Regulation Of MMP-9 Expression Research Articles

Ibulocydine Inhibits Migration and Invasion of TNBC Cells via MMP-9 Regulation.

Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancer types, indicating a poor survival prognosis with a more aggressive biology of metastasis to the lung and a short response duration to available therapies. Ibulocydine (IB) is a novel (cyclin-dependent kinase) CDK7/9 inhibitor prodrug displaying potent anti-cancer effects against various cancer cell types. We performed in vitro and in vivo experiments to determine whether IB inhibits metastasis and eventually overcomes the poor drug response in TNBC. The result showed that IB inhibited the growth of TNBC cells by inducing caspase-mediated apoptosis and blocking metastasis by reducing MMP-9 expression in vitro. Concurrently, in vivo experiments using the metastasis model showed that IB inhibited metastasis of MDA-MB-231-Luc cells to the lung. Collectively, these results demonstrate that IB inhibited the growth of TNBC cells and blocked metastasis by regulating MMP-9 expression, suggesting a novel therapeutic agent for metastatic TNBC.

Comprehensive Analysis of MICALL2 Reveals Its Potential Roles in EGFR Stabilization and Ovarian Cancer Cell Invasion.

Molecules interacting with CasL (MICALs) are critical mediators of cell motility that act by cytoskeleton rearrangement. However, the molecular mechanisms underlying the regulation of cancer cell invasion remain elusive. The aim of this study was to investigate the potential role of one member of MICALs, i.e., MICALL2, in the invasion and function of ovarian cancer cells. We showed by bioinformatics analysis that MICALL2 expression was significantly higher in tissues of advanced-stage ovarian cancer and associated with poor overall survival of patients. MICALL2 was strongly correlated with the infiltration of multiple types of immune cells and T-cell exhaustion markers. Moreover, enrichment analyses showed that MICALL2 was involved in the tumor-related matrix degradation pathway. Mechanistically, MMP9 was identified as the target gene of MICALL2 for the regulation of invadopodium formation and SKOV3, HO-8910PM cell invasion. In addition, EGFR-AKT-mTOR signaling was identified as the downstream pathway of MICALL2 in the regulation of MMP9 expression. Furthermore, MICALL2 silencing promoted EGFR degradation; however, this effect was abrogated by treatment with the autophagy inhibitors acadesine and chloroquine diphosphate. Silencing of MICALL2 resulted in a suppressive activity of Rac1 while suppressing Rac1 activation attenuated the pro-EGFR, pro-MMP9, and proinvasive effects induced by the overexpression of MICALL2. Collectively, our results indicated that MICALL2 participated in the process of immune infiltration and invasion by ovarian cancer cells. Moreover, MICALL2 prevented EGFR degradation in a Rac1-dependent manner, consequently leading to EGFR-AKT-mTOR-MMP9 signaling activation and invadopodia-mediated matrix degradation.

Regulation of matrix metalloproteinase-9 during monopoiesis and zinc deficiency by chromatin remodeling

IntroductionMatrix metalloproteinase-9 (MMP-9) cleaves various extracellular matrix proteins, hence significantly contributes to numerous physiological but also pathological processes. Monocytic differentiation is associated with increased MMP-9 gene expression. Interestingly, MMP-9 upregulation during monocytic differentiation is paralleled by a decline in intracellular zinc levels. Hence, an influence of zinc on the regulation of MMP-9 expression may exist. Although, previous studies suggest a vital role of zinc regarding MMP-9 activity, the possible relevance of zinc homeostasis during transcriptional regulation of MMP-9 for example via epigenetic mechanisms is rather unclear. AimThis study aims to find a correlation between zinc deficiency and MMP-9 transcriptional regulation, focusing on epigenetics as the possible mechanism behind zinc deficiency-induced changes. MethodsThe effect of differentiation and zinc deficiency on MMP-9 expression and MMP9 promoter accessibility was investigated using the acute promyelocytic cell line NB4. Intracellular free zinc levels were detected by flow cytometry. MMP-9 gene expression was measured by real-time PCR and ELISA. Analysis of chromatin structures was done using chromatin accessibility by real-time PCR (CHART) assay. ResultsDuring monocytic differentiation of NB4 cells, the decrease in intracellular zinc levels was paralleled by an increased production of MMP-9. Assessment of chromatin structure revealed increased accessibility of certain regions within the MMP-9 promoter in differentiated cells. Interestingly, upregulated activation-induced MMP-9 gene expression as well as a more accessible MMP-9 promoter were in zinc-deficient NB4 cells whereas zinc resupplementation reversed the effects. ConclusionThese data demonstrate an important role of epigenetic mechanisms in regulating MMP-9 expression under zinc deficiency. This could provide an encouraging step to expand the research on using zinc for the treatment of various pathological conditions such as inflammatory, vascular and autoimmune diseases resulting from MMP-9 deregulation.

Retracted: LINC01116 Promotes Migration and Invasion of Oral Squamous Cell Carcinoma by Acting as a Competed Endogenous RNA in Regulation of MMP1 Expression.

[This retracts the article DOI: 10.1155/2022/2857022.].

Wnt5a Induces ROR1-Dependent NFkB Activation to Upregulate MMP9 and Enhance Invasiveness in Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) cells migrate to the lymphoid tissue compartments, where they receive growth/survival signals, and protect from spontaneous or drug induced apoptosis. Matrix metallopeptidases (MMP) proteins such as MMP9, a type IV collagenase and key MMP, expressed and released by CLL cells, is necessary to degrade the extracellular matrix (EM) to facilitate such trafficking process. Signaling pathways such as CXCR4/CXCL12 can regulate MMP9 expression in CLL cells, and ibrutinib, a BTK inhibitor can inhibit such upregulation of MMP9. However, we found that higher-level expression of ROR1 also had high-level expression of MMP9 compared to CLL cells with low-to-negligible levels of ROR1. ROR1 (receptor tyrosine kinase-like orphan receptor 1) is an evolutionarily conserved, type I membrane protein expressed on CLL cells. Wnt5a, a non-canonical Wnt factor and ligand for ROR1, was found expressed at significantly higher levels in the plasma of patients with CLL than in age-matched adults (Yu et al., J Clin Invest, 126:585, 2016). Culture of ROR1 expressing CLL cells overnight with serum free media resulted in reduction of expression of MMP9. Such serum starved CLL cells stimulated with exogenous Wnt5a can enhance MMP9 expression. CLL cells stimulated with Wnt5a also can enhance the release of MMP9 into the cultured media. Such effects of Wnt5a could be blocked by zilovertamab (also known as UC-961, or previously known as cirmtuzumab), a humanized mAb specific for ROR1 that can inhibit leukemia-cell ROR1-signaling in patients with CLL (Choi et al., Cell Stem Cell, 22:951, 2018). Next, we examined the NFkB signaling pathway which can regulate MMP9 expression in other cancers. We discovered that Wnt5a could induce NFkB activation via ROR1 dependent mechanism in CLL. Culture of CLL cells overnight with serum free media resulted in attrition of NFkB-p65 activation. Such serum starved CLL cells stimulated with exogenous Wnt5a can induce NFkB-p65 activation. siRNA directed silencing of NFkB-p65 inhibited the Wnt5a enhanced expression and release of MMP9. Moreover, the NFkB inhibitor (CAS 545380-34-5) blocked the capacity of Wnt5a to enhance the expression and release of MMP9. We also performed functional analysis such as invasion assay and found that Wnt5a enhanced the capacity of CLL cells to invade Matrigel in a Boyden-Chamber Assay; such effects could be inhibited by zilovertamab, but not by inhibitors of B-cell receptor/chemokine signaling (e.g., ibrutinib). Moreover, combined therapy of zilovertamab and BTK inhibitors (e.g., ibrutinib) provided additional efficacy to block invasive capability of CLL cells. siRNA directed reduced expression of NFkB-p65 inhibited the capacity of Wnt5a to enhance invasive capability of CLL cells. Wnt5a enhanced invasive capability of CLL cells also could be blocked by NFkB inhibitor. In addition, siRNA directed silencing of MMP9 inhibited the Wnt5a enhanced invasive capability of CLL cells. Moreover, the MMP9 inhibitor (CAS 1177749-58-4) blocked the capacity of Wnt5a to enhance the invasive capacity of CLL cells. These results revealed a better understanding in the regulation of MMP9 expression and invasive capacity of CLL cells, and support clinical evaluation of combined therapy of zilovertamab and BTK inhibitors (e.g., ibrutinib) in CLL or other ROR1 expressing cancers.

Targeting 5‐HT1A Receptors to Correct Perineuronal Net and Social Behavioral Deficits in Fmr1 Knockout Mice, a Model of Fragile X Syndrome

Fragile X syndrome (FXS), caused by FMR1gene silencing and subsequent loss of the RNA‐binding protein FMRP, is the leading monogenic cause of intellectual disability and autism spectrum disorder, characterized by social deficits and repetitive behaviors. Currently, there are no approved medications for FXS. MMP‐9 is an extracellular matrix regulating enzyme and a significant target of FMRP—the loss of FMRP in FXS leads to overexpression of MMP‐9. MMP‐9 degrades perineuronal nets (PNNs) that stabilize glutamatergic and GABAergic neurotransmission, and imbalance in these neurotransmitter systems is a hallmark of FXS, suggesting correcting MMP‐9 overactivity may restore neuronal homeostasis in FXS by normalizing PNNs. For example, we show significantly decreased PNN density in hippocampal CA2 in juvenile Fmr1 knockout (KO) mice, a neural system critical for social memory, compared to wild‐type (WT) mice (P=0.0043, N=8 and 7, respectively). In parallel with PNN deficits, we show that juvenile Fmr1KO mice have social memory impairments compared to WT mice. Juvenile Fmr1 KO mice have no preference for interacting with novel mice than familiar mice (number of interactions, P=0.54; amount of time interacting, P=0.27; N=10). In contrast, WT mice interact more frequently and spend more time with novel mice (P=0.014 and P=0.028, respectively; N=11). Modulating distinct serotonin receptors (5‐HTRs) can regulate MMP‐9 expression, neuroanatomical plasticity, social behaviors, and memory. Previously we showed that FPT, a novel medication candidate with potent 5‐HT1AR agonist activity, increases social interactions in adult Fmr1KO and WT mice (Armstrong et al., 2020 https://doi.org/10.1021/acsptsci.9b00101). However, we did not investigate FPT’s effects on social behavior or social memory in juvenile mice—focusing on critical neurodevelopmental periods—nor have we explored mechanisms underlying FPT’s therapeutic‐like effects. We are now testing the hypothesis that FPT corrects social memory deficits in juvenile Fmr1 KO mice and works, in part, by decreasing MMP‐9 levels and restoring PNN levels in hippocampal CA2 via a 5‐HT1AR mechanism. Results from these studies will provide critical mechanistic information regarding the preclinical neurotherapeutic effects of FPT in FXS.

WFDC2 Contributes to Epithelial-Mesenchymal Transition (EMT) by Activating AKT Signaling Pathway and Regulating MMP-2 Expression [Retraction

[This retracts the article DOI: 10.2147/CMAR.S192950.].

Resveratrol Nanoparticles Suppresses Migration and Invasion of Renal Cell Carcinoma Cells by Inhibiting Matrix Metalloproteinase 2 Expression and Extracellular Signal-Regulated Kinase Pathway.

The aim of this study was to examine the impact of Resveratrol nanoparticles on migration/invasion capacity of renal cell carcinoma (RCC) cells and its mechanism. Human RCC cells were exposed to dimethyl sulfoxide or gradient concentrations of Resveratrol nanoparticles respectively, and U0126 were also added in some experiments. We examined renal cell viability by MTT assay, and wound healing test and Transwell assays were used detect invasion and migration capability of RCC cells. We used Western blotting assay to analyze the protein levels in extracellular signal-regulated kinase (ERK) signaling. We also detected the enzymatic capacity of matrix metalloproteinase 2 (MMP-2) in cells by gelatin enzymatic profiling. Resveratrol nanoparticles treatment significantly suppressed cell viability to migrate and invade RCC cells in a dose-dependent manner. Also, notably were reduced MMP-2 activity and expression, and elevated TIMP-2 level were observed in RCC cells exposed with Resveratrol nanoparticles. Further, Resveratrol nanoparticles treatment significantly decreased only the expression of p-ERK1/2, but not p-p38 and p-JNK. Moreover, U0126, which is the ERK inhibitor, exerted similar role as Resveratrol nanoparticles did. Of note was that, combined use of U0126 and Resveratrol nanoparticles displayed a more intense suppression of MMP-2 activity and expression, and also the viability to migrate and invade the RCC cells, compared with Resveratrol nanoparticles treatment alone. The Resveratrol nanoparticles inhibited RCC cells migration and invasion by regulating MMP2 expression and ERK pathways.

TRIM66 hastens the malignant progression of non-small cell lung cancer via modulating MMP9-mediated TGF-β/SMAD pathway

ObjectiveTo investigate regulatory function and underlying mechanism of TRIM66 in non-small cell lung cancer (NSCLC). MethodsTRIM66 and MMP9 expression in NSCLC cells and tissues was assayed via qRT-PCR and western blot. CCK-8, colony formation, Transwell and flow cytometry assays were conducted to measure cell functional alternations in NSCLC. Western blot was employed to measure expression as well as phosphorylation levels of epithelial-mesenchymal transition-(EMT) and TGF-β/SMAD pathways-related proteins. Co-immunoprecipitation (Co-IP) assay was done to probe interaction between TRIM66 and MMP9. Xenograft in vivo experiment and tumor metastasis model in nude mice were utilized to investigate effects of TRIM66 on tumor growth of NSCLC. ResultsTRIM66 and MMP9 were conspicuously highly expressed in NSCLC cells and tissues. High TRIM66 level was markedly correlated with metastasis. Silencing TRIM66 prominently repressed the proliferation, migration and invasion of transfected cells, while inducing cell apoptosis. Whereas forced expression of TRIM66 exerted the opposite effect. The aberrant expression of TRIM66 modulated EMT pathway. TRIM66 also regulated MMP9 expression, and the interaction between them was validated by Co-IP assay. Overexpression of MMP9 could activate TGF-β/SMAD pathway. Rescue experiments manifested that si-MMP9 or SB431542 could partially reverse phenotypes induced by TRIM66. In vivo experiments revealed that silencing TRIM66 could hamper NSCLC tumor growth and metastasis. ConclusionTRIM66 and MMP9 were up-regulated in NSCLC. TRIM66 facilitated the malignant progression of NSCLC through modulating MMP9-mediated TGF-β/SMAD pathway.

Filamin A Is a Potential Driver of Breast Cancer Metastasis via Regulation of MMP-1.

Recurrent metastasis is a major fatal cause of breast cancer. Regretfully, the driving force and the molecular beneath have not been fully illustrated yet. In this study, a cohort of breast cancer patients with locoregional metastasis was recruited. For them, we collected the matched samples of the primary tumor and metastatic tumor, and then we determined the mutation profiles with whole-exome sequencing (WES). On basis of the profiles, we identified a list of deleterious variants in eight susceptible genes. Of them, filamin A (FLNA) was considered a potential driver gene of metastasis, and its low expression could enhance 5 years’ relapse survival rate by 15%. To prove the finding, we constructed a stable FLNA knockout tumor cell line, which manifested that the cell abilities of proliferation, migration, and invasion were significantly weakened in response to the gene knockout. Subsequently, xenograft mouse experiments further proved that FLNA knockout could inhibit local or distal metastasis. Putting all the results together, we consolidated that FLNA could be a potential driver gene to metastasis of breast cancer, in particular triple-negative breast cancer. Additional experiments also suggested that FLNA might intervene in metastasis via the regulation of MMP-1 expression. In summary, this study demonstrates that FLNA may play as a positive regulator in cancer proliferation and recurrence. It provides new insight into breast cancer metastasis and suggests a potential new therapeutic target for breast cancer therapy.

Inflammatory Cells Accelerated Carotid Artery Calcification via MMP9: Evidences From Single-Cell Analysis

Background: Vascular calcification (VC) is an important predictor of prognosis in atherosclerosis, the phenotypic transformation of vascular smooth muscle cells (VSMCs) is thought to be a process of VC. However, the implications and potential mechanisms for VSMCs phenotypic transition remain unknown.Methods: To study the transformation of vascular smooth muscle cells (VSMCs) in the calcification early period, we analyzed single-cell sequencing data from carotid artery calcified core and paracellular tissue, based on the results of enrichment analysis and protein-protein interaction analysis. Upstream transcription factors were tracked and finally the results were validated using the MESA database.Results: We successfully identified a subpopulation of inflammatory macrophage-like VSMCs and determined that MMP9 is an important factor in the phenotypic transformation of VSMCs. We found that RELA regulates MMP9 expression and that knockdown of RELA attenuated MMP9 expression and reduced the expression of BMP2 and the macrophage marker LGALS3 in vascular smooth muscle in inflammatory states, while serum levels of MMP9 correlated significantly with the inflammatory response.Conclusion: This study reveals that the phenotypic transformation of VSMCs can be regulated by modulating MMP9, providing a new idea for the early treatment of VC.

Ribosomal Protein L23 Drives the Metastasis of Hepatocellular Carcinoma via Upregulating MMP9.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally. Tumor metastasis is one of the major causes of high mortality of HCC. Identifying underlying key factors contributing to invasion and metastasis is critical to understand the molecular mechanisms of HCC metastasis. Here, we identified RNA binding protein L23 (RPL23) as a tumor metastasis driver in HCC. RPL23 was significantly upregulated in HCC tissues compared to adjacent normal tissues, and closely related to poor clinical outcomes in HCC patients. RPL23 depletion inhibited HCC cell proliferation, migration and invasion, and distant metastasis. Mechanistically, RPL23 directly associated with 3’UTR of MMP9, therefore positively regulated MMP9 expression. In conclusion, we identified that RPL23 might play an important role in HCC metastasis in an MMP9-dependent manner and be a potential therapeutic target for HCC tumorigenesis and metastasis.

Downregulated microRNA-149-3p triggers malignant development and predicts worse prognosis in oral squamous cell carcinoma

ObjectiveAccumulating evidence reveals that aberrant expression of microRNAs contributes to the tumorigenesis and development of diverse human cancers. In the current study, we aimed to evaluate the functional role and prognostic value of miR-149-3p in oral squamous cell carcinoma (OSCC). MethodsReal-time polymerase chain reaction (PCR) analysis was performed to detect the expression of miR-149-3p in 70 OSCC patients (64.10 ± 11.97 years; 31 males and 39 females). The prognostic ability of miR-149-3p in OSCC patients was assessed by Kaplan–Meier survival analysis. Transwell assays and cell adhesion assays were used to investigate the impact of miR-149-3p on cell migration and invasion. The regulation of MMP2 expression by miR-149-3p was determined by real-time PCR, western blotting and dual luciferase reporter assay. ResultsOur results revealed a lower level of miR-149-3p in OSCC tissues than in adjacent normal tissues. Downregulation of miR-149-3p was correlated with malignant development and poor outcomes in patients with OSCC. MiR-149-3p repressed the migratory and invasive abilities of OSCC cells. We confirmed that miR-149-3p targeted the 3'-untranslated region of MMP2 mRNA to suppress MMP2 expression. Moreover, the miR-149-3p-mediated decrease in metastasis was reversed by overexpression of MMP2 in OSCC cells. ConclusionOur findings provide an important molecular mechanism by which miR-149-3p inhibits OSCC cell migration and invasion via negative regulation of MMP2 and implicate miR-149-3p as a prospective biomarker and therapeutic target for OSCC.

Up-regulation of matrix metalloproteinases-9 in the kidneys of diabetic rats and the association with neutrophil gelatinase-associated lipocalin

BackgroundMatrix metalloproteinases-9 (MMP-9) can regulate extracellular matrix deposition in diabetic glomerular injury. However, it remains unknown whether MMP-9 is involved in the renal tubular injury. Meanwhile, neutrophil gelatinase-associated lipocalin (NGAL), defined as a biomarker of proximal tubular injury, may influence MMP-9 by forming the MMP-9/NGAL complex. The aim of this study was to investigate MMP-9 expression in proximal renal tubules and the relationship of MMP-9 and NGAL in diabetic rat model treated with Valsartan.MethodsSprague Dawley rats were randomly divided into three groups: Diabetic group, Control group, and Treated group. The diabetic rat model was established by injection of streptozotocin. Related indexes were measured at the end of the 2nd, 4th, 8th and 12th week post-modeling.ResultsIn diabetic groups, the concentrations of MMP-9 markedly increased in the serum and urine of rats in the early stage, even before the appearance of pathological albuminuria. Markedly elevated MMP-9/NGAL complex concentrations were also tested in diabetic groups. Western blot and qPCR tests confirmed that MMP-9 expression levels in the proximal renal tubular epithelial cells of diabetic rats were significantly higher than in control groups (P < 0.05). Correlation analysis showed that MMP-9 was positively correlated with NGAL at both protein and gene expression levels. In addition, Valsartan observably reduced tubular injury as well as MMP-9 expression in diabetic rats.ConclusionsIn diabetic kidney injury, the expression of MMP-9 in the proximal renal tubular epithelial cells was significantly increased. Besides, a positive correlation was found between MMP-9 and NGAL expression, along with high levels of MMP-9/NGAL complex, which indicated that NGAL might participate in the regulation of MMP-9 expression. The administration of Valsartan may reduce this effect.

Porphyromonas gingivalis lipopolysaccharide and gingival fibroblast augment MMP-9 expression of monocytic U937 cells through cyclophilin A.

Intercellular cross-talking was suggested in matrix metalloproteinase (MMP)-9 expression with unknown mechanisms. Studies showed cyclophilin A (CypA) playing an important role in regulating MMP-9 expression in varied diseases. The aim of the study was to examine the CyPA on the MMP-9 augmentation in monocytic U937 cells after Porphyromonas gingivalis (Pg) lipopolysaccharide (LPS) treatment and human gingival fibroblast (hGF) co-culture. In independent culture or co-culture of hGF and U937 cell, quantitative real-time polymerase chain reaction (qPCR) and zymography were selected to examine the mRNA and protein activity of MMP-9, respectively. The CyPA expression was determined by qPCR. LPS could enhance MMP-9 mRNA expression and enzyme activity in U937 cell. However, the enhancements were not observed in hGF. Similarly, LPS enhanced CyPA mRNA in U937, but not in hGF. After co-cultured with hGF, however, MMP-9 and CyPA in U937 increased regardless of the presence/absence of LPS. In U937 cells, the extra-supplied CyPA increased MMP-9 mRNA and enzyme activity, whereas the CyPA inhibitor, cyclosporine A, suppressed the LPS- and co-culture-enhanced MMP-9. Moreover, the inhibitors for MAP kinase, including PD98059 (ERK) and SP600125 (JNK), suppressed the CyPA-enhanced MMP-9 in U937. Through the CyPA pathway, the LPS and the hGF could augment the MMP-9 expression in the U937 cells.

Downregulation of miR‑29b‑3p promotes α‑tubulin deacetylation by targeting the interaction of matrix metalloproteinase‑9 with integrinβ1 in nasal polyps.

Matrix metalloproteinase (MMP)-9 is a key enzyme responsible for extracellular matrix degradation and contributes to the progressive histological changes observed in lower respiratory tract infections. Integrin β1 and α-tubulin are potential MMP-9-interacting proteins, and microRNA (miR)-29b-3p can regulate MMP-9 expression. MMP-9 is highly expressed in chronic rhinosinusitis with nasal polyps (CRSwNPs), regardless of its effects on miR-29b-3p, integrin β1 and α-tubulin expression. In the present study, samples from 100 patients with CRSwNPs were examined via reverse transcription-quantitative PCR to assess the mRNA expression of miR-29b-3p, and western blotting was performed to assess the protein expression of MMP-2, MMP-9, acetyl-α-tubulin, integrin β1 and tissue inhibitor of metalloproteinase 1 (TIMP-1). A dual-luciferase reporter assay was used to verify the direct binding of miR-29b-3p and MMP-2/MMP-9. Co-immunoprecipitation (Co-IP) and GST pull-down assays showed that integrin β1 and α-tubulin were MMP-9-interacting proteins. Cell viability, apoptosis and inflammatory cytokine levels were determined via a Cell Counting Kit-8 assay, flow cytometry and ELISA, respectively. miR-29b-3p expression was found to be positively correlated with MMP-2 and MMP-9 expression. Whereas, TIMP-1 expression was negatively correlated with MMP-2 and MMP-9 expression. The dual-luciferase assay revealed that miR-29b-3p targeted the 3′ untranslated region of MMP-2/MMP-9. The Co-IP and GST pull-down assays showed that MMP-9 could directly bind to integrin β1 and indirectly bind to α-tubulin. Finally, the overexpression of miR-29b-3p decreased the expression of MMP-9 and increased the levels of acetyl-α-tubulin. By contrast, the knockdown of miR-29b-3p increased the expression of MMP-9 and decreased the levels of acetyl-α-tubulin. Additionally, MMP-9 expression was found to be negatively correlated with acetyl-α-tubulin expression. Of note, the expression of integrin β1 did not change following the overexpression and knockdown of MMP-9. Finally, the overexpression of miR-29b-3p not only decreased MMP-9 expression, but also alleviated lipopolysaccharide-induced inflammation in NP69 cells. The results showed that the downregulation of miR-29b-3p promoted α-tubulin deacetylation by increasing the number of MMP-9-integrin β1 complexes in CRSwNPs, thus targeting miR-29b-3p/MMP-9 may be a potential novel strategy for the clinical treatment of CRSwNPs.

Luteolin suppresses androgen receptor-positive triple-negative breast cancer cell proliferation and metastasis by epigenetic regulation of MMP9 expression via the AKT/mTOR signaling pathway

BackgroundTriple-negative breast cancer (TNBC) represents up to 20% of all breast cancers. This cancer lacks the expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. The current therapeutic strategy for patients with this subtype is the use of cytotoxic chemotherapy and surgery. Luteolin is a natural herbal flavonoid and a potential therapeutic candidate for multiple diseases. The use of a treatment that combines Chinese herbal medicine and western medicine is rising in Asia. PurposeThe present study evaluates the effects and molecular mechanisms involved with luteolin treatment and evaluates whether this herb affects androgen receptor-positive breast cancer cell proliferation or metastasis. Study DesignIn vitro evaluation of the effect of luteolin on androgen receptor-positive TNBC cell proliferation and metastasis MethodsCell viability analysis was used for the cytotoxicity test. Colony formation and Bromodeoxyuridine (BrdU) staining-based proliferation experiments were used for cell proliferation. Wound healing and transwell assays were used for in vitro migration/invasion. The RT-qPCR analysis was used for gene expression. Furthermore, ChIP-qPCR analysis was used for epigenetic modification of gene promoters. ResultsLuteolin significantly inhibited the proliferation and metastasis of androgen receptor-positive TNBC. Furthermore, luteolin inactivated the AKT/mTOR signaling pathway and reversed the epithelial-mesenchymal transition (EMT). The combination of luteolin and inhibitors of AKT/mTOR synergistically repressed an androgen receptor-positive TNBC cell proliferation and metastasis. Luteolin also downregulated MMP9 expression by decreasing the levels of the AKT/mTOR promoting H3K27Ac and H3K56A on the MMP9 promoter region. ConclusionOur findings indicate that luteolin inhibited the proliferation and metastasis of androgen receptor-positive TNBC by regulating MMP9 expression through a reduction in the levels of AKT/mTOR-inducing H3K27Ac and H3K56Ac.

Capn4 contributes to tumor invasion and metastasis in gastric cancer via activation of the Wnt/β-catenin/MMP9 signalling pathways

Capn4, a small regulatory subunit of the calpain proteolytic system, functions as a potential tumor promoter in several cancers. However, the biological functions and molecular mechanisms of Capn4 in gastric cancer (GC) remain poorly understood. In the current study, we found that upregulation of Capn4 was detected frequently in GC tissues, and was associated with significantly worse survival among the GC patients. Multivariate analyses revealed that abundance of Capn4 was an independent predictive marker for the poor prognosis of GC. Further, Capn4 knockdown notably suppressed GC invasion and metastasis in vitro. Consistently, a xenograft assay showed that silencing of Capn4 in GC cells suppressed their dissemination to lung tissue in vivo. Moreover, our results indicated that Capn4 promotes gastric cancer metastasis by increasing MMP9 expression, and demonstrated that MMP9 is crucial for the pro-metastasis role of Capn4 in GC cells. Further investigation revealed that Capn4 regulated MMP9 expression via activation of Wnt/β-catenin signaling pathway. Mechanistically, we found that Capn4 can decreased β-catenin ubiquitination to enhance the protein stability of β-catenin in GC cells. Collectively, Capn4 has a central role in gastric cancer metastasis, which could be a potential diagnostic and therapeutic target for GC.

Upregulation of Tubulointerstitial nephritis antigen like 1 promotes gastric cancer growth and metastasis by regulating multiple matrix metallopeptidase expression.

Tubulointerstitial nephritis antigen-like 1 (TINAGL1), as a novel matricellular protein, has been demonstrated to participate in cancer progression, whereas the potential function of TINAGL1 in gastric cancer (GC) remains unknown. The expression pattern of TINAGL1 in GC was examined by immunohistochemistry, ELISA, real-time polymerase chain reaction, and Western blot. Correlation between TINAGL1 and matrix metalloproteinases (MMPs) was analyzed by the GEPIA website and Kaplan-Meier plots database. The lentivirus-based TINAGL1 knockdown, CCK-8, and transwell assays were used to test the function of TINAGL1 in vitro. The role of TINAGL1 was confirmed by subcutaneous xenograft, abdominal dissemination, and lung metastasis model. Microarray experiments, ELISA, real-time polymerase chain reaction, and Western blot were used to identify molecular mechanism. TINAGL1 was increased in GC tumor tissues and associated with poor patient survival. Moreover, TINAGL1 significantly promoted GC cell proliferation and migration in vitro as well as facilitated GC tumor growth and metastasis in vivo. TINAGL1 expression in GC cells was accompanied with increasing MMPs including MMP2, MMP9, MMP11, MMP14, and MMP16. GEPIA database revealed that these MMPs were correlated with TINAGL1 in GC tumors and that the most highly expressed MMP was MMP2. Mechanically, TINAGL1 regulated MMP2 through the JNK signaling pathway activation. Our data highlight that TINAGL1 promotes GC growth and metastasis and regulates MMP2 expression, indicating that TINAGL1 may serve as a therapeutic target for GC.

Bromodomain Epigenetic Protein Promotes Metastatic Potential in Melanoma Cells through Increased Invasiveness and Decreased Macrophage-Mediated Phagocytosis

Bromodomain Epigenetic Protein Promotes Metastatic Potential in Melanoma Cells through Increased Invasiveness and Decreased Macrophage-Mediated Phagocytosis