MMP3

Gene Summary

Gene:MMP3; matrix metallopeptidase 3
Aliases: SL-1, STMY, STR1, CHDS6, MMP-3, STMY1
Location:11q22.2
Summary:Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. This gene encodes an enzyme which degrades fibronectin, laminin, collagens III, IV, IX, and X, and cartilage proteoglycans. The enzyme is thought to be involved in wound repair, progression of atherosclerosis, and tumor initiation. The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:stromelysin-1
Source:NCBIAccessed: 31 August, 2019

Ontology:

What does this gene/protein do?
Show (27)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MMP3 (cancer-related)

Cheng Z, Wei W, Wu Z, et al.
ARPC2 promotes breast cancer proliferation and metastasis.
Oncol Rep. 2019; 41(6):3189-3200 [PubMed] Free Access to Full Article Related Publications
Actin-related protein 2/3 complex (ARPC2) is an actin‑binding component involved in the regulation of actin polymerization. It mediates the formation of branched actin networks and contacts the mother actin filament. Migration and invasion are key processes which enable tumor cells to infiltrate blood vessels or lymphatic vessels, and the actin pathway plays a very important role. Given that ARPC2 is critical to this progression, the present study focused on ARPC2 activity in breast cancer (BrCa) cell invasion and migration. Limited data are available on the expression and role of ARPC2 proteins in breast carcinomas. We screened the Oncomine database for messenger RNAs (mRNAs) that are upregulated in BrCa and found that ARPC2 was one of the most consistently involved mRNAs in BrCa. The analysis of immunohistochemical data revealed that ARPC2 expression was higher in breast cancerous tissues than in adjacent non‑cancerous tissues. In addition, ARPC2 was highly associated with the tumor stage, nodal metastasis, and overall survival of patients with BrCa. We performed siRNA‑ARPC2 transfection to investigate the effect of ARPC2 on the proliferation, migration, invasion and arrest of BrCa cells. It was revealed that ectopic ARPC2 expression significantly upregulated N‑cadherin, vimentin, ZEB1, MMP‑9 and MMP‑3 expression and also activated the TGF‑β pathway to contribute to epithelial‑mesenchymal transition (EMT). These results collectively indicated that ARPC2 promoted the tumorigenesis of breast carcinoma and the initiation of EMT. Therefore, ARPC2 was revealed to be a potential therapeutic target in patients with BrCa.

Li H, Yang F, Chai L, et al.
CCAAT/Enhancer Binding Protein β-Mediated MMP3 Upregulation Promotes Esophageal Squamous Cell Cancer Invasion
Genet Test Mol Biomarkers. 2019; 23(5):304-309 [PubMed] Related Publications

Li Z, Ma Z, Xu X
Long non‑coding RNA MALAT1 correlates with cell viability and mobility by targeting miR‑22‑3p in renal cell carcinoma via the PI3K/Akt pathway.
Oncol Rep. 2019; 41(2):1113-1121 [PubMed] Related Publications
Renal cell carcinoma (RCC) is one of the most common types of cancer of the urinary tract in the world. Long non‑coding RNA MALAT1 (lncR‑MALAT1) is upregulated in RCC and is associated with the proliferation and migration of RCC. The present study aimed to investigate the regulating role of lncR‑MALAT1 in RCC as well as the possible underlying mechanisms. The relative expression of MALAT1 and miR‑22‑3p in RCC tumor tissues and cell lines was detected by qRT‑PCR. CCK‑8 and wound healing assay were used to evaluate cell proliferation and migration ability. Western blot analysis was used to detect the expression of Ki‑67, proliferating cell nuclear antigen (PCNA), matrix metalloproteinase‑3 (MMP‑3), migration and invasion inhibitory protein (MIIP), p‑PI3K and p‑Akt. The relationship between MALAT1 and miR‑22‑3p was examined by bioinformatic prediction analysis and luciferase reporter assay. Immunofluorescence was used to detect the activation of Akt. MALAT1 was highly expressed and the expression of miR‑22‑3p was suppressed in RCC tissues and cell lines. ShRNA‑mediated knockdown of MALAT1 significantly inhibited the viability and mobility of RCC cells in vitro and in vivo. Further experiments revealed that miR‑22‑3p was a target of MALAT1 and that miR‑22‑3p inhibitor abolished the effect of MALAT1 shRNA on cell proliferation, migration and inactivation of PI3K/AKT pathway. In conclusion, lncR‑MALAT1 affected the proliferation and migration of RCC cells by targeting miR‑22‑3p through the inactivation of the PI3K/Akt signaling pathway.

Rahman FU, Bhatti MZ, Ali A, et al.
Dimetallic Ru(II) arene complexes appended on bis-salicylaldimine induce cancer cell death and suppress invasion via p53-dependent signaling.
Eur J Med Chem. 2018; 157:1480-1490 [PubMed] Related Publications
A series of bis-salicylaldimine ligands bearing two ON-donor functions were reacted with dichloro(p-cymene)ruthenium(II) dimer in the presence of base (NaOAc) and a series of four dimetallic Ru(II) arene complexes (Ru(p-cymene))

Mendiola M, Redondo A, Heredia-Soto V, et al.
Predicting Response to Standard First-line Treatment in High-grade Serous Ovarian Carcinoma by Angiogenesis-related Genes.
Anticancer Res. 2018; 38(9):5393-5400 [PubMed] Related Publications
BACKGROUND/AIM: Predicting response to treatment in high-grade serous ovarian carcinoma (HGSOC) still remains a clinical challenge. The standard-of-care for first-line chemotherapy, based on a combination of carboplatin and paclitaxel, achieves a high response rate. However, the development of drug resistance is one of the major limitations to efficacy. Therefore, identification of biomarkers able to predict response to chemotherapy in patients with HGSOC is a critical step for prognosis and treatment of the disease. Several studies suggest that angiogenesis is an important process in the development of ovarian carcinoma and chemoresistance. The aim of this study was to identify a profile of angiogenesis-related genes as a biomarker for response to first-line chemotherapy in HGSOC.
MATERIALS AND METHODS: Formalin-fixed paraffin-embedded samples from 39 patients with HGSOC who underwent surgical cytoreduction and received a first-line chemotherapy with carboplatin and paclitaxel were included in this study. Expression levels of 82 angiogenesis-related genes were measured by quantitative real-time polymerase chain reaction using TaqMan low-density arrays.
RESULTS: Univariate analysis identified five genes [angiopoietin 1 (ANGPT1), aryl hydrocarbon receptor nuclear translocator (ARNT), CD34, epidermal growth factor (EGF) and matrix metallopeptidase 3 (MMP3)] as being statistically associated with response to treatment. Multivariable analysis by Lasso-penalized Cox regression generated a model with the combined expression of seven genes [angiotensinogen (AGT), CD34, EGF, erythropoietin receptor (EPOR), interleukin 8 (IL8), MMP3 and MMP7)]. The area under the receiver operating characteristics curve (0.679) and cross-validated Kaplan-Meier survival curves were used to estimate the accuracy of these predictors.
CONCLUSION: An angiogenesis-related gene expression profile useful for response prediction in HGSOC was identified, supporting the important role of angiogenesis in HGSOC.

Li Y, Wang Y, Sun H, et al.
Association Between Matrix Metalloproteinase-1, 2, 3 Polymorphisms and Oral Cancer Risk: A Meta-Analysis.
Genet Test Mol Biomarkers. 2018; 22(8):456-464 [PubMed] Related Publications
PURPOSE: Numerous studies have estimated the association between matrix metalloproteinases (MMPs) polymorphisms and the risk of oral cancer; the results, however, are inconsistent and conflicting. Therefore, we conducted a meta-analysis to evaluate the association of MMP-1, 2, and 3 polymorphisms with oral cancer risk.
METHODS: A computerized literature search was conducted of electronic databases and search engines. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for each gene, and the heterogeneity among studies was estimated using the Q-test and I
RESULTS: Eighteen studies were included in this meta-analysis. For MMP-1(-1607) 1G/2G, a significant association was observed using the recessive genetic model (OR = 1.47; 95% CI = 1.14-1.91; I
CONCLUSIONS: The MMP-1(-1607) 1G/2G polymorphism is associated with oral cancer risk, and the 2G allele played different roles in Asian and European populations.

Sun Y, Jiang F, Pan Y, et al.
XBP1 promotes tumor invasion and is associated with poor prognosis in oral squamous cell carcinoma.
Oncol Rep. 2018; 40(2):988-998 [PubMed] Related Publications
X‑box‑binding protein 1 (XBP1) contributes to various types of cancer including breast, bladder cancer and esophageal squamous cell carcinoma. The aim of the study was to examine the metastatic role of XBP1 in oral squamous cell carcinoma (OSCC), and identify possible downstream molecules. Immunohistochemical staining was conducted on tissue microarrays comprising 96 OSCC cases to determine the expression level of XBP1 and analyze its association with metastasis, clinicopathological characteristics and survival prognosis. Compared with the adjacent normal tissues of OSCC, the expression of XBP1 was significantly increased in the tumor center and front area, and lymph nodes metastases (P<0.05). A relatively high XBP1 expression was associated with histological grades (P<0.05), advanced clinical stages (P<0.05), unfavorable 5‑year survival (P=0.027). Suppressed XBP1 expression caused a significant reduction of cell invasion capability (P<0.05). AXL and the downstream molecules, such as PI3K, MMP1, MMP3, and uPA were significantly suppressed when XBP1 expression was inhibited in OSCC cells. Once XBP1 was activated by Thapsigargin, AXL expression was restored. Moreover, aberrant AXL expression was associated with XBP1 overexpression in OSCC tissues (P<0.05). In conclusion, XBP1 is a potential target that is relevant to suppressing cell invasion and is associated with patient prognosis in OSCC.

Li Y, Li J, Luo M, et al.
Novel long noncoding RNA NMR promotes tumor progression via NSUN2 and BPTF in esophageal squamous cell carcinoma.
Cancer Lett. 2018; 430:57-66 [PubMed] Related Publications
Long noncoding RNAs (lncRNA) have been implicated in cancer but most of them remain largely unstudied. Here, we identified a novel NSUN2 methylated lncRNA (NMR), which was significantly upregulated in esophageal squamous cell carcinoma (ESCC), functioned as a key regulator of ESCC tumor metastasis and drug resistance. Upregulation of NMR correlated with tumor metastasis and indicated poor overall survival in ESCC patients. Functionally, NMR could promote tumor cell migration and invasion, inhibit cisplatin-induced apoptosis and increase drug resistance in ESCC cells. Mechanistically, transcription of NMR could be upregulated by NF-κB activation after IL-1β and TNF-α treatment. NMR was methylated by NSUN2 and might competitively inhibit methylation of potential mRNAs. NMR could directly bind to chromatin regulator BPTF, and potentially promote MMP3 and MMP10 expression by ERK1/2 pathway through recruiting BPTF to chromatin. Taken together, NMR functions as an oncogenic gene and may serve as new biomarker and therapeutic target in ESCC.

Hong L, Chen W, Wu D, Wang Y
Upregulation of SNHG3 expression associated with poor prognosis and enhances malignant progression of ovarian cancer.
Cancer Biomark. 2018; 22(3):367-374 [PubMed] Related Publications
BACKGROUND: Aberrant expression of long non-coding RNAs is involved in the progression of ovarian cancer. However, the clinical significance and biological functions of SNHG3 expression was little known in ovarian cancer (OC).
METHODS: The SNHG3 expression in ovarian cancer tissues and paired adjacent normal tissues was detected using quantitative real time polymerase chain reaction (qRT-PCR). Gain-of function and loss-of function assays were performed in ovarian cancer cells to demonstrate the effects of SNHG3 expression on cell proliferation and invasion. The relative protein expression levels were determined using western blot analyses.
RESULTS: The expression of SNHG3 was significantly up-regulated in ovarian cancer tissues compared with adjacent normal tissues. Higher SNHG3 expression levels positively associated with FIGO stage, lymph node metastasis, and poor prognosis of ovarian cancer patients. Univariate and multivariate Cox regression analysis implied that FIGO stage, lymph node metastasis, higher SNHG3 expression were independent prognostic factors for overall survival (OS) rate in ovarian cancer patients. Gain-of function and loss-of function assays demonstrated that SNHG3 knockdown inhibited ovarian cancer cell proliferation and invasion abilities. However, SNHG3 overexpression promoted ovarian cancer cell proliferation and invasion abilities. Furthermore, cell proliferation and invasion related protein CyclinD1, CDK1, MMP9 and MMP3 were significantly downregulated after SNHG3 knockdown in ovarian cancer cells, while SNHG3 overexpression had reverse effects. In addition, SNHG3 functioned as an oncogene by regulating GSK3β/β-catenin signaling activity in ovarian cancer.
CONCLUSIONS: Taken together, our data provide that SNHG3 has potential clinical value of and may serve as target of ovarian cancer treatment.

Xu G, Meng L, Yuan D, et al.
MEG3/miR‑21 axis affects cell mobility by suppressing epithelial‑mesenchymal transition in gastric cancer.
Oncol Rep. 2018; 40(1):39-48 [PubMed] Free Access to Full Article Related Publications
The prognosis of patients with gastric cancer remains poor mainly due to distant metastasis. Maternally expressed gene 3 (MEG3), a long non‑coding RNA (lncRNA), is downregulated in various tumor tissues and suppresses tumor progression. miR‑21 is a microRNA which is expressed highly in tumor tissues. In the present study, we investigated the relationship between MEG3 and miR‑21 in regards to the cell mobility of gastric cancer. Our data demonstrated that MEG3 was downregulated while miR‑21 was upregulated in gastric cancer tissues and cell lines by qRT‑PCR. Overexpression of MEG3 suppressed cell mobility of gastric cancer cells (AGS) by downregulating the expression of MMP‑3, MMP‑9 and VEGF. As shown by western blot analysis, overexpression of MEG3 also suppressed epithelial‑mesenchymal transition (EMT) by increasing the expression of an epithelial marker (E‑cadherin) and downregulating the expression of mesenchymal markers (N‑cadherin, Snail and β‑catenin), indicating that MEG3 suppressed cell mobility through the inhibition of EMT in gastric cancer. The expression of miR‑21 was negatively regulated by MEG3 and overexpression of miR‑21 promoted cell mobility of AGS through activation of EMT. Co‑transfection of lncRNA‑MEG3 and miR‑21 mimic counteracted the inhibitory effect on the cell mobility attributed to MEG3, suggesting that the MEG3/miR‑21 axis affects cell mobility by suppressing EMT in gastric cancer. Using a mouse xenograft tumor model, we found that the overexpression of MEG3 suppressed tumor growth and metastasis while overexpression of miR‑21 had the opposite effects. The MEG3/miR‑21 axis affected gastric cancer growth and metastasis through inhibition of EMT in vivo. In conclusion, we demonstrated that the MEG3/miR‑21 axis participates in the tumor progression and metastasis of gastric cancer through the regulation of EMT.

Chu C, Liu X, Bai X, et al.
MiR-519d suppresses breast cancer tumorigenesis and metastasis via targeting MMP3.
Int J Biol Sci. 2018; 14(2):228-236 [PubMed] Free Access to Full Article Related Publications
Breast cancer (BC) is the most common cause of death in women throughout the world. Although microRNAs (miRNAs) have been identified as novel regulators in carcinogenesis, there are still abundant hidden treasure needed to be excavated. In the present study, we found that miR-519d expression was remarkably decreased in both human BC tissues and MCF-7 cells. CCK8 and 5-Ethynyl-2'-deoxyuridine (EdU) assays were used to evaluate cell proliferation. Wound-healing and transwell assays were performed for detection of cell migration and invasion. The results demonstrated miR-519d overexpression dramatically suppressed MCF-7 cells proliferation, migration and invasion. While downregulation of miR-519d by miR-519d inhibitor substantially increased MCF-7 cell carcinogenesis. Further analysis identified Matrix Metalloproteinase-3 (MMP3) as a direct target of miR-519d. QRT-PCR and western blot results indicated the correlative expression of miR-519d and MMP3 in BC tissues and MCF-7 cells. In summary, our data uncovered the novel molecular interaction between miR-519d and MMP3, indicating a therapeutic strategy of miR-519d for BC.

Křivohlavá R, Grobárová V, Neuhöferová E, et al.
Interaction of colon cancer cells with glycoconjugates triggers complex changes in gene expression, glucose transporters and cell invasion.
Mol Med Rep. 2018; 17(4):5508-5517 [PubMed] Related Publications
Glycan metabolism balance is critical for cell prosperity, and macromolecule glycosylation is essential for cell communication, signaling and survival. Thus, glycotherapy may be a potential cancer treatment. The aim of the present study was to determine whether combined synthetic glycoconjugates (GCs) induce changes in gene expression that alter the survival of colon cancer cells. The current study evaluated the effect of the GCs N‑acetyl‑D‑glucosamine modified polyamidoamine dendrimer and calix[4]arene scaffold on cancer cell proliferation, apoptosis, invasion and sensitivity to immune cell‑mediated killing. Using reverse transcription‑quantitative polymerase chain reaction, the expression of genes involved in the aforementioned processes was measured. It was determined that GCs reduce the expression of the glucosaminyltransferases Mgat3 and Mgat5 responsible for surface glycosylation and employed components of the Wnt signaling pathway Wnt2B and Wnt9B. In addition, the calix[4]arene‑based GC reduced cell colony formation; this was accompanied by the downregulation of the metalloproteinase Mmp3. By contrast, the dendrimer‑based GC affected the expression of the glucose transporter components Sglt1 and Egfr1. Therefore, to the best of our knowledge, the present study is the first to reveal that N‑acetyl‑D‑glucosamine‑dendrimer/calix[4]arene GCs alter mRNA expression in a comprehensive way, resulting in the reduced malignant phenotype of the colon cancer cell line HT‑29.

Su YC, Chang H, Sun SJ, et al.
Differential impact of CX3CL1 on lung cancer prognosis in smokers and non-smokers.
Mol Carcinog. 2018; 57(5):629-639 [PubMed] Related Publications
CX3CL1 is a unique chemokine, expressed in both soluble and membrane bound forms, which mediates different biological activities. Recent studies have revealed the potential of CX3CL1 signaling pathway as a target for the treatment of inflammation and cancer. The correlation between expression of CX3CL1 and prognosis of patients varies among cancers. In this study, based on CX3CL1 immunohistochemistry in non-small cell lung cancer, CX3CL1 levels were positively associated with cancer stage (Pearson chi-square, P = 0.048) and lymph node status (P = 0.033). Interestingly, survival effects of CX3CL1 were only observed in patients with smoking history and adenocarcinoma (AD, log rank, P = 0.027), but not in patients with squamous cell carcinoma (SQ). The median survival time of patients with smoking history and low level CX3CL1 expressing AD was 1538 days, while that of patients with smoking history and high level CX3CL1 expressing AD was 396 days. Cox regression models showed adverse effects of high CX3CL1 levels only in AD patients with smoking history (hazard ratio = 3.01, p = 0.034), but not in AD patients without smoking history or in SQ patients with smoking history. The results of this study suggest that CX3CL1 plays different roles in lung tumorigenesis in smokers and non-smokers, and different CX3CL1-based therapeutic strategies are needed depending on patient smoking status and tumor type. Furthermore, high level of CX3CL1 expression enhances nodal metastasis by activating JNK & MMP2/MMP9 activity in lung cancer cells.

Schulten HJ, Bangash M, Karim S, et al.
Comprehensive molecular biomarker identification in breast cancer brain metastases.
J Transl Med. 2017; 15(1):269 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Breast cancer brain metastases (BCBM) develop in about 20-30% of breast cancer (BC) patients. BCBM are associated with dismal prognosis not at least due to lack of valuable molecular therapeutic targets. The aim of the study was to identify new molecular biomarkers and targets in BCBM by using complementary state-of-the-art techniques.
METHODS: We compared array expression profiles of three BCBM with 16 non-brain metastatic BC and 16 primary brain tumors (prBT) using a false discovery rate (FDR) p < 0.05 and fold change (FC) > 2. Biofunctional analysis was conducted on the differentially expressed probe sets. High-density arrays were employed to detect copy number variations (CNVs) and whole exome sequencing (WES) with paired-end reads of 150 bp was utilized to detect gene mutations in the three BCBM.
RESULTS: The top 370 probe sets that were differentially expressed between BCBM and both BC and prBT were in the majority comparably overexpressed in BCBM and included, e.g. the coding genes BCL3, BNIP3, BNIP3P1, BRIP1, CASP14, CDC25A, DMBT1, IDH2, E2F1, MYCN, RAD51, RAD54L, and VDR. A number of small nucleolar RNAs (snoRNAs) were comparably overexpressed in BCBM and included SNORA1, SNORA2A, SNORA9, SNORA10, SNORA22, SNORA24, SNORA30, SNORA37, SNORA38, SNORA52, SNORA71A, SNORA71B, SNORA71C, SNORD13P2, SNORD15A, SNORD34, SNORD35A, SNORD41, SNORD53, and SCARNA22. The top canonical pathway was entitled, role of BRCA1 in DNA damage response. Network analysis revealed key nodes as Akt, ERK1/2, NFkB, and Ras in a predicted activation stage. Downregulated genes in a data set that was shared between BCBM and prBT comprised, e.g. BC cell line invasion markers JUN, MMP3, TFF1, and HAS2. Important cancer genes affected by CNVs included TP53, BRCA1, BRCA2, ERBB2, IDH1, and IDH2. WES detected numerous mutations, some of which affecting BC associated genes as CDH1, HEPACAM, and LOXHD1.
CONCLUSIONS: Using complementary molecular genetic techniques, this study identified shared and unshared molecular events in three highly aberrant BCBM emphasizing the challenge to detect new molecular biomarkers and targets with translational implications. Among new findings with the capacity to gain clinical relevance is the detection of overexpressed snoRNAs known to regulate some critical cellular functions as ribosome biogenesis.

Hu J, Zhang L, Chen Q, et al.
Knockdown of CPEB4 expression suppresses cell migration and invasion via Akt pathway in non-small cell lung cancer.
Cell Biol Int. 2018; 42(11):1484-1491 [PubMed] Related Publications
Cytoplasmic polyadenylation element binding protein 4 (CPEB4) could be an important regulator in variety of cancers. However, the biological function and the underlying molecular mechanism of CPEB4 in non-small cell lung cancer (NSCLC) remains unknown. In this study, we investigated the metastasis role of CPEB4 in NSCLC cells, we knocked down CPEB4 using siRNA. Transwell migration assay and cell invasion assay on Matrigel were presented, and cell migration was also determined by scratch-healing assay. ROS generation were determined by fluorescence probe DCFH2-DA. The protein expression was assessed by ELISA and Western blot analysis. LY294002 were used to inhibit PI3 K/Akt signaling. The data showed that knockdown of CPEB4 inhibited the migration and invasion of NSCLC. Moreover, silencing of CPEB4 reduced Snail and MMP-3 expression in vitro. We also indicated that CPEB4 knockdown increased the ROS expression. Furthermore, we found that silencing of CPEB4 decreased pAkt expression. Taken all together, our data demonstrated that silencing of CPEB4 induces ROS generation, thus suppressing the Akt expression, which finally prevents NSCLC cells invasion and migration. Therefore, CPEB4 may regard as a target to inhibit NSCLC invasion and metastasis through Akt pathway.

Guo L, Hao R, Tian F, et al.
Interferon regulatory factor 5 (IRF5) regulates the expression of matrix metalloproteinase-3 (MMP-3) in human chondrocytes.
Int Immunopharmacol. 2018; 55:231-236 [PubMed] Related Publications
Matrix metalloproteinase-3 (MMP-3) plays a pivotal role in the destruction of articular cartilage in osteoarthritis (OA). The regulation of gene expression of MMP-3 is complicated. Interferon regulatory factor 5 (IRF5) is a member of the interferon regulatory factor family of transcription factors. Little information regarding the biological function of IRF5 on chondrocytes and the pathogenesis of OA has been reported. In the current study, for the first time, we report that IRF5 is expressed in human primary chondrocytes and human chondrosarcoma cell line SW1353 cells. In addition, IRF5 is upregulated in response to TNF-α treatment in a dose dependent manner. Interestingly, IRF5 is significantly higher in chondrocytes from OA patients compared to those from normal subjects. Notably, IRF5 mediates TNF-α- induced expression of MMP-3 in chondrocytes. Overexpression of IRF5 promotes the expression of MMP-3, however, knockdown of IRF5 reduces the expression of MMP-3. Mechanistically, IRF5 is able to enhance the transcription of MMP-3 by binding to its promoter. Also, we found that NF-κB was involved in the effects of IRF-5 on MMP-3 expression. These findings suggest that IRF5 might be a novel pharmacological target for the treatment of OA and RA.

Jędroszka D, Orzechowska M, Hamouz R, et al.
Markers of epithelial-to-mesenchymal transition reflect tumor biology according to patient age and Gleason score in prostate cancer.
PLoS One. 2017; 12(12):e0188842 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Prostate carcinoma (PRAD) is one of the most frequently diagnosed malignancies amongst men worldwide. It is well-known that androgen receptor (AR) plays a pivotal role in a vast majority of prostate tumors. However, recent evidence emerged stating that estrogen receptors (ERs) may also contribute to prostate tumor development. Moreover, progression and aggressiveness of prostate cancer may be associated with differential expression genes of epithelial-to-mesenchymal transition (EMT). Therefore we aimed to assess the significance of receptors status as well as EMT marker genes expression among PRAD patients in accordance to their age and Gleason score.
MATERIALS AND METHODS: We analyzed TCGA gene expression profiles of 497 prostate tumor samples according to 43 genes involved in EMT and 3 hormone receptor genes (AR, ESR1, ESR2) as well as clinical characteristic of cancer patients. Then patients were divided into four groups according to their age and 5 groups according to Gleason score. Next, we evaluated PRAD samples according to relationship between the set of variables in different combinations and compared differential expression in subsequent groups of patients. The analysis was applied using R packages: FactoMineR, gplots, RColorBrewer and NMF.
RESULTS: MFA analysis resulted in distinct grouping of PRAD patients into four age categories according to expression level of AR, ESR1 and ESR2 with the most distinct group of age less than 50 years old. Further investigations indicated opposite expression profiles of EMT markers between different age groups as well as strong association of EMT gene expression with Gleason score. We found that depending on age of prostate cancer patients and Gleason score EMT genes with distinctly altered expression are: KRT18, KRT19, MUC1 and COL4A1, CTNNB1, SNAI2, ZEB1 and MMP3.
CONCLUSIONS: Our major observation is that prostate cancer from patients under 50 years old compared to older ones has entirely different EMT gene expression profiles showing potentially more aggressive invasive phenotype, despite Gleason score classification.

ElSheshtawy NM, Nour MS, Hefny Z, Samir A
Gene polymorphisms of Interleukin 1? and Metalloproteinase 3 in Hepatitis C Infected Patients and Hepatocellular Carcinoma Patients.
Egypt J Immunol. 2017; 24(1):1-8 [PubMed] Related Publications
Cytokines as IL 1? and matrix metalloproteinases (MMPs) are involved in tumor growth, invasion, and remote metastasis in various cancers. IL-1? ?31T/C polymorphism in the promoter region has been linked to an elevated risk of Hepatocellular carcinoma (HCC). MMP3 polymorphism at 1171 has also been linked to an elevated risk and a highly invasive type of HCC. Studying the association between IL-1? 31C/T gene polymorphism and MMP3 11715A/6A gene polymorphism in cases of Hepatitis C virus (HCV) and HCC. The study was done on 20 HCV infected patients, 20 HCC patients and 15 healthy controls. IL-1? 31 C/T and MMP3 1171 5A/6A gene polymorphisms was investigated using restriction fragment length polymorphism discrimination assay. Data revealed that the frequency of IL-1? C/T and MMP3 5A/6A polymorphisms was higher in patient groups (HCC and HCV) compared with healthy controls. A significant association was found between IL-1? C/T, MMP3 5A/6A polymorphism and HCC susceptibility. In conclusion, IL-1? C/T and MMP3 5A/6A polymorphisms are associated with an increased risk of developing HCC in Egyptian patients.

Ni X, Cao X, Wu Y, Wu J
FSTL1 suppresses tumor cell proliferation, invasion and survival in non-small cell lung cancer.
Oncol Rep. 2018; 39(1):13-20 [PubMed] Free Access to Full Article Related Publications
Follistatin like-1 (FSTL1) is a secreted glycoprotein involved in a series of physiological and pathological processes. However, its contribution to the development of cancer, especially the pathogenesis of NSCLC, remains to be elucidated. We explored the expression, function, and molecular mechanism of FSTL1 in NSCLC. In this study, we detected the expression of FSTL1 in a panel of NSCLC cell lines and lung normal epithelial cell line by qRT-PCR and western blot analysis and found that FSTL1 was downregulated in NSCLC cells compared with normal control. Knockdown of FSTL1 with different shRNA sequences result in increased cell proliferation and cell migration, invasion and reduced cell apoptosis in A549 cell line with high FSTL1 endogenous level. FSTL1 overexpression in H446 cell line with low FSTL1 endogenous level suppressed cell proliferation and migration, invasion and increased cell apoptosis. Knockdown and overexpression of FSTL1 caused altered cell cycle. Reduced cell apoptosis was revealed in FSTL1 knockdown cells accompanied by increased FAS expression and decreased FASL, cleaved caspase‑3 and ‑7 expression. By contrast, overexpression of FSTL1 caused reduced FAS level and increased activated caspase‑3 and ‑7 expression, which may lead to increased cell apoptosis. Moreover, the changed migration and invasion ability in FSTL1 sufficient or deficient cells may be caused by alterations in MMP2, MMP3 and MMP9 expression. Altogether, our results revealed the critical tumor-suppression function of FSTL1 in NSCLC progression, suggesting that FSTL1 might be an important factor in NSCLC progression.

Liao S, Xiao S, Chen H, et al.
The receptor for activated protein kinase C promotes cell growth, invasion and migration in cervical cancer.
Int J Oncol. 2017; 51(5):1497-1507 [PubMed] Free Access to Full Article Related Publications
Cervical cancer is one of the most common malignant tumors in women all over the world. However, the exact etiology of cervical cancer remains unclear. The receptor for activated protein kinase C (RACK1) is reported to be involved in tumorigenesis and tumor progression. Besides, the prognostic value of RACK1 in several kinds of tumors has been identified. However, there are limited studies on the functional role of RACK1 in cervical cancer. In this study, we tested the expression level of RACK1 by immunohistochemistry and western blot technologies and find that it is upregulated in cervical cancer. Colony formation and CCK8 assays indicate that RACK1 promotes cell proliferation in CaSki cervical cancer cells. While the silence of RACK1 decreases the cell proliferation in CCK8 analysis. β-galactosidase staining suggests that RACK1 decreases cell senescence in cervical cancer cells. Invasion and migration assay show that RACK1 promotes the invasion and migration of cervical cancer cells. Also, when RACK1 was silenced, it exerts the opposite result. Furthermore, the mRNA expression levels of MMP‑3, MMP‑9 and MMP‑10 were upregulated in RACK1‑overexpressed CaSki cells by qPCR analysis. RACK1 also induces S phase accumulation in cell cycle analysis and suppresses cell apoptosis in cervical cancer cells. Flow cytometry analysis of mitochondria functions suggests that RACK1 increases the mitochondrial membrane potential (Δψm) levels to prevent mitochondrial apoptosis in cervical cancer cells. To explore the possible mechanism of RACK1, we tested and found that RACK1 upregulates the expression of NF-κB, cyclin D1 and CDK4 and downregulates the expression of p53, p38, p21 and STAT1 in cervical cancer cells. These results suggest that RACK1 promotes cell growth and invasion and inhibits the senescence and apoptosis in cervical cancer cells probably by affecting the p53 pathway.

Padala C, Tupurani MA, Puranam K, et al.
Synergistic effect of collagenase-1 (MMP1), stromelysin-1 (MMP3) and gelatinase-B (MMP9) gene polymorphisms in breast cancer.
PLoS One. 2017; 12(9):e0184448 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Extracellular matrix degradation by matrix metalloproteinases (MMPs) is an important mechanism involved in tumor invasion and metastasis. Genetic variations of MMPs have shown association with multiple cancers. The present study is focused to elucidate the association of MMP-1, 3 and 9 genetic variants with respect to epidemiological and clinicopathological variables by haplotype, LD, MDR, survival in silico analyses among South Indian women.
MATERIAL AND METHODS: MMP3-1171 5A/6A and MMP9-1562 C/T SNPs were genotyped by Allele specific polymerase chain reaction and MMP1-1607 1G/2G polymorphism by restriction fragment length polymorphism assays respectively, in 300 BC patients and age-matched 300 healthy controls. Statistical analysis was performed using the SNPStats and SPSS software. Linkage disequilibrium and gene-gene interactions were performed using Haploview and MDR software respectively. Further, transcription factor binding sites in the promoter regions of SNPs under study were carried out using AliBaba2.1 software.
RESULTS: We have observed an increased frequency of 2G-allele of MMP1, 6A-allele of MMP3 and T-allele of MMP9 (p<0.05) respectively in BC subjects. The 2G-6A haplotype (minor alleles of MMP-1 and MMP-3 respectively) has shown an increased susceptibility to BC. Further, MMP polymorphisms were associated with the clinical characteristics of BC patients such as steroid hormone receptor status, lymph node involvement and metastasis. SNP combinations were in perfect LD in controls. MDR analysis revealed a positive interaction between the SNPs. 5-years survival rate and cox-regression analysis showed a significant association with clinicopathological variables.
CONCLUSION: Our results suggest that MMP1-1607 1G/2G, MMP3-1171 5A/6A and MMP9-1562 C/T gene polymorphisms have synergistic effect on breast cancer. The interactions of MMPs clinical risk factors such as lymph node involvement has shown a strong correlation and might influence the 5-years survival rate, suggesting their potential role in the breast carcinogenesis.

Liu H, Dai C, Wu Q, et al.
Expression profiling of long noncoding RNA identifies lnc-MMP3-1 as a prognostic biomarker in external auditory canal squamous cell carcinoma.
Cancer Med. 2017; 6(11):2541-2551 [PubMed] Free Access to Full Article Related Publications
Our previous studies suggested external auditory canal squamous cell carcinoma (EACSCC) is a rare malignancy with heterogeneous outcomes. This study aimed to identify lncRNA profile of EACSCC and determine the clinical application. Differential expression genes (DEGs) were investigated in EACSCC by whole transcriptome lncRNA arrays (GPL23178). RT-PCR was used to quantify the microarray data. Bioinformatics analyses were performed to evaluate DEGs regulations in gene ontology and cellular pathways. Fluorescence in situ hybridization (FISH) was utilized to validate lncRNA expression. The overall survival was determined by Kaplan-Meier and log-rank analyses. Our microarrays data had been submitted to Gene Expression Omnibus (GSE98912). We identified 5621 DEGs (3185 mRNAs, 2436 lncRNAs) in EACSCC. Lnc-MMP3-1 was the top one upregulated lncRNA in EACSCC with fold change of 237.2 (P < 0.001). RT-PCR results showed similar expression levels as microarrays data. Bioinformatics analyses indicated development of EACSCC was involved in aberrant alternations of multiple biological processes and cellular pathways. FSIH assays also found lnc-MMP3-1 was significantly differentially overexpressed in EACSCC (P < 0.001). Tumor lnc-MMP3-1 levels were closely associated with differentiation degree (P = 0.016), tumor invasion (P = 0.015) and TNM stage (P = 0.015). Moreover, lnc-MMP3-1 expression was a significant prognostic factor in EACSCC (χ

Hsieh CL, Liu CM, Chen HA, et al.
Reactive oxygen species-mediated switching expression of MMP-3 in stromal fibroblasts and cancer cells during prostate cancer progression.
Sci Rep. 2017; 7(1):9065 [PubMed] Free Access to Full Article Related Publications
Studies on the aberrant control of extracellular matrices (ECMs) have mainly focused on the role of malignant cells but less on that of stromal fibroblasts during cancer development. Herein, by using paired normal and prostate cancer-associated stromal fibroblasts (CAFs) derived from a coculture cell model and clinical patient samples, we demonstrated that although CAFs promoted prostate cancer growth, matrix metalloproteinase-3 (MMP-3) was lower in CAFs but elevated in prostate cancer cells relative to their normal counterparts. Furthermore, hydrogen peroxide was characterized as the central modulator for altered MMP-3 expression in prostate cancer cells and CAFs, but through different regulatory mechanisms. Treatment of CAFs but not prostate cancer cells with hydrogen peroxide directly inhibited mmp-3 promoter activity with concomitant nuclear translocation of nuclear factor-κB (NF-κB), indicating that NF-κB is the downstream pathway for the transcriptional repression of MMP-3 in CAFs. Hydrogen peroxide reduced thrombospondin 2 (an MMP-3 suppressor) expression in prostate cancer cells by upregulating microRNA-128. To the best of our knowledge, this is the first study to demonstrate the crucial role of reactive oxygen species in the switching expression of MMP-3 in stromal fibroblasts and prostate cancer cells during tumor progression, clarifying how the tumor microenvironment modulates ECM homeostasis control.

Wang S, Zhang C, Zhang Z, et al.
Transcriptome analysis in primary colorectal cancer tissues from patients with and without liver metastases using next-generation sequencing.
Cancer Med. 2017; 6(8):1976-1987 [PubMed] Free Access to Full Article Related Publications
Colorectal cancer (CRC) is the third most common cancer worldwide and liver metastases are the leading cause of death in patients with CRC. In this study, we performed next-generation sequencing profiling on primary colorectal tumor tissues obtained from three CRC patients with liver metastases and three CRC patients without liver metastases to identify differentially expressed genes (DEGs) that might be responsible for the metastases process. After filtering 2690 DEGs, comprising 996 upregulated and 1694 downregulated RNAs, 22 upregulated and 73 downregulated DEGs were identified. Gene ontology (GO) and pathway analyses were performed to determine the underlying mechanisms. Single-organism process (biological process), cell (cellular component), and binding (molecular function) were the most related terms in the GO analysis. We selected the top 13 upregulated and top 12 downregulated genes by fold change to verify their differential expression using quantitative real-time reverse transcription PCR (qRT-PCR) and immunohistochemistry (IHC). The validation showed that three most significantly upregulated DEGs were HOXD10, UGT2A3, and SLC13A2, whereas the five most significantly downregulated DEGs were SPP1, CXCL8, MMP3, OSM, and CXCL6, respectively. These aberrantly expressed genes may play pivotal roles in promoting or inhibiting metastases. Further studies are required to determine the functions of DEGs to promote the diagnosis of metastases and provide novel chemotherapy targets.

Sun Y, Fan X, Zhang Q, et al.
Cancer-associated fibroblasts secrete FGF-1 to promote ovarian proliferation, migration, and invasion through the activation of FGF-1/FGFR4 signaling.
Tumour Biol. 2017; 39(7):1010428317712592 [PubMed] Related Publications
Ovarian cancer is the most lethal gynecologic malignancy, due to its high propensity for metastasis. Cancer-associated fibroblasts, as the dominant component of tumor microenvironment, are crucial for tumor progression. However, the mechanisms underlying the regulation of ovarian cancer cells by cancer-associated fibroblasts remain little known. Here, we first isolated cancer-associated fibroblasts from patients' ovarian tissues and found that cancer-associated fibroblasts promoted SKOV3 cells' proliferation, migration, and invasion. Fibroblast growth factor-1 was identified as a highly increased factor in cancer-associated fibroblasts compared with normal fibroblasts by quantitative reverse transcription polymerase chain reaction (~4.6-fold, p < 0.01) and ELISA assays (~4-fold, p < 0.01). High expression of fibroblast growth factor-1 in cancer-associated fibroblasts either naturally or through gene recombination led to phosphorylation of fibroblast growth factor receptor 4 in SKOV3 cells, which is followed by the activation of mitogen-activated protein kinase/extracellular signal-regulated protein kinase pathway and epithelial-to-mesenchymal transition-associated gene Snail1 and MMP3 expression. Moreover, treatment of SKOV3 cell with fibroblast growth factor receptor inhibitor PD173074 terminated cellular proliferation, migration, and invasion, reduced the phosphorylation level of fibroblast growth factor receptor 4, and suppressed the activation of mitogen-activated protein kinase/extracellular signal-regulated protein kinase pathway. In addition, the expression level of Snail1 and MMP3 was reduced, while the expression level of E-cadherin increased. These observations suggest a crucial role for cancer-associated fibroblasts and fibroblast growth factor-1/fibroblast growth factor receptor 4 signaling in the progression of ovarian cancer. Therefore, this fibroblast growth factor-1/fibroblast growth factor receptor 4 axis may become a potential target for the treatment of ovarian cancer.

Gao Y, Zhang Z, Li K, et al.
Linc-DYNC2H1-4 promotes EMT and CSC phenotypes by acting as a sponge of miR-145 in pancreatic cancer cells.
Cell Death Dis. 2017; 8(7):e2924 [PubMed] Free Access to Full Article Related Publications
The acquisition of epithelial-mesenchymal transition (EMT) and/or existence of a sub-population of cancer stem-like cells (CSC) are associated with malignant behavior and chemoresistance. To identify which factor could promote EMT and CSC formation and uncover the mechanistic role of such factor is important for novel and targeted therapies. In the present study, we found that the long intergenic non-coding RNA linc-DYNC2H1-4 was upregulated in pancreatic cancer cell line BxPC-3-Gem with acquired gemcitabine resistance. Knockdown of linc-DYNC2H1-4 decreased the invasive behavior of BxPC-3-Gem cells while ectopic expression of linc-DYNC2H1-4 promoted the acquisition of EMT and stemness of the parental sensitive cells. Linc-DYNC2H1-4 upregulated ZEB1, the EMT key player, which led to upregulation and downregulation of its targets vimentin and E-cadherin respectively, as well as enhanced the expressions of CSC makers Lin28, Nanog, Sox2 and Oct4. Linc-DYNC2H1-4 is mainly located in the cytosol. Mechanically, it could sponge miR-145 that targets ZEB1, Lin28, Nanog, Sox2, Oct4 to restore these EMT and CSC-associated genes expressions. We proved that MMP3, the nearby gene of linc-DYNC2H1-4 in the sense strand, was also a target of miR-145. Downregulation of MMP3 by miR-145 was reverted by linc-DYNC2H1-4, indicating that competing with miR-145 is one of the mechanisms for linc-DYNC2H1-4 to regulate MMP3. In summary, our results explore the important role of linc-DYNC2H1-4 in the acquisition of EMT and CSC, and the impact it has on gemcitabine resistance in pancreatic cancer cells.

Saladino S, Salamone M, Ghersi G
MDA-MB-231 and 8701BC breast cancer lines promote the migration and invasiveness of ECV304 cells on 2D and 3D type-I collagen matrix.
Cell Biol Int. 2017; 41(9):1030-1038 [PubMed] Related Publications
Tumor angiogenesis is a multiphasic process, having the extracellular matrix remodeling as critical step. Different classes of proteolytic enzymes in matrix digestion/remodeling are involved. The role of lytic enzymes and their activation mode have not been completely elucidated. Herein, the crosstalk between endothelia and tumor cells, by realization of bi- and three-dimensional endothelial and breast cancer cells co-cultures, were studied in vitro. Particularly, the effects of two tumor conditioned media (TCM) were assessed about endothelial proliferation, migration, and invasiveness. An increase in expression of pro-MMP9 was detected when endothelial cells were cultured in the presence of both TCM; such as an up-regulation of MMP1 and MMP14 and a down-regulation of MMP7. Moreover the increased MMP2 gene expression from one of them and the stimulation MMP3 synthesis from the other one were observed; an increases of β3-integrin, VEGFA, and DPP4 molecules were detected when endothelia cells are cultured with both TCM. The selection/characterization of elements present in conditioned media from breast cancer cells differently affect endothelial cells, make them potential effectors useful in breast cancer treatment.

Kondo A, Nonaka A, Shimamura T, et al.
Long Noncoding RNA JHDM1D-AS1 Promotes Tumor Growth by Regulating Angiogenesis in Response to Nutrient Starvation.
Mol Cell Biol. 2017; 37(18) [PubMed] Free Access to Full Article Related Publications
Long noncoding RNAs play a pivotal role in tumor progression, but their role in cancer cells in the nutrient-starved tumor microenvironment remains unknown. Here, we show that a nutrient starvation-responsive long noncoding RNA, JHDM1D antisense 1 (JHDM1D-AS1), promotes tumorigenesis by regulating angiogenesis in response to nutrient starvation. Expression of JHDM1D-AS1 was increased in cancer cells. In addition, expression of JHDM1D-AS1 was increased in clinical tumor samples compared to that in normal tissue. Stable expression of JHDM1D-AS1 in human pancreatic cancer (PANC-1 and AsPC-1) cells promoted cell growth

Neuhaus J, Schiffer E, Mannello F, et al.
Protease Expression Levels in Prostate Cancer Tissue Can Explain Prostate Cancer-Associated Seminal Biomarkers-An Explorative Concept Study.
Int J Mol Sci. 2017; 18(5) [PubMed] Free Access to Full Article Related Publications
Previously, we described prostate cancer (PCa) detection (83% sensitivity; 67% specificity) in seminal plasma by CE-MS/MS. Moreover, advanced disease was distinguished from organ-confined tumors with 80% sensitivity and 82% specificity. The discovered biomarkers were naturally occurring fragments of larger seminal proteins, predominantly semenogelin 1 and 2, representing endpoints of the ejaculate liquefaction. Here we identified proteases putatively involved in PCa specific protein cleavage, and examined gene expression and tissue protein levels, jointly with cell localization in normal prostate (nP), benign prostate hyperplasia (BPH), seminal vesicles and PCa using qPCR, Western blotting and confocal laser scanning microscopy. We found differential gene expression of chymase (CMA1), matrix metalloproteinases (MMP3, MMP7), and upregulation of MMP14 and tissue inhibitors (TIMP1 and TIMP2) in BPH. In contrast tissue protein levels of MMP14 were downregulated in PCa. MMP3/TIMP1 and MMP7/TIMP1 ratios were decreased in BPH. In seminal vesicles, we found low-level expression of most proteases and, interestingly, we also detected TIMP1 and low levels of TIMP2. We conclude that MMP3 and MMP7 activity is different in PCa compared to BPH due to fine regulation by their inhibitor TIMP1. Our findings support the concept of seminal plasma biomarkers as non-invasive tool for PCa detection and risk stratification.

Zeng L, Rong XF, Li RH, Wu XY
Icariin inhibits MMP‑1, MMP‑3 and MMP‑13 expression through MAPK pathways in IL‑1β‑stimulated SW1353 chondrosarcoma cells.
Mol Med Rep. 2017; 15(5):2853-2858 [PubMed] Related Publications
Osteoarthritis (OA) is the most common type of arthritis and is a leading cause of disability worldwide, resulting in pain, reduced quality of life and socioeconomic burden. Current therapies for OA focus on mitigating the symptoms of advanced disease, but novel therapeutic agents are needed to inhibit the processes leading to OA. The present study aimed to investigate the effects of Icariin on matrix metalloproteinase (MMP)‑1, MMP‑3 and MMP‑13 expression in interleukin (IL)‑1β‑stimulated human SW1353 chondrosarcoma cells, and to investigate the possible mechanism underlying the chondroprotective effects of Icariin. In the present study, IL‑1β was applied on SW1353 chondrosarcoma cells to mimic the microenvironment of osteoarthritis. The cells were treated with Icariin and mitogen‑activated protein kinase (MAPK) signaling pathway activators or inhibitors. MMP‑1, MMP‑3, MMP‑13, phosphorylated (P)‑p38, P‑c‑Jun N‑terminal kinase (JNK) and P‑extracellular signal‑regulated kinase (ERK) expression was assessed using reverse transcription‑quantitative polymerase chain reaction, ELISA and western blot analysis. The results of the present study demonstrated that Icariin inhibited the expression of MMP‑1, MMP‑3, MMP‑13, P‑p38, P‑ERK and P‑JNK. Furthermore, it was revealed that the inhibition of p38 and ERK contributed to the inhibition of MMP‑1 and MMP‑3 by Icariin, whereas the inhibition of p38 and JNK contributed to the inhibition of MMP‑13. The present results suggested that Icariin may have a chondroprotective effect, exerted through the inhibition of MMP‑1, MMP‑3 and MMP‑13 via MAPK pathways. Therefore, Icariin may have potential as a novel therapeutic strategy for the treatment of osteoarthritis.

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