. The expression of INPP4B in 102 surgically resected CRC tumors was determined by immunohistochemistry (IHC), and the correlation between INPP4B and clinical pathological indicators was analyzed. In CRC cells with overexpressed/knocked-down INPP4B , the expression of INPP4B and MMP7 were examined by real time fluorogenic quantitative PCR, the protein expression of INPP4B was assessed by Western blot, cell proliferation was determined using the CellTiter 96® AQueous One assay, and cell migration and invasion were assessed using wound healing assay and real-time label-free dynamic cell analysis (RTCA). The LinkedOmics database was used to analyze signaling pathways related to INPP4B function, and the role of potential key molecules was validated at the cellular level., Results: Analysis with the TIMER2.0 database and GEPIA2 database showed elevated INPP4B expression (colon adenocarcinoma [COAD]: 2.30, rectal adenocarcinoma [READ]: 2.33) in CRC compared to normal tissue (COAD: 1.91, READ: 1.89). IHC testing confirmed that INPP4B was upregulated in clinical CRC tissues and paracancerous tissues ( P <0.001). Cox regression model analysis showed that INPP4B (hazards ratio [HR]=1.457, 95% confidence interval [CI]: 1.003-2.115) affected the prognosis of CRC, and the Kaplan-Meier curve showed that patients with high INPP4B expression had shorter overall survival ( P <0.05). χ 2 test was performed to analyze the relationship between INPP4B expression and clinicopathological indexes, and it was found that high expression of INPP4B was correlated with lymph node metastasis ( χ 2 =3.997, P =0.046) and neural invasion( χ 2 =8.511, P =0.004). In in vitro experiments, CRC cells overexpressing INPP4B showed a significantly increased cell proliferation and migration compared to the cells in the control group ( P <0.05). Analysis using the LinkedOmics database showed that INPP4B was correlated with extracellular matrix remodeling and cell migration. Pearson's correlation analysis showed that MMP7 was positively correlated with INPP4B ( r =0.3782, P <0.001). INPP4B overexpression or knockdown in vitro also led to the upregulation or the downregulation of MMP7 expression in CRC cells., Conclusion: INPP4B is highly expressed in CRC tissues and significantly correlated with lymph node metastasis, neural invasion, and patient prognosis. MMP7 may mediate the role of INPP4B in promoting CRC cell migration and invasion., Competing Interests: 利益冲突　本文作者王玉芳是本刊编委会编委。该文在编辑评审过程中所有流程严格按照期刊政策进行，且未经其本人经手处理。除此之外，所有作者声明不存在利益冲突。, (© 2024《四川大学学报（医学版）》编辑部 版权所有Copyright ©2024 Editorial Office of Journal of Sichuan University (Medical Sciences).)

Intra-tumour immune infiltration is a crucial determinant affecting immunotherapy response in non-small cell lung cancer (NSCLC). However, its phenotype and related spatial structure have remained elusive. To overcome these restrictions, we undertook a comprehensive study comprising spatial transcriptomic (ST) data (28 712 spots from six samples). We identified two distinct intra-tumour infiltration patterns: immune exclusion (characterised by myeloid cells) and immune activation (characterised by plasma cells). The immune exclusion and immune activation signatures showed adverse and favourable roles in NSCLC patients' survival, respectively. Notably, CD14+APOE+ cells were recognised as the main cell type in immune exclusion samples, with increased epithelial‒mesenchymal transition and decreased immune activities. The co-location of CD14+APOE+ cells and MMP7+ tumour cells was observed in both ST and bulk transcriptomics data, validated by multiplex immunofluorescence performed on 20 NSCLC samples. The co-location area exhibited the upregulation of proliferation-related pathways and hypoxia activities. This co-localisation inhibited T-cell infiltration and the formation of tertiary lymphoid structures. Both CD14+APOE+ cells and MMP7+ tumour cells were associated with worse survival. In an immunotherapy cohort from the ORIENT-3 clinical trial, NSCLC patients who responded unfavourably exhibited higher infiltration of CD14+APOE+ cells and MMP7+ tumour cells. Within the co-location area, the MK, SEMA3 and Macrophage migration inhibitory factor (MIF) signalling pathway was most active in cell‒cell communication. This study identified immune exclusion and activation patterns in NSCLC and the co-location of CD14+APOE+ cells and MMP7+ tumour cells as contributors to immune resistance., (© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Colorectal cancer (CRC) is a prevalent cancer with high morbidity and mortality rates worldwide. Late diagnosis is a significant contributor to low survival rates in a minority of cases. The study aimed to perform a robust pipeline using integrated bioinformatics tools that will enable us to identify potential diagnostic and prognostic biomarkers for early detection of CRC by exploring differentially expressed genes (DEGs). In addition to, testing the capability of replacing chemotherapy with plant extract in CRC treatment by validating it using real-time PCR. RNA-seq data from cancerous and adjacent normal tissues were pre-processed and analyzed using various tools such as FastQC, Kallisto, DESeq@ R package, g:Profiler, GNEMANIA-CytoScape and CytoHubba, resulting in the identification of 1641 DEGs enriched in various signaling routes. MMP7, TCF21, and VEGFD were found to be promising diagnostic biomarkers for CRC. An in vitro experiment was conducted to examine the potential anticancer properties of 5-fluorouracile, Withania somnifera extract, and their combination. The extract was found to exhibit a positive trend in gene expression and potential therapeutic value by targeting the three genes; however, further trials are required to regulate the methylation promoter. Molecular docking tests supported the findings by revealing a stable ligand-receptor complex. In conclusion, the study's analysis workflow is precise and robust in identifying DEGs in CRC that may serve as biomarkers for diagnosis and treatment. Additionally, the identified DEGs can be used in future research with larger sample sizes to analyze CRC survival., (© 2023. The Author(s).)

Background/aim: The activity and expression of matrix metalloproteinase-7 (MMP7) have been found to be upregulated in the late stages of endometriosis. However, the contribution of MMP7 genotype to endometriosis has seldom been examined. This study aimed to investigate the role of MMP7 promoter A-181G (rs11568818) and C-153T (rs11568819) genotypes in determining personal susceptibility to endometriosis in a Taiwanese cohort., Patients and Methods: In this hospital-based case-control study, MMP7 genotypes were analyzed in 153 endometriosis and 636 individuals without endometriosis using typical polymerase chain reaction-restriction fragment length polymorphism methodology., Results: The statistical analysis revealed that MMP7 rs11568818 genotypes were differentially distributed between the endometriosis and control groups (p for trend=0.0048). Specifically, the MMP7 rs11568818 homozygous variant GG was associated with endometriosis risk compared to the wild-type AA genotype (OR=4.59, 95% CI=1.46-14.48, p=0.0136). However, the MMP7 rs11568818 heterozygous variant AG was not associated with endometriosis risk (OR=1.57, 95% CI=0.97-2.53, p=0.0854). The frequency of than variant allele G of MMP7 rs11568818 was 12.7% in the endometriosis group, significantly higher than the 7.2% observed in the control group (OR=1.90, 95% CI=1.27-2.82, p=0.0021)., Conclusion: MMP7 rs11568818 GG genotype was found to be a novel marker for endometriosis risk in Taiwanese., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

In sexual assault cases, it is crucial to discriminate between peripheral blood and menstrual blood to provide evidence for vaginal intercourse with traumatic injury. In this study, the menstrual blood mRNA markers progestagen-associated endometrial protein (PAEP), matrix metallopeptidase 7 (MMP7), and left-right determination factor 2 (LEFTY2) were evaluated by quantitative RT-PCR (RT-qPCR) for the discrimination of menstrual blood from peripheral blood and vaginal fluid. As a result, all markers with cutoff delta cycle quantification (ΔCq) values were specifically determined in menstrual blood among forensically relevant body fluids. Even though the changes in the expression levels of each marker differed during the menstrual cycle, all markers were determined to be positive in most of the randomly collected menstrual blood samples that were analyzed. Additionally, the markers with proposed cutoff ΔCq values could discriminate between menstrual blood and peripheral blood-mixed vaginal fluid samples. The determination of positive markers was less affected by storage temperature under dry conditions than under wet conditions, while PAEP was detectable in samples stored below room temperature under wet conditions. The detectability of PAEP was considered to be the result of its higher expression level compared with MMP7 and LEFTY2. In conclusion, menstrual blood markers for the RT-qPCR procedure evaluated in this study were highly specific for menstrual blood. The proposed procedure could be useful for discriminating between menstruation and traumatic bleeding in the female genital tract. In particular, PAEP is expected to be applicable to forensic casework samples because of its high specificity and robustness., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In clinical practice, the diagnosis of ulcerative colitis (UC) mainly relies on a comprehensive analysis of a series of signs and symptoms of patients. The current biomarkers for diagnosis of UC and prognostic prediction of anti-TNF-α therapy are inaccurate. The present study aimed to perform an integrative analysis of gene expression profiles in patients with UC. A total of seven datasets from the GEO database that met our strict inclusion criteria were included. After identifying differentially expressed genes (DEGs) between UC patients and healthy individuals, the diagnostic and prognostic utility of the DEGs were then analyzed via least absolute shrinkage and selection operator and support-vector machine recursive feature elimination. Subgroup analyses of the treated and untreated groups, as well as the treatment-response group and non-response group, were also performed. Furthermore, the relationship between the expressions of UC-related genes and infiltration of immune cells in the course of treatment was also investigated. Immunohistochemical (IHC) assay was used to verify the gene expression in inflamed UC tissues. When considering all the applied methods, DUOX2, PI3, S100P, MMP7, and S100A8 had priority to be defined as the characteristic genes among DEGs. The area under curve (AUC) of the five genes, which were all consistently over-expressed, based on an external validation dataset, were all above 0.94 for UC diagnosis. Four of the five genes (DUOX2, PI3, MMP7, and S100A8) were down-regulated between treatment-responsive and nonresponsive patients. A significant difference was also observed concerning the infiltration of immune cells, including macrophage and neutrophil, between the two groups (treatment responsive and nonresponsive). The changes in the expression of DUOX2 and MMP7 based on the IHC assay were highly consistent with the results obtained in the current study. This confirmed the mild to moderate diagnostic and predictive value of DUOX2 and MMP7 in patients with UC. The conducted analyses showed that the expression profile of the five identified biomarkers accurately detects UC, whereas four of the five genes evidently predicted the response to anti-TNF-α therapy., (© 2024 International Union of Biochemistry and Molecular Biology.)

Matrix metalloproteinases (MMPs) had a variety of subtypes, which may be related to tumor invasion and angiogenesis, and the polymorphisms from MMPs have been also associated with the susceptibility to a variety of tumors, including prostate cancer (PCa). However, previous studies have not systematically analyzed the association between MMP and prostate cancer, so we conducted systematic data collection and analyzed to evaluate the relationship among polymorphisms in MMPs and PCa susceptibility. We searched PubMed, Web of Science, Embase and Google Scholar for all papers published up to Apr 3rd, 2023, and systematically analyzed the relationship among MMP1-1607 2G/1G, MMP2-1306 T/C, MMP2-735 T/C, MMP7-181 G/A, MMP9-1562 T/C and PCa susceptibility using multiple comparative models and subgroup analyses. We found that MMP2-1306 T/C polymorphism showed associations with PCa susceptibility, with the Ethnicity subgroup (Asian) being more pronounced. Similarly, MMP9-1562 T/C has also had associations with PCa susceptibility. Our current study found that the polymorphisms of, MMP2-1306 T/C, and MMP9-1562 T/C had strong associations with PCa risk., (© 2024. The Author(s).)

The skin wound healing process consists of hemostatic, inflammatory, proliferative, and maturation phases, with a complex cellular response by multiple cell types in the epidermis, dermis, and immune system. Magnesium is a mineral essential for life, and although magnesium treatment promotes cutaneous wound healing, the molecular mechanism and timing of action of the healing process are unknown. This study, using human epidermal-derived HaCaT cells and human normal epidermal keratinocyte cells, was performed to investigate the mechanism involved in the effect of magnesium on wound healing. The expression levels of epidermal differentiation-promoting factors were reduced by MgCl 2 , suggesting an inhibitory effect on epidermal differentiation in the remodeling stage of the late wound healing process. On the other hand, MgCl 2 treatment increased the expression of matrix metalloproteinase-7 (MMP7), a cell migration-promoting factor, and enhanced cell migration via the MEK/ERK pathway activation. The enhancement of cell migration by MgCl 2 was inhibited by MMP7 knockdown, suggesting that MgCl 2 enhances cell migration which is mediated by increased MMP7 expression. Our results revealed that MgCl 2 inhibits epidermal differentiation but promotes cell migration, suggesting that applying magnesium to the early wound healing process could be beneficial.

Microfibril-associated glycoprotein-1 (MAGP1), a crucial extracellular matrix protein, contributes to the initiation and progression of different cancers. However, the role of MAGP1 in laryngeal cancer is not clear. The purpose of this study was to investigate the clinical significance and biological function of MAGP1 in laryngeal cancer. MAGP1 was upregulated in public databases and laryngeal cancer tissues, and high MAGP1 expression led to a poor prognosis and was identified as an independent prognostic marker. Knocking-down MAGP1 inhibited laryngeal cancer cell growth and metastasis. According to gene set enrichment analysis, high MAGP1 expression revealed enrichment in Wnt/β-catenin signaling and knocking-down MAGP1 in laryngeal cancer cells also caused degradation, de-activation, re-location and loss of stability of β-catenin. Additionally, we observed MAGP1 in laryngeal cancer cells inhibits angiogenesis in an MMP7-dependent way. In conclusion, our study suggests a clinical role of MAGP1 in laryngeal cancer, signifying its potential as a therapeutic target in the future., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The expression of metastasis tumor-associated protein 2 (MTA2) and protein tyrosine kinase 7 (PTK7) is associated with hepatocellular carcinoma (HCC) progression. However, the functional effect and mechanism through which MTA2 regulates PTK7-mediated HCC progression remains unclear. Here, we found that MTA2 knockdown significantly down-regulated PTK7 expression in HCC cells (SK-Hep-1 and PLC/PRF/5). Data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases show that the PTK7 expression level was higher in HCC tissues than in normal liver tissues. In HCC patients, the PTK7 expression level clearly correlated with tumor stage and grade, lower overall survival (OS) correlated positively with MTA2 level, and PTK7 expression acted as a downstream factor for MTA2 expression. In addition, matrix metalloproteinase 7 (MMP7) expression was closely regulated by PTK7, and the mRNA and protein expression levels of MTA2 and PTK7 correlated positively with lower OS. MMP7 downregulation by PTK7 knockdown clearly decreased the migration and invasion abilities of HCC cells. In HCC cells, recombinant human MMP7 reversed the PTK7 knockdown-induced suppression of migration and invasion. Furthermore, deactivation of FAK using siFAK or FAK inhibitor (PF-573228, PF) synergistically contributed to PTK7 knockdown-inhibited FAK activity, MMP7 expression, and the migration and invasion abilities of HCC cells. Collectively, our findings show that PTK7 mediates HCC progression by regulating the MTA2-FAK-MMP7 axis and may be a diagnostic value for HCC patients., (© 2023 Wiley Periodicals LLC.)

Previous work showed that matrix metalloproteinase-7 (MMP-7) regulates colon cancer activities through an interaction with syndecan-2 (SDC-2) and SDC-2-derived peptide that disrupts this interaction and exhibits anticancer activity in colon cancer. Here, to identify potential anticancer agents, a library of 1,379 Food and Drug Administration (FDA)-approved drugs that interact with the MMP-7 prodomain were virtually screened by protein-ligand docking score analysis using the GalaxyDock3 program. Among five candidates selected based on their structures and total energy values for interacting with the MMP-7 prodomain, the known mechanistic target of rapamycin kinase (mTOR) inhibitor, everolimus, showed the highest binding affinity and the strongest ability to disrupt the interaction of the MMP-7 prodomain with the SDC-2 extracellular domain in vitro. Everolimus treatment of the HCT116 human colon cancer cell line did not affect the mRNA expression levels of MMP-7 and SDC-2 but reduced the adhesion of cells to MMP-7 prodomain-coated plates and the cell-surface localization of MMP-7. Thus, everolimus appears to inhibit the interaction between MMP-7 and SDC-2. Everolimus treatment of HCT116 cells also reduced their gelatin-degradation activity and anticancer activities, including colony formation. Interestingly, cells treated with sirolimus, another mTOR inhibitor, triggered less gelatin-degradation activity, suggesting that this inhibitory effect of everolimus was not due to inhibition of the mTOR pathway. Consistently, everolimus inhibited the colony-forming ability of mTOR-resistant HT29 cells. Together, these data suggest that, in addition to inhibiting mTOR signaling, everolimus exerts anticancer activity by interfering with the interaction of MMP-7 and SDC-2, and could be a useful therapeutic anticancer drug for colon cancer. NEW & NOTEWORTHY The utility of cancer therapeutics targeting the proteolytic activities of MMPs is limited because MMPs are widely distributed throughout the body and involved in many different aspects of cell functions. This work specifically targets the activation of MMP-7 through its interaction with syndecan-2. Notably, everolimus, a known mTOR inhibitor, blocked this interaction, demonstrating a novel role for everolimus in inhibiting mTOR signaling and impairing the interaction of MMP-7 with syndecan-2 in colon cancer.

In this study, we explore the dynamic process of colorectal cancer progression, emphasizing the evolution toward a more metastatic phenotype. The term "evolution" as used in this study specifically denotes the phenotypic transition toward a higher metastatic potency from well-formed glandular structures to collective invasion, ultimately resulting in the development of cancer cell buddings at the invasive front. Our findings highlight the spatial correlation of this evolution with tumor cell senescence, revealing distinct types of senescent tumor cells (types I and II) that play different roles in the overall cancer progression. Type I senescent tumor cells (p16 INK4A+ /CXCL12 + /LAMC2 - /MMP7 - ) are identified in the collective invasion region, whereas type II senescent tumor cells (p16 INK4A+ /CXCL12 + /LAMC2 + /MMP7 + ), representing the final evolved form, are prominently located in the partial-EMT region. Importantly, type II senescent tumor cells associate with local invasion and lymph node metastasis in colorectal cancer, potentially affecting patient prognosis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Gastric cancer (GC) is one of the most common malignancies and ranks third in terms of cancer-related mortality. This study aims to identify the hub genes and potential mechanisms in GC using a bioinformatics approach., Methods: Microarray data GSE54129, GSE79973, GSE55696 were extracted from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) was identified using Benjamini-Hochberg method in the limma package. GO and KEGG pathway enrichment analyses of the DEGs were conducted. Furthermore, protein-protein interaction network was constructed the STRING platform, and the hub genes were discovered using Maximal Clique Centrality method via cytoHubba. The predictive significance of hub genes was evaluated through GSE15459 dataset., Results: A total of 73 genes was identified as DEGs in GC. Volcano plots and heatmaps of DEGs were visualized. Functional enrichment analysis revealed that the genes were mostly enriched in response to xenobiotic stimulus, digestion, cellular hormone metabolic process, extracellular matrix structural constituent, calcium-dependent cysteine-type endopeptidase activity, aromatase activity, apical part of cell, basal part of cell, and apical plasma membrane. Regarding KEGG pathway-enrichment, the genes were mainly involved in Drug metabolism-cytochrome P450, Retinol metabolism, Chemical carcinogenesis-DNA adducts, Gastric acid secretion, and Metabolism of xenobiotics by cytochrome P450. By combining the results of Cytohubba, the top five intersecting genes identified were SPP1, INHBA, MMP7, THBS2 and FAP. Kapplan-Meier analysis results showed that these 5 hub genes were highly related to the overall survival of patients., Conclusion: SPP1, INHBA, MMP7, THBS2, and FAP were identified as prospective biomarkers and therapeutic targets for GC that might be utilized for prognostic evaluation and scheme selection.

Background & Aims: The liver is a common site of cancer metastasis, most commonly from colorectal cancer, and primary liver cancers that have metastasized are associated with poor outcomes. The underlying mechanisms by which the liver defends against these processes are largely unknown. Prohibitin 1 (PHB1) and methionine adenosyltransferase 1A (MAT1A) are highly expressed in the liver. They positively regulate each other and their deletion results in primary liver cancer. Here we investigated their roles in primary and secondary liver cancer metastasis., Methods: We identified common target genes of PHB1 and MAT1A using a metastasis array, and measured promoter activity and transcription factor binding using luciferase reporter assays and chromatin immunoprecipitation, respectively. We examined how PHB1 or MAT1A loss promotes liver cancer metastasis and whether their loss sensitizes to colorectal liver metastasis (CRLM)., Results: Matrix metalloproteinase-7 (MMP-7) is a common target of MAT1A and PHB1 and its induction is responsible for increased migration and invasion when MAT1A or PHB1 is silenced. Mechanistically, PHB1 and MAT1A negatively regulate MMP7 promoter activity via an AP-1 site by repressing the MAFG-FOSB complex. Loss of MAT1A or PHB1 also increased MMP-7 in extracellular vesicles, which were internalized by colon and pancreatic cancer cells to enhance their oncogenicity. Low hepatic MAT1A or PHB1 expression sensitized to CRLM, but not if endogenous hepatic MMP-7 was knocked down first, which lowered CD4 + T cells while increasing CD8 + T cells in the tumor microenvironment. Hepatocytes co-cultured with colorectal cancer cells express less MAT1A/PHB1 but more MMP-7. Consistently, CRLM raised distant hepatocytes' MMP-7 expression in mice and humans., Conclusion: We have identified a PHB1/MAT1A-MAFG/FOSB-MMP-7 axis that controls primary liver cancer metastasis and sensitization to CRLM., Impact and Implications: Primary and secondary liver cancer metastasis is associated with poor outcomes but whether the liver has underlying defense mechanism(s) against metastasis is unknown. Here we examined the hypothesis that hepatic prohibitin 1 (PHB1) and methionine adenosyltransferase 1A (MAT1A) cooperate to defend the liver against metastasis. Our studies found PHB1 and MAT1A form a complex that suppresses matrix metalloproteinase-7 (MMP-7) at the transcriptional level and loss of either PHB1 or MAT1A sensitizes the liver to metastasis via MMP-7 induction. Strategies that target the PHB1/MAT1A-MMP-7 axis may be a promising approach for the treatment of primary and secondary liver cancer metastasis., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background/aim: In the literature, the studies about the role of matrix metalloproteinase-2 (MMP-2) in pterygium diagnosis are mainly based on its protein expression. The role of MMP-2 variants has never been examined. The aim of this study was to examine the association of MMP-2 genotypes with pterygium risk., Materials and Methods: MMP-2 rs243865 and rs2285053 were genotyped in 140 pterygium cases and 280 non-pterygium controls by typical polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) genotyping technology., Results: The genotypic frequency of MMP-2 rs243865 CC, CT and TT were 86.4%, 12.9% and 0.7% in the pterygium group and 81.1%, 17.1% and 1.8% in the non-pterygium group (p for trend=0.3389). The variant CT and TT carriers had a 0.70- and 0.38-fold pterygium risk (95%CI=0.39-1.26 and 0.04-3.25, p=0.2982 and 0.6686, respectively). As for MMP-2 rs2285053, the genotypic frequency of CC, CT and TT were 67.1%, 28.6% and 4.3% in the pterygium group, non-significantly different from those in non-pterygium group (p for trend=0.7081). The CT and TT carriers had a 0.88- and 0.71-fold pterygium risk (95%CI=0.56-1.38 and 0.27-1.88, p=0.6612 and 0.6456, respectively). The allelic analysis results showed that MMP-2 rs243865 variant T allele was not associated with pterygium risk (7.1% versus 10.4%, OR=0.67, 95%CI=0.39-1.13, p=0.1649). As for MMP-2 rs2285053, the T allele was not associated with pterygium risk either (18.6% versus 21.1%, OR=0.85, 95%CI=0.59-1.23, p=0.4136)., Conclusion: The genotypes at MMP-2 rs243865 or rs2285053 played minor role in determining individual susceptibility for pterygium among Taiwanese., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

MMP7 is the smallest member of the MMP family and plays multiple physiological and pathological roles through interaction with a variety of molecules. Purified MMP7 would be beneficial for studying its function and for the development of inhibitors, which could be potential therapeutics. Due to low levels of endogenously produced MMP7, its recombinant expression and purification using E. coli have been established. Here, we describe an effective method to express and purify an active form of MMP7. Our recent discovery is that adding high concentration of CaCl 2 during refolding process prevents nonspecific binding of MMP7 to plastic and its aggregation, significantly improving the yield of active monomeric forms of MMP7., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: The current study aimed to investigate the association of matrix metalloproteinase- (MMP-) 1, -2, -3, -7, and -13 gene polymorphisms with chronic periodontitis (CP) in an Iranian population., Materials and Methods: In this case-control study, 87 subjects with CP and 89 periodontally healthy subjects were allocated to case and control groups, respectively. Subjects' venous blood samples (5 cc) were collected, and DNA extraction was performed. A spectrophotometer was utilized to assess the concentration of extracted DNAs. The desired gene polymorphisms were examined using restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) followed by electrophoresis. Statistical analyses were done using the Pearson Chi-Square test, odds ratio, and t-Test using SPSS Version 28., Results: The MMP-1 (-1607 1G/2G) rs1799750, MMP-3 (-1171 5A/6A) rs3025058, and MMP-7 (-181 A/G) rs11568818 gene polymorphisms significantly differed between case and control groups (PV = 0.019, 0.007, and 0.028, respectively). In contrast, the gene polymorphisms of MMP-2 (-1306 C/T) rs243865 and MMP-13 (-77 A/G) rs2252070 did not make a significant difference. Regarding allele frequencies, the presence of the 2G allele in the MMP-1 (-1607) rs1799750 genotype increased the CP susceptibility significantly, while subjects with the 6A allele in their MMP-3 (-1171) rs3025058 genotype showed significantly lower susceptibility to CP (PV = 0.008 and < 0.001, respectively)., Conclusion: In the studied population, gene polymorphisms in the DNA sequences of MMP-1 (-1607 1G/2G) rs1799750, MMP-3 (-1171 5A/6A) rs3025058, and MMP-7 (-181 A/G) rs11568818 may have impacts on CP incidence., Clinical Relevance: Clinicians should be cautious about the association between MMP-1, MMP-3, and MMP-7 gene polymorphisms and the incidence of chronic periodontitis during periodontal treatment planning., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Colorectal cancer (CRC) is the third most common malignant tumor. Fusobacterium nucleatum (F. nucleatum) is overabundant in CRC and associated with metastasis, but the role of F. nucleatum in CRC cell migration and metastasis has not been fully elucidated., Methods: Differential gene analysis, protein-protein interaction, robust rank aggregation analysis, functional enrichment analysis, and gene set variation analysis were used to figure out the potential vital genes and biological functions affected by F. nucleatum infection. The 16S rDNA sequencing and q-PCR were used to detect the abundance of F. nucleatum in tissues and stools. Then, we assessed the effect of F. nucleatum on CRC cell migration by wound healing and transwell assays, and confirmed the role of Matrix metalloproteinase 7 (MMP7) induced by F. nucleatum in cell migration. Furthermore, we dissected the mechanisms involved in F. nucleatum induced MMP7 expression. We also investigated the MMP7 expression in clinical samples and its correlation with prognosis in CRC patients. Finally, we screened out potential small molecular drugs that targeted MMP7 using the HERB database and molecular docking., Results: F. nucleatum infection altered the gene expression profile and affected immune response, inflammation, biosynthesis, metabolism, adhesion and motility related biological functions in CRC. F. nucleatum was enriched in CRC and promoted the migration of CRC cell by upregulating MMP7 in vitro. MMP7 expression induced by F. nucleatum infection was mediated by the MAPK(JNK)-AP1 axis. MMP7 was highly expressed in CRC and correlated with CMS4 and poor clinical prognosis. Small molecular drugs such as δ-tocotrienol, 3,4-benzopyrene, tea polyphenols, and gallic catechin served as potential targeted therapeutic drugs for F. nucleatum induced MMP7 in CRC., Conclusions: Our study showed that F. nucleatum promoted metastasis-related characteristics of CRC cell by upregulating MMP7 via MAPK(JNK)-AP1 axis. F. nucleatum and MMP7 may serve as potential therapeutic targets for repressing CRC advance and metastasis., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Patients with chronic obstructive pulmonary disease (COPD) have obstructed airflow through their lungs. Single nucleotide polymorphisms in matrix metalloproteinases (MMPs) genes and the risk of COPD have been the subject of numerous studies, with conflicting results. This investigation was conducted to determine whether the MMP7 (T>C) gene variant (rs10502001) was associated with an increased risk of COPD. A case-control study was conducted with 360 subjects (180 healthy controls and 180 COPD cases). The polymerase chain reaction (PCR)-restriction fragment length polymorphism method was used to genotype the SNP rs1050200. mRNA expression of MMP7 was performed using RT-PCR. The genotypic/allelic frequencies and carriage rates of rs10502001 (T>C) polymorphism were evaluated in 180 each of healthy controls and COPD cases. Cases have higher TC/CC genotype frequencies than controls. The "CC" genotype was found to be significantly associated with increased COPD risk ( p  = 0.016). The "C" allele frequency was higher in cases than in controls and showed significant association with COPD ( p  = 0.005). The carriage rate frequencies of T(-) and C(+) were significantly higher in cases than in controls ( p  = 0.031 and 0.047, respectively). MMP7 expression was significantly upregulated ( p  = 0.001) in COPD cases as compared with the controls. In addition, comparisons of MMP7 expression between the COPD cases with different genotypes showed that the "CC" genotype cases had significantly higher expression than those with "TT" genotype. The present findings showed statistically significant correlation of MMP7 (T>C) polymorphism and expression with COPD. Therefore, MMP7 responsible for degradation of elastin has been strongly linked to the progression of COPD.

The Wnt/β-catenin signaling pathway is associated with the regulation of cancer stem cells, and it can be driven by epigenetic modifications. Here, we aim to identify epigenetic modifications involved in the control of the Wnt/β-catenin signaling and investigate the role of this pathway in the accumulation of cancer stem cells (CSC) and chemoresistance of Head and Neck Squamous Cell Carcinoma (HNSCC). Quantitative-PCR, western blot, shRNA assay, viability assay, flow cytometry assay, spheres formation, xenograft model, and chromatin immunoprecipitation were employed to evaluate the Wnt/β-catenin pathway and EZH2 in wild-type and chemoresistant oral carcinoma cell lines, and in the populations of CSC and non-stem cells. We demonstrated that β-catenin and EZH2 were accumulated in cisplatin-resistant and CSC population. The upstream genes of the Wnt/β-catenin signaling (APC and GSK3β) were decreased, and the downstream gene MMP7 was increased in the chemoresistant cell lines. The inhibition of β-catenin and EZH2 combined effectively decreased the CSC population in vitro and reduced the tumor volume and CSC population in vivo. EZH2 inhibition increased APC and GSK3β, and the Wnt/β-catenin inhibition reduced MMP7 levels. In contrast, EZH2 overexpression decreased APC and GSK3β and increased MMP7. EZH2 and β-catenin inhibitors sensitized chemoresistant cells to cisplatin. EZH2 and H3K27me3 bounded the promoter of APC, leading to its repression. These results suggest that EZH2 regulates β-catenin by inhibiting the upstream gene APC contributing to the accumulation of cancer stem cells and chemoresistance. Moreover, the pharmacological inhibition of the Wnt/β-catenin combined with EZH2 can be an effective strategy for treating HNSCC., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Aims: The expression of tissue and serum matrix metalloproteinase-7 (MMP-7) was shown to be elevated both in colon cancer and dysplastic lesions. We aimed to evaluate, for the first time, its role as a diagnostic marker in Lynch syndrome (LS) carriers, a hereditary syndrome with predisposition to colon cancer., Methods: This was a case control study. Baseline serum MMP-7 levels were determined by ELISA in 40 colon cancer patients, 62 LS-carriers and 60 healthy controls. Retrieved data from medical files included demographics, background diseases, clinical data regarding tumor characteristics and genetic data. We assessed the association of serum MMP-7 levels with different variables in the study cohort using linear regression model adjusted for potential confounders., Results: In crude analysis, serum MMP-7 levels were significantly higher in colon cancer group compared to LS-carriers and controls [median (IQR) 4.1 ng/ml (2.7-6.0), 2.3 ng/ml (1.7-3.1), 2.5 ng/ml (1.5-3.7), respectively; p value - p < 0.001) while there was no difference between the two last groups (p value = 0.583). However, after adjusting for age and gender, LS-carriers' patients had 18% higher concentrations of serum MMP-7 compared to healthy controls (p value = 0.037), while colon cancer patients had 50% higher serum MMP-7 level in comparison to healthy controls (p value < 0.001). Additionally, age was positively associated with higher serum MMP-7 levels across all study groups (r = 0.67, p value < 0.001). In contrast, no correlation was observed between serum MMP-7 and either tumor staging and gene mutation., Conclusions: Age-adjusted serum MMP-7 levels in asymptomatic LS carriers are higher than its levels in healthy population. While in colon cancer, MMP-7 higher level probably reflects the tumor burden and may have a prognostic effect, its significance and clinical applicability as a biomarker for tumorigenesis in LS is less clear and should be elucidated., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

The expression level of the progesterone receptor (PGR) plays a crucial role in determining the biological characteristics of serous ovarian carcinoma. Low PGR expression is associated with chemoresistance and a poorer outcome. In this study, our objective was to explore the relationship between tumor progesterone receptor levels and RNA profiles (miRNAs, piwiRNAs, and mRNAs) to understand their biological characteristics and behavior. To achieve this, we employed next-generation sequencing of small non-coding RNAs, quantitative RT-PCR, and immunohistochemistry to analyze both FFPE and frozen tumor samples, as well as blood plasma from patients with benign cystadenoma (BSC), serous borderline tumor (SBT), low-grade serous ovarian carcinoma (LGSOC), and high-grade serous ovarian carcinoma (HGSOC). Our findings revealed significant upregulation of MMP7 and MUC16 , along with downregulation of PGR , in LGSOC and HGSOC compared to BSC. We observed significant correlations of PGR expression levels in tumor tissue with the contents of miR-199a-5p, miR-214-3p, miR-424-3p, miR-424-5p, and miR-125b-5p, which potentially target MUC16, MMP7 , and MMP9 , as well as with the tissue content of miR-16-5p, miR-17-5p, miR-20a-5p, and miR-93-5p, which are associated with the epithelial-mesenchymal transition (EMT) of cells. The levels of EMT-associated miRNAs were significantly correlated with the content of hsa&#95;piR&#95;022437, hsa&#95;piR&#95;009295, hsa&#95;piR&#95;020813, hsa&#95;piR&#95;004307, and hsa&#95;piR&#95;019914 in tumor tissues. We developed two optimal logistic regression models using the quantitation of hsa&#95;piR&#95;020813, miR-16-5p, and hsa&#95;piR&#95;022437 or hsa&#95;piR&#95;004307, hsa&#95;piR&#95;019914, and miR-93-5p in the tumor tissue, which exhibited a significant ability to diagnose the PGR-negative tumor phenotype with 93% sensitivity. Of particular interest, the blood plasma levels of miR-16-5p and hsa&#95;piR&#95;022437 could be used to diagnose the PGR-negative tumor phenotype with 86% sensitivity even before surgery and chemotherapy. This knowledge can help in choosing the most effective treatment strategy for this aggressive type of ovarian cancer, such as neoadjuvant chemotherapy followed by cytoreduction in combination with hyperthermic intraperitoneal chemotherapy and targeted therapy, thus enhancing the treatment's effectiveness and the patient's longevity.

Background: Compared to other breast cancer subtypes, triple-negative breast cancer (TNBC) has always been challenging for clinicians due to its aggressive behavior and lack of a specific treatment. There is a confirmed association between invasive features of tumors and increased epithelial-mesenchymal transition (EMT) process, which is consistent with a higher rate of EMT in TNBC., Methods and Results: We investigated the expression of EMT-related genes, SNAI1 and MMP7, and EMT-related lncRNAs, treRNA and SBF2-AS1, in 50 TNBC tumors and 50 non-TNBC tumors to reveal more regulators and effectors involved in TNBC malignancy. In the present study, we showed the overexpression of all the studied genes and lncRNAs in TNBC tumors compared to non-TNBC samples. Moreover, a significant association was observed between MMP7 and treRNA expression levels and larger tumor size. A positive correlation between SNAI1 and lncRNA treRNA expression levels was also detected., Conclusions: Due to the differential expression and the potential diagnostic power of the studied genes, SBF2-AS1 and treRNA can be proposed as new probable biomarkers and therapeutic targets in TNBC., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Significance Statement: Although gene expression changes have been characterized in human diabetic kidney disease (DKD), unbiased tissue proteomics information for this condition is lacking. The authors conducted an unbiased aptamer-based proteomic analysis of samples from patients with DKD and healthy controls, identifying proteins with levels that associate with kidney function (eGFR) or fibrosis, after adjusting for key covariates. Overall, tissue gene expression only modestly correlated with tissue protein levels. Kidney protein and RNA levels of matrix metalloproteinase 7 (MMP7) strongly correlated with fibrosis and with eGFR. Single-cell RNA sequencing indicated that kidney tubule cells are an important source of MMP7. Furthermore, plasma MMP7 levels predicted future kidney function decline. These findings identify kidney tissue MMP7 as a biomarker of fibrosis and blood MMP7 as a biomarker for future kidney function decline., Background: Diabetic kidney disease (DKD) is responsible for close to half of all ESKD cases. Although unbiased gene expression changes have been extensively characterized in human kidney tissue samples, unbiased protein-level information is not available., Methods: We collected human kidney samples from 23 individuals with DKD and ten healthy controls, gathered associated clinical and demographics information, and implemented histologic analysis. We performed unbiased proteomics using the SomaScan platform and quantified the level of 1305 proteins and analyzed gene expression levels by bulk RNA and single-cell RNA sequencing (scRNA-seq). We validated protein levels in a separate cohort of kidney tissue samples as well as in 11,030 blood samples., Results: Globally, human kidney transcript and protein levels showed only modest correlation. Our analysis identified 14 proteins with kidney tissue levels that correlated with eGFR and found that the levels of 152 proteins correlated with interstitial fibrosis. Of the identified proteins, matrix metalloprotease 7 (MMP7) showed the strongest association with both fibrosis and eGFR. The correlation between tissue MMP7 protein expression and kidney function was validated in external datasets. The levels of MMP7 RNA correlated with fibrosis in the primary and validation datasets. Findings from scRNA-seq pointed to proximal tubules, connecting tubules, and principal cells as likely cellular sources of increased tissue MMP7 expression. Furthermore, plasma MMP7 levels correlated not only with kidney function but also associated with prospective kidney function decline., Conclusions: Our findings, which underscore the value of human kidney tissue proteomics analysis, identify kidney tissue MMP7 as a diagnostic marker of kidney fibrosis and blood MMP7 as a biomarker for future kidney function decline., (Copyright © 2023 by the American Society of Nephrology.)

Chromosome 1 open reading frame 109 (C1orf09) is a protein whose expression pattern and biological function in humans, particularly in malignant tumors, have not been explored. In this study, both bioinformatics and immunohistochemical staining revealed that C1orf109 was overexpressed in the cytoplasm of liver cancer cells, and the positive ratio of C1orf109 in liver cancer samples (42.5%, 37/87) was significantly higher than that in normal liver tissues (10%, 3/30, P = 0.0012). C1orf109 expression was correlated with an advanced TNM stage (P = 0.017) and vascular invasion (P = 0.023) and predicted the poor overall survival of patients with liver cancer (P = 0.001). C1orf109 facilitated tumor growth, colony formation, migration, and invasion by activating Wnt signaling by upregulating non-phosphorylated β-catenin and its downstream target genes such as CyclinD1, c-myc, and MMP7. Our results also suggest that C1orf109 interacts and co-localizes with casein kinase II (CK2) to activate Wnt signaling. Treatment with a CK2-specific inhibitor markedly counteracted the increased expression of CyclinD1, c-Myc, and MMP7, as well as the upregulation of tumor proliferation and invasion caused by C1orf109 overexpression. Taken together, our results indicate that C1orf109 accelerates liver cancer cell proliferation and invasion by strengthening the Wnt signaling pathway in a CK2-dependent manner., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Currently, the clinical outcome of cervical cancer (CC) is still undesirable, and it is urgent to explore more treatment strategies for CC. In this study, the effects of CENPU on migration and stemness of CC was studied. The CENPU expression were retrieved from The Cancer Genome Atlas (TCGA). The effects of CENPU on the viability and proliferation of cells were evaluated by CCK-8 assay and colony formation assay. Wound healing assay and invasion assay were chosen to assess migration and invasion of cells. Tumorsphere-forming assay was applied for testing the stemness. Western blot analysis was applied for assessing the level of CENPU, Nanog, Oct4, FOXM1, β-catenin, c-myc and MMP-7. The tumor sizes and volumes were also measured. The TCGA data and WB assay suggested that CENPU was upregulated in CC. CENPU knockdown would inhibit the viability of CC cells and prohibit the migration and invasion of cells. Tumorsphere-forming assay and WB results suggested that CENPU silencing decreased the sphere formation rate and the expression of Nanog and Oct4. Moreover, CENPU knockdown suppressed the expression of FOXM1, β-catenin, c-myc and MMP-7 by WB. In vivo study demonstrated that CENPU knockdown inhibited the growth of CC, indicated by reduced sizes and volumes of CC. In summary, our results suggested that knockdown of CENPU inhibited CC migration and stemness through the FOXM1/Wnt/β-catenin pathway., Competing Interests: Competing interest The authors state that there are no conflicts of interest to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background/aim: Prostate cancer is one of the most commonly diagnosed malignancies among males worldwide. It has been shown that MMP-7 gene is closely correlated with prostate carcinogenesis. However, the role of the MMP-7 genotypes has been seldom examined among prostate cancer patients. Therefore, the purpose of the study was to evaluate the contribution of MMP-7 promoter genotypes A-181G (rs11568818) and C-153T (rs11568819) to prostate cancer risk in Taiwan., Materials and Methods: Two hundred and eighteen prostate cancer patients and 436 sex- and age-matched healthy controls were genotyped for MMP-7 rs11568818 and rs11568819 by polymerase chain reaction-restriction fragment length polymorphism and direct sequencing methodologies., Results: The percentages of wild-type AA, and variant AG and GG genotypes on MMP-7 rs11568818 were 85.3, 13.5, and 1.2% among the prostate cancer cases and 87.6, 10.1, and 2.3% among the healthy controls, respectively (p for trend=0.2557). Interestingly, no MMP-7 rs11568819 genotypes were identified among Taiwanese. The allelic frequency distribution also showed that the variant G allele of MMP-7 rs11568818 seemed not to be a determinant of prostate cancer risk (p=0.7977). There was no joint effect between the genotypes of MMP-7 rs11568818 and age and smoking status on prostate cancer risk., Conclusion: rs11568818 and rs11568819 at MMP-7 promoter region, played no role in determining personal susceptibility to prostate cancer in Taiwan., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Telocytes (TCs) have crucial functions to promote the metastasis of hepatocellular carcinoma (HCC) by over-expressing matrix metalloproteinases (MMPs), but the mechanism by which TCs secrete MMPs in the genome is still unknown. We first cultured and isolated primary TCs from distinct liver cancer tissues and hepatic hemangioma surrounding tissues (Control group). Their whole exon genes were tested by Illumina HiSeq family of platforms and by high-throughput sequencing as well as variant mutations. Moreover, immunohistochemistry, Western blot, and quantitative reverse transcription-polymerase chain reaction assays were utilized to assess the expression of MMPs. The perniciousness of signal-nucleotide polymorphism (SNP) mutations of proteins were predicted by the Polyphen-2 database. Divergent expression and overall survival (OS) of MMPs was screened by StarBase-Pan Cancer plate; and MMPs associated signaling pathways were found by Kyoto Encyclopedia Genes and Genomes. The "competing endogenous RNA (ceRNA)" network was constructed by Cytoscape software. We found that 12 specific types of SNP mutations related to 5 types of MMPs occurred in TCs of liver malignant tumors as a potential result of MMP1, MMP9, and MMP17 overexpression. High levels of MMP1, MMP7, and MMP9 represented poor OS in HCC, and an interactive network of MMPs is shown. Allele shifts of C/T (rs20544) and G/C (rs2250889) in MMP9 were risk factors for TCs in HCC by the prediction of the Polyphen-2 Database. (MMP9 (-3 C/T)) mutation might be a genetic mechanism of upregulating MMP9 in TCs., (© 2022 International Federation for Cell Biology.)

Bullous lung diseases may cause primary spontaneous pneumothorax (PSP) in children. The microRNAs (miRNAs) are non-coding RNAs that participate in regulation of inflammation and cancer. We hypothesized that children with bullous lung disease and PSP may have altered miRNA expressions in their exhaled breath condensates (EBCs). Therefore, a prospective study was performed to evaluate the miRNA-24 and 21 expression, and the matrix metalloproteinase-7 (MMP-7) levels in EBC of children with PSP. Children with PSP were evaluated for age, gender, clinical features and results of surgical treatment. EBC samples (500-1000 ml) were collected to evaluate the miRNA-21, 24 expressions, and MMP-7, and tissue-inhibitor-MMP-1 (TIMP-1) levels. miRNA expressions and MMP levels of patients were compared with healthy controls (control group (CG), n = 12). Subjects ( n = 16) with a mean age of 15 years (10-19 years), and a male-to-female ratio of 14:2 were enrolled in this study. The most common presenting symptom was sudden chest pain ( n = 14). In 62.5% of the cases an underlying bullous lung disease were detected. During an average of 16.6 months (1-60 months) follow up period, four subjects relapsed. The mean MMP-7 (1.74-1.57 ng ml -1 ), and TIMP-1 (1.92-1.84 ng ml -1 ) levels were similar between both groups ( p > 0.05). miRNA-24 expression was significantly decreased in the PSP group, when compared to the CG (0.16-1 2 -ΔΔCT , p < 0.05). In addition, the miRNA-21 expression was not different between the two groups ( p > 0.05). In conclusion, the miRNA-24 levels were significantly decreased in children with PSP. Taken together, children with PSP, especially those with bullous disease, should be closely monitored in the long-term period., (© 2022 IOP Publishing Ltd.)

Background/aim: Metalloproteinase-7 (MMP-7) has been previously found to be up-regulated in hepatocellular carcinoma (HCC) specimens and cells, favoring epithelial-mesenchymal transition. However, the contribution of MMP-7 genotypes to HCC has not been revealed to date. The study aimed to evaluate the contribution of MMP-7 promoter A-181G (rs11568818) and C-153T (rs11568819) genotypes on the risk of HCC in Taiwan, where HCC incidence is extremely high compared to worldwide data., Materials and Methods: In this case-control study, MMP-7 genotypes and their association with cigarette smoking and alcohol drinking habits were determined in 298 HCC patients and 889 healthy subjects by a typical polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology., Results: Ever smokers and alcohol drinkers were represented with higher percentages in the case group compared to the control group. MMP-7 rs11568818 genotypes were not found differentially distributed in case and control groups (p for trend=0.5246). People of the analyzed cohort of the present study were all of CC genotypes at their rs11568819 polymorphic sites, without any CT or TT genotypes. As for gene-lifestyle interactions, people with variant genotypes at MMP-7 rs11568818 had the same odds for HCC development compared to the wild-type AA genotype, no matter whether the subjects belonged to the smoker, non-smoker alcohol drinker, or non-drinker groups., Conclusion: MMP-7 variant genotypes did not present any significance towards being a marker for HCC risk in Taiwanese., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Obesity is a global epidemic elevating the risk of various metabolic disorders. As there is a lack of effective drugs to treat obesity, we combined bioinformatics and reverse network pharmacology in this study to identify effective herbs to treat obesity. We identified 1011 differentially expressed genes (DEGs) of adipose tissue after weight loss by analyzing five expression profiles (GSE103766, GSE35411, GSE112307, GSE43471, and GSE35710) from the Gene Expression Omnibus (GEO) database. We identified 27 hub genes from the protein-protein interaction (PPI) network by performing MCODE using the Search Tool for the Retrieval of Interacting Genes (STRING) database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses revealed that these hub genes have roles in the extracellular matrix-receptor interaction, cholesterol metabolism, PI3K-Akt signaling pathway, etc. Ten herbs (Aloe, Portulacae Herba, Mori Follum, Silybum Marianum, Phyllanthi Fructus, Pollen Typhae, Ginkgo Semen, Leonuri Herba, Eriobotryae Folium, and Litseae Fructus) targeting the nine hub genes (COL1A1, MMP2, MMP9, SPP1, DNMT3B, MMP7, CETP, COL1A2, and MUC1) using six ingredients were identified as the key herbs. Quercetin and (-)-epigallocatechin-3-gallate were determined to be the key ingredients. Lastly, Ingredients-Targets, Herbs-Ingredients-Targets, and Herbs-Taste-Meridian Tropism networks were constructed using Cytoscape to elucidate this complex relationship. This study could help identify promising therapeutic targets and drugs to treat obesity., (© 2022. The Author(s).)

Background: Previous studies implicated matrix metalloproteinases (MMPs), such as MMP-7, in inflammatory bowel diseases (IBD) by showing increased activity during inflammation of the gut. However, the pathophysiological roles of MMP-7 have not been clearly elucidated., Methods: The expression of MMP-7 was assessed in colonic biopsies of patients with ulcerative colitis (UC), in rodents with experimental colitis, and in cell-based assays with cytokines. Wild-type and MMP-7-null mice treated with dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid were used for determining the pro-inflammatory function(s) of MMP-7 in vivo ., Results: MMP-7 was highly expressed in patients with UC and in rodents with experimental colitis. IL-1β, IL-4, IL-13, TNFα, or lipopolysaccharide enhanced MMP-7 expression in human colonic epithelial cells, rat colonic smooth muscle cells, and THP-1-derived macrophages. Active MMP-7 degraded tight junction protein Claudin-7 in epithelial cells, cleaved recombinant Claudin-7 in cell-free system, and increased Caco-2 monolayer permeability. Immunostaining of colon biopsies revealed up-regulation of MMP-7 and reduction of Claudin-7 in UC patients. Compared to wild-type mice, Mmp7 -/- mice had significantly less inflammation in the colon upon DSS insult. DSS-induced alterations in junction proteins were mitigated in Mmp7 -/- mice, suggesting that MMP-7 disrupts the intestinal barrier. MMP-7 antibody significantly ameliorated colonic inflammation and Claudin-7 reduction in 2 different rodent models of colitis., Summary: MMP-7 impairs intestinal epithelial barrier by cleavage of Claudin-7, and thus aggravating inflammation. These studies uncovered Claudin-7 as a novel substrate of MMP-7 in the intestinal epithelium and reinforced MMP-7 as a potential therapeutic target for IBD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xiao, Lian, Zhong, Krishnachaitanya, Cong, Dashwood, Savidge, Powell, Liu and Li.)

Prior studies have shown that genetic factors play important roles in ovarian endometriosis. Herein, we first analyzed the whole-exome sequencing data from 158 patients with ovarian endometriosis and 385 local control women without endometriosis. Among which, a rare missense variant in the MMP7 (p.I79T, rs150338402) gene exhibited a significant frequency difference. This rare variant was screened in an additional 1176 patients and 600 control women via direct DNA sequencing. Meanwhile, a total of 38 available clinical characteristics were collected. Our results showed 45 out of 1334 (3.37%) patients, while 15 out of 985 control women (1.52%) (P = 0.0076) harbored this rare variant, respectively. This rare variant was associated with clinical features such as follicle-stimulating hormone (Padj = 0.0342), luteinizing hormone (Padj = 0.0038), progesterone (Padj = 1.4e-7), testosterone (Padj = 0.0923), total bilirubin (Padj = 0.0699), carcinoembryonic antigen (Padj = 0.0665) and squamous cell carcinoma antigen (Padj = 0.0817), respectively. Functional assays showed that this rare variant could promote cell migration, invasion, epithelial-mesenchymal transition (EMT) and increase the proteolytic protein activity of MMP7, implicating that the increased capacities of cell invasion, migration and EMT might be mediated by enhanced proteolytic activity of MMP7 mutant. These results showed that the MMP7 rare missense variant (p.I79T) played important roles in the pathogenesis of ovarian endometriosis. In conclusion, we identified, for the first time, a significantly enriched MMP7 rare variant in ovarian endometriosis; this rare variant was closely associated with certain clinical features in ovarian endometriosis; thus, it could be a promising early diagnostic biomarker for this disease., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Importance: The use of neoadjuvant therapy (NAT) in resectable pancreatic ductal adenocarcinoma (PDAC) remains controversial. A favorable pathologic response (complete or marked tumor regression) to NAT is associated with better outcomes in patients with resected PDAC. The role of NAT for early systemic control compared with immediate surgical resection for PDAC is under investigation. In the era of precision medicine, biomarkers for patient selection and prediction of therapy response are crucial., Objective: To evaluate the use of assessment for protein expression on fine-needle aspiration (FNA) biopsy specimens in predicting pathologic response to NAT in treatment-naive patients., Design, Setting, and Participants: This was a single-institution prognostic study from a high-volume center for pancreatic cancer. All specimens were obtained between January 1, 2009, and December 31, 2018, with a median (SE) follow-up of 20.2 (1.4) months. Analysis of the data was performed from October 1, 2019, to April 30, 2021. Targeted RNA sequencing of frozen FNA biopsy specimens from a discovery cohort of 23 patients was performed to identify genes with aberrant expression that was associated with patients' pathologic response to NAT. Immunohistochemical staining was performed on an additional 80 FNA biopsy specimens to assess expression of matrix metalloproteinase 7 (MMP-7) and its association with pathologic response. Receiver operating characteristic curves for prediction of favorable pathologic response were determined., Results: In the discovery cohort (12 [52.1%] male; 3 [13.0%] Black and 20 [86.9%] White), RNA sequencing showed that lower MMP-7 expression was associated with favorable pathologic response (College of American Pathologists system scores of 0 [complete response] and 1 [marked response]). In the validation cohort (40 [50.0%] female; 9 [11.3%] Black and 71 [88.7%] White), patients with negative MMP-7 expression were significantly more likely to have a favorable pathologic response (odds ratio, 21.25; 95% CI, 6.19-72.95; P = .001). Receiver operating characteristic curves for prediction of favorable pathologic response from multivariable Cox proportional hazards regression modeling showed that MMP-7 expression increased the area under the curve from 0.726 to 0.906 (P < .001) even after stratifying by resectability status. The positive predictive value and negative predictive value of MMP-7 protein expression on FNA biopsy specimens in predicting unfavorable pathologic response (scores of 2 [partial response] or 3 [poor or no response]) were 88.2% and 73.9%, respectively., Conclusions and Relevance: Assessment of MMP-7 expression on FNA biopsy specimens at the time of diagnosis may help identify patients who would benefit the most from NAT.

Epithelial-to-mesenchymal transition (EMT) displays a critical role in the development of renal fibrosis, an important pathological process of chronic kidney disease (CKD). Transcription factor Cut-like homeobox 1 (CUX1) has shown profound effects on several kidney diseases. However, its role in CKD has not been understood yet. In this study, unilateral ureteric obstruction (UUO) surgery was performed on male C57BL/6 mice to simulate CKD in vivo. Renal fibrosis was further induced in human proximal tubular epithelial cell (HK-2) by TGF-β1 stimulation. CUX1 and MMP7 were found to be over-expressed in renal tissue of UUO mice. Renal functional analyses and histological assessment indicated that CUX1 knockdown alleviated renal injury in UUO mice. Mitochondrial dysfunction was determined in UUO group and improved after CUX1 silencing. Besides, CUX1 knockdown suppressed EMT in UUO mice and TGF-β1 treated HK-2 cells, as evidenced by reduced expressions of α-SMA, vimentin, fibronectin and augmented abundance of E-cadherin. Furthermore, CUX1 knockdown decreased MMP7 expression by targeting at its promoter region. MMP7 was responsible for the inhibitory effect of CUX1 knockdown on EMT in HK-2 cells. In summary, our findings suggest that CUX1 promotes EMT in CKD by targeting MMP7, and highlight the crucial role of CUX1 in CKD pathogenesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Chronic pancreatitis (CP) is a fibroinflammatory disorder of the pancreas. Our understanding of CP pathogenesis is partly limited by the incomplete characterization of pancreatic cell types. Here, we performed single-cell RNA sequencing on 3825 cells from the pancreas of one control mouse and mice with caerulein-induced CP. An analysis of the single-cell transcriptomes revealed 16 unique clusters and cell type-specific gene expression patterns in the mouse pancreas. Sub-clustering of the pancreatic mesenchymal cells from the control mouse revealed four clusters of cells with specific gene expression profiles (combinatorial expressions of Smoc2 , Cxcl14 , Tnfaip6 , and Fn1 ). We observed that immune cells in the pancreas of the CP mice were abundant and diverse in cellular type. Compared to the control, 547 upregulated genes (including Mmp7 , Ttr , Rgs5 , Adh1 , and Cldn2 ) and 257 downregulated genes were identified in ductal cells from the CP group. The elevated expression levels of MMP7 and TTR were further verified in the pancreatic ducts of CP patients. This study provides a preliminary description of the single-cell transcriptome profiles of mouse pancreata and accurately demonstrates the characteristics of pancreatic ductal cells in CP. The findings provide insight into novel disease-specific biomarkers and potential therapeutic targets of CP.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a malignant cancer and chemotherapy ineffectively treats PDAC, leading to the requirement for alternative tumor-targeted treatment. Human amniotic fluid mesenchymal stem cells (hAFMSCs) have been revealed to suppress tumor growth in various cancers and they are a strong candidate for treating PDAC., Methods: To evaluate the effects of hAFMSCs on human pancreatic carcinoma cells (PANC1, AsPC1 and BxPC3 cell lines) and the possible mechanism involved, an in vitro cell coculture system was used. A PANC1 orthotopic xenograft mouse model was established and hAFMSCs were injected intravenously at 4 weeks post-xenograft., Results: An in vitro coculture assay showed that hAFMSCs inhibited PANC1 cell proliferation by inducing S phase cell cycle arrest and increased cell apoptosis in a time-dependent manner. In PANC1 cells, hAFMSCs caused the downregulation of Cyclin A and Cyclin B1 as well as the upregulation of p21 (CDKN1A) at 24 h post coculture. The upregulation of pro-apoptotic factors Caspase-3/-8 and Bax at 24 h post coculture reduced the migration and invasion ability of PANC1 cells through inhibiting the epithelial-mesenchymal transition (EMT) process. In a PANC1 orthotopic xenograft mouse model, a single injection of hAFMSCs showed significant tumor growth inhibition with evidence of the modulation of cell cycle and pro-apoptotic regulatory genes and various genes involved in matrix metallopeptidase 7 (MMP7) signaling-triggered EMT process. Histopathological staining showed lower Ki67 levels in tumors from hAFMSCs-treated mice., Conclusions: Our data demonstrated that hAFMSCs strongly inhibit PDAC cell proliferation, tumor growth and invasion, possibly by altering cell cycle arrest and MMP7 signaling-triggered EMT., (© 2022. The Author(s).)

NPC is a type of cancer with a poor prognosis. We aim to excavate the regulatory roles of miR-135b-5p in NPC and uncover the underlying mechanism. The levels of miR-135b-5p and Sirtuin 1 (SIRT1) in NPC and normal tissues and cells were tested via quantitative real-time PCR, western blotting, and immunohistochemistry, respectively. The binding relationship between them was predicted with ENCORI databases and validated with dual-luciferase reporter assay. The impact of miR-135b-5p and SIRT1 on the expressions of matrix metalloproteinase 7 (MMP7) and epithelial-mesenchymal transformation (EMT) proteins in NPC cells was evaluated by western blotting. Metastasis of NPC cells was evaluated by Transwell assay. The binding of c-JUN at the MMP7 promoter and deacetylation of c-JUN were examined using chromatin-immunoprecipitation and co-immunoprecipitation, respectively. The level of miR-135b-5p was increased and SIRT1 was decreased in NPC tissues and cells. miR-135b-5p was validated to target SIRT1. Silencing of miR-135b-5p accelerated EMT and metastasis of NPC cells, whereas knockdown of SIRT1 showed opposite results. Notably, knockdown of SIRT1 partially reversed the miR-135b-5p-induced change of EMT markers and metastasis of NPC cells. Mechanistically, miR-135b-5p disrupted SIRT1-induced deacetylation of c-JUN to promote the activation of MMP7 in NPC cells. miR-135b-5p targeted SIRT1 to inhibit deacetylation of c-JUN and increase MMP7 expression to promote malignancy of NPC cells., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Matrix metalloproteinase 7 (MMP7) is involved in the degradation of extracellular matrix in disease processes and therefore plays an important role in host disease resistance/susceptibility. To better understanding the effects of porcine MMP7 (pMMP7) on piglets diarrhea trait, we characterized pMMP7 gene, identified genetic variations in pMMP7 and explored the relationship between pMMP7 polymorphisms and piglets diarrhea in Min pig and Landrace populations. The complete coding sequence of pMMP7 is 804 bp encoding a protein of 267 amino acids. Sequence alignment showed that the identity between pMMP7 and human MMP7 was approximately 80%. The expression of pMMP7 in the gut of healthy piglets were weak and the distribution of the pMMP7-EGFP fusion protein was observed mainly in the cytoplasm. After the identification of 21 genetic variations in 5' flanking region and exons, Hae III and Eco72 Ⅰ PCR-RFLP were established to genotype SNP rs327380117 and rs329429922, respectively. Statistical analysis indicated that Landrace piglets with a TT genotype at rs327380117 had a lower diarrhea score and day-14 wt than TC piglets (p < 0.05); the diarrhea score of AA Landrace animals with rs329429922 was lower than that of GG individuals (p < 0.05). The findings presented here contribute to the understanding of the biological function of pMMP7 and may provide new molecular markers for pig breeding., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: Matrix metallopeptidase 7 (MMP7) can promote renal fibrosis in diabetic kidney disease (DKD). A study found that LINC01510 overexpression inhibits MMP7 to play a role in renal cancer, but the relationship between the two in DKD had not been revealed, and the function of LINC01510 also needed to be explored, which was also the focus of this study., Methods: The morphological changes of HK-2 cells induced by high glucose were observed by an inverted microscope, and fluorescence in situ hybridization was used to determine the subcellular localization of LINC01510. Quantitative realtime polymerase chain reaction was used to detect the levels of LINC01510 and MMP7. The effect of LINC01510 and MMP7 overexpression on high glucose-induced HK-2 cell migration and epithelial-mesenchymal transition (EMT)-related protein changes was confirmed by wound healing experiments and western blot., Results: High glucose induced HK-2 cells to gradually lose their epithelial phenotype, and decreased LINC01510 in a time-dependent manner. LINC01510 was located in the nucleus of HK-2 cells. LINC01510 overexpression increased the level of LINC01510, inhibited cell migration, and reduced the expression of MMP-7, Vimentin, α-SMA, and Fibronectin protein, and promoted the expression of E-cadherin protein in high glucose-induced cells. The effect of MMP7 overexpression on migration and EMT-related proteins was opposite to the effect of LINC01510 overexpression, and partially reversed the effect of LINC01510 overexpression in high glucose-induced cells., Conclusion: Our research shows that LINC01510 overexpression inactivates MMP7 to attenuate high glucose-induced EMT of renal tubular epithelial cells., (© 2022 by the Association of Clinical Scientists, Inc.)

KRT15 has been reported to act as an oncogene in colorectal cancer. However, whether KRT15 promotes colorectal cancer migration and invasion remain unclear. In this study, western blot and qRT-PCR assay were used to determine the expression of KRT15 in colorectal cancer cells. Wound-healing and transwell migration assay were performed to assess the migration of colorectal cancer cells. Matrigel transwell invasion assay was employed to examine the invasion of colorectal cancer cells. We found that KRT15 was highly expressed in colorectal cancer cells. Ectopic expression of KRT15 dramatically promoted colorectal cancer cell migration and invasion. Conversely, silencing KRT15 remarkably suppressed the migration and invasion of colorectal cancer cells. Importantly, we found that MMP-7 was crucial for KRT15-induced migration and invasion of colorectal cancer cells. Knockdown of MMP-7 significantly diminished the migration and invasion induced by KRT15; overexpression of MMP-7 almost completely rescued the inhibitory effects of KRT15 shRNAs on colorectal cancer cell migration and invasion. In addition, by gain- and loss-of function, we confirmed that β-catenin was responsible for the increased expression of MMP-7 induced by KRT15 colorectal cancer cell lines. In conclusion, KRT15 promotes migration and invasion of colorectal cancer cell at least partly through β-catenin/MMP7 signaling pathway, suggesting KRT15 is a potential therapeutic target for patients with metastatic colorectal cancer., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

To date, no potential markers have been established for predicting prognosis in gastric cancer. Matrix metalloproteinase-7 (MMP-7) has been suggested as a prognostic marker in several cancers. In this study, we aimed to determine the expression of the MMP-7 protein and its polymorphisms in gastric cancer tissues. The association between MMP-7 expression level and clinicopathological characteristics was also evaluated. MMP-7 protein expression and its polymorphisms were investigated in a total of 400 patients using immunohistochemistry and TaqMan SNP genotyping assays. The correlation of MMP-7 expression with clinicopathological characteristics, including tumor location, tumor size, histologic type, lymphatic invasion, vascular invasion, pathological T stage, pathological TNM stage, residual tumor, and CEA level, was investigated. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a multivariate Cox proportional hazards regression model. MMP-7 expression was found in 283 of 400 (70.75%) gastric cancer tissues. Expression of MMP-7 was significantly associated with poor clinicopathological characteristics, including vascular invasion (OR = 6.61, 95%CI = 4.26-9.89, p = 0.024), lymphatic invasion (OR = 8.17, 95%CI = 4.47-12.39, p = 0.017), undifferentiated histologic type (OR = 2.46; 95% CI, 1.31-4.52; p = 0.014), higher TNM stage (stage IV) (OR = 1.48, 95%CI = 1.08-3.08, p = 0.047), and high CEA level (OR = 5.96, 95%CI = 2.12-8.12, p = 0.026). We further observed a significant association of the variant genotype; gastric cancer patients carrying GG of MMP-7 (-181A/G; rs11568818) had a greater increased risk of MMP-7 expression than did wild-type (WT) carriers (AG: odds ratio (OR) = 5.67; 95%CI = 1.57-7.23; p = 0.024 and GG: OR = 8.32; 95%CI = 2.94-11.42;  p = 0.016). These findings suggest that MMP-7 expression can be used to predict the prognosis of gastric cancer patients., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2022 Wareeporn Wattanawongdon et al.)

Background: Acetyl-CoA acyltransferase 1 (ACAT1) is a key enzyme catalyzing the production of mitochondrial ketone bodies. We have shown that ACAT1 is down-regulated in kidney renal clear cell carcinoma (KIRC) previously., Objective: To investigate the reasons for downregulation of ACAT1 in KIRC and explore the underlying mechanisms involved in metastatic inhibition regulated by ACAT1., Methods: The Gene Expression Omnibus (GEO) database was queried for meta-analysis of ACAT1 mRNA expression in KIRC. The UALCAN website was used to compare the methylation levels of the ACAT1 promoter region in KIRC and normal tissues. RT-qPCR was used to quantitate ACAT1 transcription levels. The GCBI and Tarbase V.8 databases were used to predict miRNAs that may target the mRNA of ACAT1. The correlation between mRNA expression of ACAT1, MMP7 (matrix metallopeptidase 7), CDH1 (E-cadherin), EpCAM (epithelial cell adhesion molecule), and VIM (vimentin) was analyzed. Extracellular MMP7 protein was quantitated using an ELISA assay., Results: The methylation level of the ACAT1 promoter region in KIRC was significantly higher than that in the normal kidney tissues. The ACAT1 mRNA expression in the KIRC cell lines was restored after treatment with 5-aza-dC (p < 0.05). MiR-21-5p is a conserved microRNA targeting ACAT1. It is expressed at a significantly higher level in KIRC than in normal tissues (p < 0.001). MiR-21-5p miRNA expression negatively correlates with ACAT1 mRNA expression. The expression of miR-21-5p is higher at the T3-T4 stages and in the histologic grades G3-G4. Patients with high miR-21-5p expression tended to have lower overall survival, suggesting that miR-21-5p could serve as a potentially valuable diagnostic biomarker for KIRC (AUC = 0.957; p < 0.001). A mimetic of miR-21-5p inhibited the expression of ACAT1 mRNA and protein. In addition, ACAT1 mRNA expression positively correlates with CDH1 and EpCAM but is negatively correlated with VIM. Overexpression of ACAT1 suppresses the secretion of MMP7 in KIRC cells., Conclusion: Expression of ACAT1 in KIRC is controlled at two levels, firstly by the hypermethylation of the ACAT1 promoter region and secondly by overexpression of miR-21-5p. Downregulation of ACAT1 expression correlates with epithelial-mesenchymal transition (EMT)., (© 2022. The Author(s) under exclusive licence to The Genetics Society of Korea.)

Background: COVID-19 is an infectious disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Many COVID-19 patients require invasive mechanical ventilation (IMV) while others, even with acute respiratory failure, do not (NIMV). Therefore, we aimed to evaluate serum levels of MMP-7 and molecules related to exhausted T-cells as potential biomarkers to differentiate between IMV and NIMV patients. Methods: 105 patients diagnosed with COVID-19 and confirmed by RT-PCR for SARS-CoV-2 were divided into two groups according to the requirement for IMV. Serum levels of sPD-L1, sPD-L2, sTIM-3, sGal-9 and sMMP-7 were quantified by ELISA and correlated with clinical data. Twelve patients were followed up after eight months to compare the levels of the biomarkers between acute disease and post-COVID-19. Results: IMV patients experienced a lower PaO2/FiO2 (p < 0.0001) and a longer hospital stay (p < 0.0001), and exhibited higher levels of sPD-L1 (p < 0.05), sTIM-3 (p < 0.01) and sMMP-7 (p < 0.0001) when compared with NIMV patients. According to a ROC analysis, sMMP-7 had the highest sensitivity (78%) and specificity (76%) with a cut point of 4.5 ng/mL, followed by sTIM-3 and sPD-L1. Eight months post-COVID-19, IMV patients displayed a significant decrease in the initially high levels of sPD-L1, sTIM-3 and sGal-9, while sPD-L2 was increased, and sMMP-7 was unchanged. Conclusion: Circulating levels of sPD-L1, sTIM-3 and sMMP-7 are potential biomarkers of disease severity to distinguish patients requiring IMV. MMP-7 could also be a marker for the persistence of lung lesions post-COVID-19.