Gene Summary

Gene:MMP1; matrix metallopeptidase 1
Aliases: CLG, CLGN
Summary:This gene encodes a member of the peptidase M10 family of matrix metalloproteinases (MMPs). Proteins in this 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. The encoded preproprotein is proteolytically processed to generate the mature protease. This secreted protease breaks down the interstitial collagens, including types I, II, and III. The gene is part of a cluster of MMP genes on chromosome 11. Mutations in this gene are associated with chronic obstructive pulmonary disease (COPD). Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:interstitial collagenase
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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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.

  • Breast Cancer
  • Stomach Cancer
  • Circulating Cancer Cells
  • Polymorphism
  • Pulmonary Disease, Chronic Obstructive
  • Ubiquitin-Protein Ligases
  • Trefoil Factor-3
  • Zonula Occludens-1 Protein
  • Chondrosarcoma
  • Wnt-5a Protein
  • Tuberous Sclerosis
  • RT-PCR
  • Cancer Gene Expression Regulation
  • p53 Protein
  • Transcription Factor AP-1
  • Lung Cancer
  • Ubiquitin-Conjugating Enzymes
  • Spain
  • Point Mutation
  • RB1
  • TNF
  • Melanoma
  • Viral Matrix Proteins
  • Zinc Finger E-box-Binding Homeobox 1
  • Xeroderma Pigmentosum
  • Xenograft Models
  • Chromosome 11
  • Promoter Regions
  • Risk Factors
  • Thiocyanates
  • ROC Curve
  • VHL
  • Transcriptional Activation
  • Young Adult
  • TIMP1
  • RNA Interference
  • DNA Sequence Analysis
  • RHOB
  • Smoking
  • MMP1
  • Sensitivity and Specificity
  • Tissue Inhibitor of Metalloproteinases
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

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: MMP1 (cancer-related)

Akashi M, Hisaka T, Sakai H, et al.
Expression of Matrix Metalloproteinases in Intraductal Papillary Mucinous Neoplasm of the Pancreas.
Anticancer Res. 2019; 39(8):4485-4490 [PubMed] Related Publications
BACKGROUND/AIM: Intraductal papillary mucinous neoplasm (IPMN) has a variety of histological and morphological appearances. Matrix metalloproteinases (MMPs) have been considered to be associated with tumor progression or poor prognosis. The aim of this study was to elucidate the molecular basis of IPMN variation in different types of lesions.
MATERIALS AND METHODS: The expression of MMP-1,2,7,9 in 51 cases of IPMN were investigated. The MMP score was calculated as the sum of the score of staining distribution and the score of the intensity staining.
RESULTS: MMP scores were correlated with histological grade, histological subtype, and type of invasion. MMP high expression groups (MMP score ≥5) had worse prognosis than low-expression groups.
CONCLUSION: MMP expression varied between different types of IPMN, a result supporting differences in molecular basis of malignancies. These considerations may be helpful for optimal management or treatment according to various types of IPMN.

Zhong X, Huang G, Ma Q, et al.
Identification of crucial miRNAs and genes in esophageal squamous cell carcinoma by miRNA-mRNA integrated analysis.
Medicine (Baltimore). 2019; 98(27):e16269 [PubMed] Free Access to Full Article Related Publications
Esophageal squamous cell carcinoma (ESCC) is a malignancy that severely threatens human health and carries a high incidence rate and a low 5-year survival rate. MicroRNAs (miRNAs) are commonly accepted as a key regulatory function in human cancer, but the potential regulatory mechanisms of miRNA-mRNA related to ESCC remain poorly understood.The GSE55857, GSE43732, and GSE6188 miRNA microarray datasets and the gene expression microarray datasets GSE70409, GSE29001, and GSE20347 were downloaded from Gene Expression Omnibus databases. The differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) were obtained using GEO2R. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for DEGs were performed by Database for Annotation, Visualization and Integrated Discovery (DAVID). A protein-protein interaction (PPI) network and functional modules were established using the STRING database and were visualized by Cytoscape. Kaplan-Meier analysis was constructed based on The Cancer Genome Atlas (TCGA) database.In total, 26 DEMs and 280 DEGs that consisted of 96 upregulated and 184 downregulated genes were screened out. A functional enrichment analysis showed that the DEGs were mainly enriched in the ECM-receptor interaction and cytochrome P450 metabolic pathways. In addition, MMP9, PCNA, TOP2A, MMP1, AURKA, MCM2, IVL, CYP2E1, SPRR3, FOS, FLG, TGM1, and CYP2C9 were considered to be hub genes owing to high degrees in the PPI network. MiR-183-5p was with the highest connectivity target genes in hub genes. FOS was predicted to be a common target gene of the significant DEMs. Hsa-miR-9-3p, hsa-miR-34c-3p and FOS were related to patient prognosis and higher expression of the transcripts were associated with a poor OS in patients with ESCC.Our study revealed the miRNA-mediated hub genes regulatory network as a model for predicting the molecular mechanism of ESCC. This may provide novel insights for unraveling the pathogenesis of ESCC.

Wu TK, Chen CH, Pan YR, et al.
Cetrimonium Bromide Inhibits Cell Migration and Invasion of Human Hepatic SK-HEP-1 Cells Through Modulating the Canonical and Non-canonical TGF-β Signaling Pathways.
Anticancer Res. 2019; 39(7):3621-3631 [PubMed] Related Publications
BACKGROUND/AIM: Cetrimonium bromide (CTAB), a quaternary ammonium surfactant, is an antiseptic agent against bacteria and fungi. However, the mechanisms by which its pharmacological actions affect epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) cells, such as adenocarcinoma in SK-HEP-1 cells, have not been investigated. We, thereby, investigated whether CTAB inhibits cellular mobility and invasiveness of human hepatic adenocarcinoma in SK-HEP-1 cells.
MATERIALS AND METHODS: SK-HEP-1 cells were treated with CTAB, and subsequent migration and invasion were measured by wound healing and transwell assays. Protein expression was detected by immunoblotting analysis.
RESULTS: Our data revealed that treatment of SK-HEP-1 cells with CTAB altered their mesenchymal spindle-like morphology. CTAB exerted inhibitory effects on the migration and invasion of SK-HEP-1 cells dose-dependently, and reduced protein levels of matrix metalloproteinase-2 (MMP-2), MMP-9, snail, slug, twist, vimentin, fibronectin, N-cadherin, Smad2, Smad3, Smad4, phosphoinositide-3-kinase (PI3K), p-PI3K, Akt, p-Akt, β-catenin, mammalian target of rapamycin (mTOR), p-mTOR, p-p70S6K, p-extracellular signal-regulated kinases (ERK)1/2, p-p38 mitogen-activated protein kinase (MAPK) and p-c-Jun N-terminal kinase (JNK), but increased protein levels of tissue inhibitor matrix metalloproteinase-1 (TIMP-1), TIMP-2, claudin-1 and p-GSK3β. Based on these observations, we suggest that CTAB not only inhibits the canonical transforming growth factor-β (TGF-β) signaling pathway though reducing SMADs (an acronym from the fusion of Caenorhabditis elegans Sma genes and the Drosophila Mad, Mothers against decapentaplegic proteins), but also restrains the non-canonical TGF-β signaling including MAPK pathways like ERK1/2, p38 MAPK, JNK and PI3K.
CONCLUSION: CTAB is involved in the suppression of TGF-β-mediated mesenchymal phenotype and could be a potent medical agent for use in controlling the migration and invasion of hepatic adenocarcinoma.

Lin J, Yu X, Xie L, et al.
eIF6 Promotes Colorectal Cancer Proliferation and Invasion by Regulating AKT-Related Signaling Pathways.
J Biomed Nanotechnol. 2019; 15(7):1556-1567 [PubMed] Related Publications
Although abnormal expression of eukaryotic initiation factor 6 (eIF6) has been found in several human solid tumors, the functions and underlying mechanisms of eIF6 in the progression of colorectal cancer (CRC) still needs further elucidation. In the present study, large-scale gene analysis based on Oncomine and The Cancer Genome Atlas (TCGA) database revealed significantly higher baseline expression of eIF6 in colorectal cancer than in normal tissues. Furthermore, our Chinese cohort study revealed that high expression of eIF6 was correlated with aggressive characteristics and poor survival in CRC patients. Functional studies using magnetic nanoparticle extraction indicated that eIF6 was an oncogene in CRC cells. Regarding its mechanism, through Gene ontology (GO) and KEGG pathway analysis based on TCGA RNAseq database, we found that eIF6 can activate multiple AKT-related cancer signaling pathways, such as p-AKT\MMP1\cyclinD1\Bcl2-related signaling, to regulate cell proliferation, invasion, cell cycle and apoptosis in CRC. Collectively, these findings suggested that eIF6 can positively regulate AKT-related cancer signaling and enhance tumorigenicity in CRC, and may serve as a potential prognostic indicator and therapeutic target in CRC.

Ding X, Li F, Zhang L
Knockdown of Delta-like 3 restricts lipopolysaccharide-induced inflammation, migration and invasion of A2058 melanoma cells via blocking Twist1-mediated epithelial-mesenchymal transition.
Life Sci. 2019; 226:149-155 [PubMed] Related Publications
AIMS: To investigate the effects and mechanisms of DLL3 in inflammation-mediated A2058 melanoma cell invasion and metastasis.
MATERIALS AND METHODS: Melanoma A2058 cells was stimulated with lipopolysaccharide (LPS), with or without transfection of DLL3 siRNA, or DLL3 overexpression vector, or Twist1 siRNA. Cell migration and invasion were detected by wound healing and transwell invasion assay. The production of inflammatory factors TNF-α and IL-6 was measured by ELISA. The expression of Notch signaling-related molecules was detected by PCR and western blot. The protein expression of MMP1, MMP9, VEGF, DLL3, and EMT-related molecules was tested by western blot.
KEY FINDINGS: LPS treatment increased migration and invasion of A2058 cells, accompanied by increased expression of TNF-α and IL-6. DLL3 was both upregulated in the LPS- or TNF-α-stimulated A2058 cells, and DLL3 knockdown inhibited LPS-induced inflammation, migration and invasion of A2058 cells, accompanied by down-regulation of MMP1, MMP9 and VEGF. Besides, DLL3 knockdown inhibits the expression of Twist1, a key EMT regulating factor, as well as the EMT hallmarks slug, N-cadherin and vimentin. Moreover, Twist1 silence inhibited EMT, and limited LPS-induced migration and invasion of A2058 cells, with decreased expression of MMP1, MMP9 and VEGF and reduced production of TNF-α and IL-6 in LPS-stimulated A2058 cells.
SIGNIFICANCE: Knockdown of DLL3 restricts LPS-induced inflammation, migration and invasion of A2058 melanoma cells via blocking Twist1-mediated EMT. Therefore, targeting DLL3 may be a promising therapeutic strategy against inflammation-aggravated melanoma progression.

Tiwari A, Mukherjee B, Hassan MK, et al.
Reduced FRG1 expression promotes prostate cancer progression and affects prostate cancer cell migration and invasion.
BMC Cancer. 2019; 19(1):346 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Prostate cancer is the most common form of cancer in males and accounts for high cancer related deaths. Therapeutic advancement in prostate cancer has not been able to reduce the mortality burden of prostate cancer, which warrants further research. FRG1 which affects angiogenesis and cell migration in Xenopus, can be a potential player in tumorigenesis. In this study, we investigated the role of FRG1 in prostate cancer progression.
METHODS: Immunohistochemistry was performed to determine FRG1 expression in patient samples. FRG1 expression perturbation was done to investigate the effect of FRG1 on cell proliferation, migration and invasion, in DU145, PC3 and LNCaP cells. To understand the mechanism, we checked expression of various cytokines and MMPs by q-RT PCR, signaling molecules by western blot, in FRG1 perturbation sets. Results were validated by use of pharmacological inhibitor and activator and, western blot.
RESULTS: In prostate cancer tissue, FRG1 levels were significantly reduced, compared to the uninvolved counterpart. FRG1 expression showed variable effect on PC3 and DU145 cell proliferation. FRG1 levels consistently affected cell migration and invasion, in both DU145 and PC3 cells. Ectopic expression of FRG1 led to significant reduction in cell migration and invasion in both DU145 and PC3 cells, reverse trends were observed with FRG1 knockdown. In androgen receptor positive cell line LNCaP, FRG1 doesn't affect any of the cell properties. FRG1 knockdown led to significantly enhanced expression of GM-CSF, MMP1, PDGFA and CXCL1, in PC3 cells and, in DU145, it led to higher expression of GM-CSF, MMP1 and PLGF. Interestingly, FRG1 knockdown in both the cell lines led to activation of p38 MAPK. Pharmacological activation of p38 MAPK led to increase in the expression of GM-CSF and PLGF in DU145 whereas in PC3 it led to enhanced expression of GM-CSF, MMP1 and CXCL1. On the other hand, inhibition of p38 MAPK led to reduction in the expression of above mentioned cytokines.
CONCLUSION: FRG1 expression is reduced in prostate adenocarcinoma tissue. FRG1 expression affects migration and invasion in AR negative prostate cancer cells through known MMPs and cytokines, which may be mediated primarily via p38 MAPK activation.

Chen YJ, Liao YJ, Lin F, et al.
[Shared functional modules for nasopharyngeal and oral squamous cell carcinoma identified by network analysis of transcriptomes].
Yi Chuan. 2019; 41(2):146-157 [PubMed] Related Publications
Although nasopharyngeal carcinoma (NPC) and oral squamous cell carcinoma (OSCC) are highly correlated clinical diseases, the underling molecular mechanisms to link the two diseases remain largely unknown. The aim of this study is to identify the shared functional modules for NPC and OSCC by using large-scale transcriptomic data. Gene expression profile datasets of NPC and OSCC were obtained from the GEO database. A total of 1279 differentially expressed genes (DEGs) of NPC and 1293 DEGs of OSCC were identified by fold change and empirical Bayes method, and 278 DEGs were common to these two diseases. These overlapped genes were translated into a primary network consisting of 1290 nodes (genes) and 1766 edges. The primary network was then decomposed into 15 compacted modules (subnets) with high modularity by Newman's algorithm. Topological analysis of these modules identified a total of 58 hub genes, most of which (e.g., PCNA, CDK1, STAT1, CCL5, and MMP1) have been proved to be associated with NPC and/or OSCC, while the rest (e.g., MELK, NME1, RACGAP1, INHBA, and NID1) might be novel risk genes for the two diseases. Further bioinformatics analysis of KEGG databases revealed that these modules are involved in multiple pathogenic biological pathways for either NPC or OSCC (e.g., p53 signaling pathway, ECM-receptor interaction, focal adhesion, and cell cycle). This study demonstrates that NPC and OSCC have similar molecular bases, and the identified pleiotropic modules may shape the complicated molecular interplays underlying the two clinically correlated diseases.

Pietrzak J, Mirowski M, Jeleń A, et al.
Decreased MMP1 gene expression in acute myeloid leukaemia.
Mol Biol Rep. 2019; 46(2):2293-2298 [PubMed] Related Publications
Acute myeloid leukaemia (AML) is a heterogeneous disorder of haematopoietic stem cells or progenitor cells. Metalloproteinases (MMPs) are proteolytic enzymes whose activity is increased in different types of solid tumours. These enzymes regulate many processes associated with tumour progression. In haematological malignancy, the role of MMPs seems to be underestimated, and only metalloproteinase 2 (MMP2) and metalloproteinase 9 (MMP9) have been widely examined so far. In this work, differences in metalloproteinase 1 (MMP1) gene expression between patients with AML and healthy individuals were assessed. The relative expression level of the MMP1 gene was obtained by a real time PCR method preceded by reverse transcription. The relative level of MMP1 gene expression in patients with AML was decreased when compared to that of the control group. The role of MMP1 in AML could be different from that in solid tumours. Decreased MMP1 gene expression in AML similar to that of MMP9, shows a greater role for MMP1 in normal haematopoiesis than in the development of leukaemic cells.

Lv J, Guo L, Wang JH, et al.
Biomarker identification and trans-regulatory network analyses in esophageal adenocarcinoma and Barrett's esophagus.
World J Gastroenterol. 2019; 25(2):233-244 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Esophageal adenocarcinoma (EAC) is an aggressive disease with high mortality and an overall 5-year survival rate of less than 20%. Barrett's esophagus (BE) is the only known precursor of EAC, and patients with BE have a persistent and excessive risk of EAC over time. Individuals with BE are up to 30-125 times more likely to develop EAC than the general population. Thus, early detection of EAC and BE could significantly improve the 5-year survival rate of EAC. Due to the limitations of endoscopic surveillance and the lack of clinical risk stratification strategies, molecular biomarkers should be considered and thoroughly investigated.
AIM: To explore the transcriptome changes in the progression from normal esophagus (NE) to BE and EAC.
METHODS: Two datasets from the Gene Expression Omnibus (GEO) in NCBI Database ( were retrieved and used as a training and a test dataset separately, since NE, BE, and EAC samples were included and the sample sizes were adequate. This study identified differentially expressed genes (DEGs) using the R/Bioconductor project and constructed trans-regulatory networks based on the Transcriptional Regulatory Element Database and Cytoscape software. Enrichment of Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) terms was identified using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) Bioinformatics Resources. The diagnostic potential of certain DEGs was assessed in both datasets.
RESULTS: In the GSE1420 dataset, the number of up-regulated DEGs was larger than that of down-regulated DEGs when comparing EAC
CONCLUSION: After the construction and analyses of the trans-regulatory networks in EAC and BE, the results indicate that COL1A1 and MMP1 could be potential biomarkers for EAC and BE, respectively.

Chen L, Lu D, Sun K, et al.
Identification of biomarkers associated with diagnosis and prognosis of colorectal cancer patients based on integrated bioinformatics analysis.
Gene. 2019; 692:119-125 [PubMed] Related Publications
BACKGROUND: The current study aimed to identify potential diagnostic and prognostic gene biomarkers for colorectal cancer (CRC) based on the Gene Expression Omnibus (GEO) datasets and The Cancer Genome Atlas (TCGA) dataset.
METHODS: Microarray data of gene expression profiles of CRC from GEO and RNA-sequencing dataset of CRC from TCGA were downloaded. After screening overlapping differentially expressed genes (DEGs) by R software, functional enrichment analyses of the DEGs were performed using the DAVID database. Then, the STRING database and Cytoscape were used to construct a protein-protein interaction (PPI) network and identify hub genes. The receiver operating characteristic (ROC) curves were conducted to assess the diagnostic values of the hub genes. Cox proportional hazards regression was performed to screen the potential prognostic genes. Kaplan-Meier curve and the time-dependent ROC curve were used to assess the prognostic values of the potential prognostic genes for CRC patients.
RESULTS: Integrated analysis of GEO and TCGA databases revealed 207 common DEGs in CRC. A PPI network consisted of 70 nodes and 170 edges were constructed and top 10 hub genes were identified. The area under curve (AUC) of the ROC curves of the hub genes were 0.900, 0.927, 0.869, 0.863, 0.980, 0.682, 0.903, 0.790, 0.995, and 0.989 for CCL19, CXCL1, CXCL5, CXCL11, CXCL12, GNG4, INSL5, NMU, PYY, and SST, respectively. A prognostic gene signature consisted of 9 genes including SLC4A4, NFE2L3, GLDN, PCOLCE2, TIMP1, CCL28, SCGB2A1, AXIN2, and MMP1 was constructed with a good performance in predicting overall survivals of CRC patients. The AUC of the time-dependent ROC curve was 0.741 for 5-year survival.
CONCLUSION: The results in this study might provide some directive significance for further exploring the potential biomarkers for diagnosis and prognosis prediction of CRC patients.

Chu CN, Wu KC, Chung WS, et al.
Etomidate Suppresses Invasion and Migration of Human A549 Lung Adenocarcinoma Cells.
Anticancer Res. 2019; 39(1):215-223 [PubMed] Related Publications
BACKGROUND/AIM: Etomidate, an intravenous anesthetic, has been shown to have anticancer effects, including induction of cell-cycle arrest and apoptosis. However, to our knowledge, there are no reports about the anti-metastasis effects of etomidate on A549 human lung adenocarcinoma cells.
MATERIALS AND METHODS: The cell viability, cell adhesion, gelatin zymography assay, transwell migration and invasion assay, and western blotting analysis were used to investigate the effects of etomidate on A549 cells.
RESULTS: In our study, etomidate showed low cytotoxicity, inhibited cell adhesion, and suppressed the migration and invasion in A549 cells. The activity of matrix metallopeptidase 2 (MMP2) was reduced by 48 h treatment of etomidate. Results of western blotting analysis indicated that etomidate down-regulated the expression of protein kinase C, MMP7, MMP1, MMP9, and p-p-38, but up-regulated that of RAS, phosphoinositide 3-kinase, and phosphor-extracellular-signal related kinase after 24 and 48 h treatment, in A549 cells.
CONCLUSION: Etomidate suppressed the migration and invasion of lung adenocarcinoma A549 cells via inhibiting the expression of MMP1, MMP2, MMP7 and MMP9, and provides potential therapeutic targets for lung cancer treatment.

Desai V, Jain A, Shaghaghi H, et al.
Combination of Biochanin A and Temozolomide Impairs Tumor Growth by Modulating Cell Metabolism in Glioblastoma Multiforme.
Anticancer Res. 2019; 39(1):57-66 [PubMed] Related Publications
BACKGROUND/AIM: Several epidemiological studies have reported the chemopreventive potential of biochanin A, in cancer development and progression. We investigated the anticancer potential of combination of biochanin A and temozolomide against U-87 MG and T98 G [glioblastoma multiforme (GBM)] cells.
MATERIALS AND METHODS: We evaluated the effect of biochanin A and temozolomide treatment on cell viability, expression of survival proteins, cell cycle, cell metabolism and mitochondrial function.
RESULTS: Enhanced inhibitory effects of the combination treatment were observed on cell viability, expression of cell survival proteins EGFR, p-ERK, p-AKT, c-myc and MT-MMP1, and increased expression of the tumor suppressor, p-p53. Combination treatment also induced arrest in the G
CONCLUSION: Biochanin A significantly enhanced the anticancer efficacy of temozolomide in GBM cells.

Zhao L, Chi W, Cao H, et al.
Screening and clinical significance of tumor markers in head and neck squamous cell carcinoma through bioinformatics analysis.
Mol Med Rep. 2019; 19(1):143-154 [PubMed] Free Access to Full Article Related Publications
In order to identify potential diagnostic and prognostic biomarkers, and treatment targets for head and neck squamous cell carcinoma (HNSCC), the present study obtained the gene expression profiles in HNSCC through public data mining, and core genes were identified using a series of bioinformatics analysis methods and databases. A total of nine hub genes (SPP1, ITGA6, TMPRSS11D, MMP1, LAMC2, FAT1, ACTA1, SERPINE1 and CEACAM1) were identified to be significantly correlated with HNSCC. Furthermore, overall survival analysis demonstrated that the expression values of hub genes were associated with overall survival in HNSCC. Furthermore, certain of the identified genes, including, TMPRSS11D, ACTA1 and CEACAM1, have not been thoroughly investigated in HNSCC previously. Taken together, the nine hub genes obtained by screening in the present study may serve as potential tumor markers and important prognostic indicators for HNSCC.

Li S, Zhao X, Chang S, et al.
ERp57‑small interfering RNA silencing can enhance the sensitivity of drug‑resistant human ovarian cancer cells to paclitaxel.
Int J Oncol. 2019; 54(1):249-260 [PubMed] Related Publications
ERp57 has been identified to be associated with the chemoresistance of human ovarian cancer. However, its biological roles in the chemoresistance phenotype remain unclear. In the present study, the association of ERp57 with paclitaxel‑resistant cellular behavior was investigated and the sensitivity enhancement of chemoresistant human ovarian cancer cells to paclitaxel was examined using ERp57‑small interfering (si)RNA silencing. Cell viability, cell proliferation, cell apoptosis and cell migration were detected using an MTT assay, clonogenic assay, flow cytometry analysis and transwell assay. Furthermore, mRNA expression levels of ERp57 and protein expression levels of ERp57, STAT3, phosphorylated STAT3, PCNA, nucelolin, TUBB3, P-gp, vimentin, Bcl-2, Bax, Bcl-xl, p53, MMP1, MMP2 and MMP9 of paclitaxel-sensitive human SKOV3 ovarian cancer cells were compared with paclitaxel-resistant counterpart SKOV3/tax using the real-time PCR and western blot analysis. ERp57 was highly expressed in the paclitaxel‑resistant SKOV3/tax cells, and experimental results concluded that the paclitaxel‑resistance phenotype was due primarily to the activation of the STAT3 signaling pathway. ERp57 overexpression by lentiviral particle infection decreased the sensitivity of SKOV3 cells to paclitaxel. Furthermore, ERp57‑siRNA silencing restored paclitaxel sensitivity of SKOV3/tax cells. Notably, the IC50 value of ERp57‑siRNA silenced SKOV3/tax cells was reduced to the original level and colony survival was significantly decreased in comparison with that of SKOV3/tax cells. Additionally, co‑treatment of ERp57‑siRNA silencing and paclitaxel could inhibit the STAT3 signaling pathway and downregulate the expression levels of downstream proteins. Notably, ERp57‑siRNA and 100 nM paclitaxel co‑treatment downregulated Bcl‑2, Bcl‑xl, MMP2, MMP9, TUBB3 and P‑gp expression levels and upregulated the expression of Bax protein. Furthermore, co‑treatment promoted change of the isoform of p53 to p53/p47. Bioinformatics analyses supported the experimental observations that ERp57 was associated with drug resistance in ovarian cancer. The present study implies that ERp57 is a potential therapeutic target for the treatment of paclitaxel‑resistant human ovarian cancer.

Zhang S, Zheng C, Yao S, et al.
Proteomic analysis of human prostate cancer PC-3M-1E8 cells and PC-3M-2B4 cells of same origin but with different metastatic potential.
PLoS One. 2018; 13(10):e0206139 [PubMed] Free Access to Full Article Related Publications
Prostate cancer (PCa) is the second most frequently diagnosed cancer and the fifth leading cause of death from cancer in men worldwide. Increased understanding of the prostate cancer metastasis mechanisms will help identify more efficient intervention strategies to prevent or treat this deadly disease in the future. To identify the candidate proteins that contribute to metastasis of PCa, isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic analysis was performed to explore differentially expressed proteins between two homologous human prostate cancer cell lines including highly-metastatic PC-3M-1E8 cell line and poorly-metastatic PC-3M-2B4 cell line. Here, a total of 58 proteins were identified to be significantly differentially expressed between PC-3M-1E8 and PC-3M-2B4 cells, which were further verified using real-time quantitative PCR and western blot analysis. The bioinformatic analysis suggested that the differentially expressed proteins, like MMP1 and FHL1, may contribute to the higher metastatic ability of PC-3M-1E8 cells than PC-3M-2B4 cells. In addition, functional analyses proved MMP1's positive effect on the higher metastatic ability of PC-3M-1E8 cells than PC-3M-2B4 cells. These findings provided a unique resource to specifically reveal the complex molecular regulatory mechanisms underlying the progression of prostate cancer from poorly-metastatic to highly-metastatic stage.

Lin CZ, Ou RW, Hu YH
Lentiviral-mediated microRNA-26b up-regulation inhibits proliferation and migration of hepatocellular carcinoma cells.
Kaohsiung J Med Sci. 2018; 34(10):547-555 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a frequently occurred malignancy worldwide with a high mortality. The treatment for HCC is still controversial. Emerging evidences have demonstrated that microRNAs (miRs) play a role in HCC. This study aims to investigate the effects of lentiviral-mediated miRNA-26b (miR-26b) on the proliferation and metastasis of HCC cells. The normal hepatic cell line HL-7702 and HCC cell lines HepG2 (without metastatic potential), SMMC-7721 (with low metastatic potential) and MHCC97H (with high metastatic potential) were purchased for our experiment. The lentiviral-mediated miR-26b overexpression (miR-26b-LV) and low expression (sh-miR-26b) were constructed to transfect the cells. The miR-26b expression and expressions of Karyopherin α-2 (KPNA2), matrix metalloproteinase 1 (MMP-1), MMP-7 and MMP-14 were determined by RT-qPCR and western blot analysis. The proliferation and metastasis of transfected HCC cells were detected by MTT and Transwell assay respectively. The miR-26b expressions were decreased significantly in MHCC97H cells. With lentiviral-mediated miR-26b overexpression, the proliferation and migration of HepG2, MHCC97H and SMMC-7721 cells were decreased significantly. The RT-qPCR and western blot analysis results revealed that the mRNA and protein expressions of KPNA2, MMP-1, MMP-7 and MMP-14 were decreased by lentiviral-mediated miR-26b overexpression. All the above indexes in the HepG2, MHCC97H and SMMC-7721 cells treated by sh-miR-26b exhibited opposite trends. These results show that overexpressed miR-26b could inhibit the proliferation and metastasis of HCC cells significantly, which provides a novel target and theoretical foundation for the treatment of HCC.

Wang P, Magdolen V, Seidl C, et al.
Kallikrein-related peptidases 4, 5, 6 and 7 regulate tumour-associated factors in serous ovarian cancer.
Br J Cancer. 2018; 119(7):1-9 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
BACKGROUND: Tissue kallikrein-related peptidases 4, 5, 6 and 7 (KLK4-7) strongly increase the malignancy of ovarian cancer cells. Deciphering their downstream effectors, we aimed at finding new potential prognostic biomarkers and treatment targets for ovarian cancer patients. KLK4-7-transfected (OV-KLK4-7) and vector-control OV-MZ-6 (OV-VC) ovarian cancer cells were established to select differentially regulated factors.
METHODS: With three independent approaches, PCR arrays, genome-wide microarray and proteome analyses, we identified 10 candidates (MSN, KRT19, COL5A2, COL1A2, BMP5, F10, KRT7, JUNB, BMP4, MMP1). To determine differential protein expression, we performed western blot analyses, immunofluorescence and immunohistochemistry for four candidates (MSN, KRT19, KRT7, JUNB) in cells, tumour xenograft and patient-derived tissues.
RESULTS: We demonstrated that KLK4-7 clearly regulates expression of MSN, KRT19, KRT7 and JUNB at the mRNA and protein levels in ovarian cancer cells and tissues. Protein expression of the top-upregulated effectors, MSN and KRT19, was investigated by immunohistochemistry in patients afflicted with serous ovarian cancer and related to KLK4-7 immunoexpression. Significant positive associations were found for KRT19/KLK4, KRT19/KLK5 and MSN/KLK7.
CONCLUSION: These findings imply that KLK4-7 exert key modulatory effects on other cancer-related genes and proteins in ovarian cancer. These downstream effectors of KLK4-7, MSN and KRT19 may represent important therapeutic targets in serous ovarian cancer.

Zhao C, Zou H, Zhang J, et al.
An integrated methylation and gene expression microarray analysis reveals significant prognostic biomarkers in oral squamous cell carcinoma.
Oncol Rep. 2018; 40(5):2637-2647 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
Oral squamous cell carcinoma (OSCC) is a life‑threatening disease with a poor prognosis. Although previous studies have reported that the methylation of certain genes is associated with the pathogenesis of OSCC, the methylation of genes that have relevance to OSCC progression is not clearly documented. The present study aimed to gain insights into the mechanisms underlying DNA methylation regulation associated with OSCC progression and to identify potential prognostic markers for OSCC treatment. DNA methylation dataset GSE41114 and gene expression dataset GSE74530 were downloaded from the Gene Expression Omnibus database. The global methylation status of OSCC tumor samples and normal control samples was determined, and differentially methylated genes (DMGs) in OSCC samples compared with control samples were identified. The mRNA expression data were then integrated to identify differentially expressed genes (DEGs) in OSCC samples compared with control samples. Overlapping genes between DEGs and DMGs were identified, and functional enrichment analysis was performed. In addition, survival analysis of the overlapping genes was performed to screen genes with prognostic significance in OSCC. A total of 40,115 differential methylation CpG sites spanning 3,360 DMGs were identified; CpG sites in the promoter, gene body and intergenic regions were generally highly hypermethylated or hypomethylated. Additionally, 508 DEGs in OSCC samples were identified, including 332 upregulated and 176 downregulated genes. A total of 82 overlapping genes between DEGs and DMGs were found, which were mainly involved in protein metabolism, regulation of the metabolic process and the immune system. Additionally, differential methylation or expression of several genes, including fibroblast activation protein α (FAP), interferon α inducible protein 27 (IFI27), laminin subunit γ2 (LAMC2), matrix metallopeptidase 1 (MMP1), serine peptidase inhibitor Kazal‑type 5 (SPINK5) and zinc finger protein 662 (ZNF662), was significantly associated with the survival of OSCC patients, and their differential expression in OSCC patients was further confirmed by reverse transcription‑quantitative polymerase chain reaction in OSCC and normal oral cell lines. Overall, FAP, IFI27, LAMC2, MMP1, SPINK5 and ZNF662 genes caused by epigenetic changes via DNA methylation may be associated with the development and progression of OSCC, and should be valuable OSCC therapeutic biomarkers.

Ahmed W, Malik MFA, Saeed M, Haq F
Copy number profiling of Oncotype DX genes reveals association with survival of breast cancer patients.
Mol Biol Rep. 2018; 45(6):2185-2192 [PubMed] Related Publications
Copy number variations (CNVs) are key contributors in breast cancer initiation and progression. However, to date, no CNV-based gene signature is developed for breast cancer. 21-gene Oncotype DX, a clinically validated signature, was identified using only RNA expression data in breast cancer patients. In this study, we evaluated whether CNVs of Oncotype DX genes can be used to predict the prognosis of breast cancer patients. Transcriptomic data of 547 and genomic data of 816 of breast cancer patients were downloaded from The Cancer Genome Atlas database. To establish the prognostic relevance between the CNVs of Oncotype DX genes and clinicopathological features, statistical analysis including Pearson Correlation, Fisher-exact, Chi square, Kaplan-Meier survival and Cox regression analyses were performed. 86% genes showed positive CNV-expression correlation. CNVs in 52% and 47.6% genes showed association with ER+ and PR+ status, respectively. 71% of the genes (including ERBB2, CTSV, CD68, GRB7, MKI67, MMP1, PGR, RPLP0, TFRC, BAG1, BCL2, BIRC5, FLNB, GSTM1 and SCUBE2) showed association with poor overall survival. 14% of the genes (including CTSV, RPLP0 and BIRC5) genes showed association with disease free survival. Cox regression analysis revealed ESR1, metastasis and node stage as independent prognostic factors for overall survival of breast cancer patients. The results suggested that CNV-based assay of Oncotype DX genes can be used to predict the survival of breast cancer patients. In future, identifying new gene signatures for better breast cancer prognosis using CNV level information will be worth investigating.

Lu Y, Li C, Chen H, Zhong W
Identification of hub genes and analysis of prognostic values in pancreatic ductal adenocarcinoma by integrated bioinformatics methods.
Mol Biol Rep. 2018; 45(6):1799-1807 [PubMed] Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in the world, and more molecular mechanisms should be illuminated to meet the urgent need of developing novel detection and therapeutic strategies. We analyzed the related microarray data to find the possible hub genes and analyzed their prognostic values using bioinformatics methods. The mRNA microarray datasets GSE62452, GSE15471, GSE102238, GSE16515, and GSE62165 were finally chosen and analyzed using GEO2R. The overlapping genes were found by Venn Diagrams, functional and pathway enrichment analyses were performed using the DAVID database, and the protein-protein interaction (PPI) network was constructed by STRING and Cytoscape. OncoLnc, which was linked to TCGA survival data, was used to investigate the prognostic values. In total, 179 differentially expressed genes (DEGs) were found in PDAC, among which, 130 were up-regulated genes and 49 were down-regulated. DAVID showed that the up-regulated genes were significantly enriched in extracellular matrix and structure organization, collagen catabolic and metabolic process, while the down-regulated genes were mainly involved in proteolysis, reactive oxygen species metabolic process, homeostatic process and cellular response to starvation. From the PPI network, the 21 nodes with the highest degree were screened as hub genes. Based on Molecular Complex Detection (MCODE) plug-in, the top module was formed by ALB, TGM, PLAT, PLAU, EGF, MMP7, MMP1, LAMC2, LAMA3, LAMB3, COLA1, FAP, CDH11, COL3A1, ITGA2, and VCAN. OncoLnc survival analysis showed that, high expression of ITGA2, MMP7, ITGB4, ITGA3, VCAN and PLAU may predict poor survival results in PDAC. The present study identified hub genes and pathways in PDAC, which may be potential targets for its diagnosis, treatment, and prognostic prediction.

Yu GI, Mun KH, Yang SH, et al.
Polymorphisms in the 3'-UTR of SCD5 gene are associated with hepatocellular carcinoma in Korean population.
Mol Biol Rep. 2018; 45(6):1705-1714 [PubMed] Related Publications
The purpose of the study was to assess the relationship between polymorphisms of the SCD5 and MMP1 gene and hepatocellular carcinoma (HCC). The gene polymorphisms with a minor allele frequency (MAF) > 0.05 were selected eight SNPs (rs6840, rs1065403, rs3821974, and rs3733230 in 3'-UTR; rs4693472, rs3733227, rs1848067, and rs6535374 in intron region) of SCD5 gene and two SNPs (rs1799750 and rs1144393 in promoter region) of MMP1 gene. The genotype of SCD5 and MMP1 gene SNPs were determined by direct sequencing and pyrosequencing, respectively. One hundred sixty-two patients with HCC and two hundred twenty-five control subjects were recruited in Korean male population. In terms of genotype frequencies, SCD5 genotype TC, GA, AG, and CG of rs6840, rs1065403, rs3821974, and rs3733230, respectively were higher in control group than HCC. In addition, these genotype decreased the risk (rs6840; OR 0.55, 95% CI 0.31-0.99; rs1065403; OR 0.46, 95% CI 0.26-0.83; rs3821974; OR 0.56, 95% CI 0.31-0.99; rs3733230; OR 0.62, 95% CI 0.34-1.12) of HCC, which may work as a prevention of HCC. At least one minor allele carrier of SCD5 gene polymorphisms were related to decreased risk of HCC for AFP cut-point levels > 200 or > 400 ng/ml, respectively. Our results indicate that polymorphisms in the 3'-UTR of the SCD5 gene may associated with HCC in the Korean male population.

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.

Yahiro Y, Maeda S, Shinohara N, et al.
PEG10 counteracts signaling pathways of TGF-β and BMP to regulate growth, motility and invasion of SW1353 chondrosarcoma cells.
J Bone Miner Metab. 2019; 37(3):441-454 [PubMed] Related Publications
Recently, we reported highly active transforming growth factor (TGF)-β and bone morphogenetic protein (BMP) signaling in human chondrosarcoma samples and concurrent downregulation of paternally expressed gene 10 (PEG10). PEG10 expression was suppressed by TGF-β signaling, and PEG10 interfered with the TGF-β and BMP-SMAD pathways in chondrosarcoma cells. However, the roles of PEG10 in bone tumors, including chondrosarcoma, remain unknown. Here, we report that PEG10 promotes SW1353 chondrosarcoma cell growth by preventing TGF-β1-mediated suppression. In contrast, PEG10 knockdown augments the TGF-β1-induced motility of SW1353 cells. Individually, TGF-β1 and PEG10 siRNA increase AKT phosphorylation, whereas an AKT inhibitor, MK2206, mitigates the effect of PEG10 silencing on cell migration. SW1353 cell invasion was enhanced by BMP-6, which was further increased by PEG10 silencing. The effect of siPEG10 was suppressed by inhibitors of matrix metalloproteinase (MMP). BMP-6 induced expression of MMP-1, -3, and -13, and PEG10 lentivirus or PEG10 siRNA downregulated or further upregulated these MMPs, respectively. PEG10 siRNA increased BMP-6-induced phosphorylation of p38 MAPK and AKT, whereas the p38 inhibitor SB203580 and MK2206 diminished SW1353 cell invasion by PEG10 siRNA. SB203580 and MK2206 impeded the enhancing effect of PEG10 siRNA on the BMP-6-induced expression of MMP-1, -3, and -13. Our findings suggest dual functions for PEG10: accelerating cell growth by suppressing TGF-β signaling and inhibiting cell motility and invasion by interfering with TGF-β and BMP signaling via the AKT and p38 pathways, respectively. Thus, PEG10 might be a molecular target for suppressing the aggressive phenotypes of chondrosarcoma cells.

Hamaidi I, Coquard C, Danilin S, et al.
The Lim1 oncogene as a new therapeutic target for metastatic human renal cell carcinoma.
Oncogene. 2019; 38(1):60-72 [PubMed] Related Publications
Metastatic clear cell renal cell carcinoma (CCC) remains incurable despite advances in the development of anti-angiogenic targeted therapies and the emergence of immune checkpoint inhibitors. We have previously shown that the sonic hedgehog-Gli signaling pathway is oncogenic in CCC allowing us to identify the developmental Lim1 transcription factor as a Gli target and as a new oncogene in CCC regulating cell proliferation and apoptosis, and promoting tumor growth. In this previous study, preliminary in vitro results also suggested that Lim1 may be implicated in metastatic spread. Here we investigated the potential pro-metastatic role of Lim1 in advanced CCC (1) in vitro using a panel of CCC cell lines expressing or not the von Hippel-Lindau (VHL) tumor suppressor gene either naturally or by gene transfer and (2) ex vivo in 30 CCC metastatic tissues, including lymph nodes, lung, skin, bone, and adrenal metastases, and (3) in vivo, using a metastatic model by intravenous injection of siRNA-transfected cells into Balb/c nude. Our in vitro results reveal that Lim1 knockdown time-dependently decreased CCC cell motility, migration, invasion, and clonogenicity by up to 50% regardless of their VHL status. Investigating the molecular machinery involved in these processes, we identified a large panel of Lim1 targets known to be involved in cell adhesion (paxillin and fibronectin), epithelial-mesenchymal transition (Twist1/2 and snail), invasion (MMP1/2/3/8/9), and metastatic progression (CXCR4, SDF-1, and ANG-1). Importantly, Lim1 was found constitutively expressed in all metastatic tissues. The H-score in metastatic tissues being significantly superior to the score in the corresponding primary tumor tissues (P value = 0.009). Furthermore, we showed that Lim1 silencing decreases pulmonary metastasis development in terms of number and size in the in vivo metastatic model of human CCC. Taken together, these experiments strengthen the potential therapeutic value of Lim1 targeting as a promising novel approach for treating metastatic human CCC.

Jiang XF, Ding L, Tian Y, et al.
Interaction of STAT3 and RelB modulates MMP-1 in colon cancer.
Chem Biol Interact. 2018; 293:94-99 [PubMed] Related Publications
BACKGROUND: MMP-1 (Matrix metalloproteinase-1) promotes carcinogenesis and distant metastasis in different cancers. Regulation of MMP-1 could occur at multiple levels: epigenetically, post-transcriptionally, or post-translationally. An increasing body of evidence supports that the cytoplasmic transcription factor STAT3 (signal transducer and activator of transcription 3) is activated constitutively in a variety of cancers wherein it significantly affects the growth of tumors and also facilitates metastasis. In addition, STAT3 has been found to regulate nuclear activity pro-inflammatory transcriptional factor, NF-κB signaling, especially, the alternative one (RelB/p100) by directly interacting with them METHOD AND RESULTS: In this proof of concept study, we tested the hypothesis that STAT3 interacts with RelB to promote tumor invasion by positively regulating MMP-1 in colon cancer. We found that RelB and STAT3 were constitutively localized in the nucleus of colon cancer in surgically-resected specimens with use of Western blot analysis, which was further confirmed by immunofluorescence (IF) staining in colon carcinoma cell line HT29. We further observed that STAT3/RelB knockdown resulted in reduced MMP-1. Our results from chromatin immunoprecipitation studies further established that association between RelB and MMP-1 promoter decreased when STAT3 was depleted, and conversely, STAT3 association with MMP-1 decreased with the knockdown of RelB.
CONCLUSION: These results suggest that STAT3 and ReB constitute a minimal activator complex for positive regulation of MMP-1 in colon cancer.

Białkowska K, Marciniak W, Muszyńska M, et al.
Association of zinc level and polymorphism in MMP-7 gene with prostate cancer in Polish population.
PLoS One. 2018; 13(7):e0201065 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
INTRODUCTION: Prostate cancer is one of the most commonly diagnosed malignancies among men in Western populations. Evidence reported in the literature suggests that zinc may be related to prostate cancer. In this study we evaluated the association of serum zinc levels and polymorphisms in genes encoding zinc-dependent proteins with prostate cancer in Poland.
METHODS: The study group consisted of 197 men affected with prostate cancer and 197 healthy men. Serum zinc levels were measured and 5 single nucleotide polymorphisms in MMP-1, MMP-2, MMP-7, MMP-13, MT2A genes were genotyped.
RESULTS: The mean serum zinc level was higher in prostate cancer patients than in healthy controls (898.9±12.01 μg/l vs. 856.6±13.05 μg/l, p<0.01). When compared in quartiles a significant association of higher zinc concentration with the incidence of prostate cancer was observed. The highest OR (OR = 4.41, 95%CI 2.07-9.37, p<0.01) was observed in 3rd quartile (>853.0-973.9 μg/l). Among five analyzed genetic variants, rs11568818 in MMP-7 appeared to be correlated with 2-fold increased prostate cancer risk (OR = 2.39, 95% CI = 1.19-4.82, p = 0.015).
CONCLUSION: Our results suggest a significant correlation of higher serum zinc levels with the diagnosis of prostate cancer. The polymorphism rs11568818 in MMP-7 gene was also associated with an increased prostate cancer risk in Poland.

Omar OM, Soutto M, Bhat NS, et al.
TFF1 antagonizes TIMP-1 mediated proliferative functions in gastric cancer.
Mol Carcinog. 2018; 57(11):1577-1587 [PubMed] Related Publications
Tissue inhibitor matrix metalloproteinase-1 (TIMP1) is one of four identified members of the TIMP family. We evaluated the role of TIMP1 in gastric cancer using human and mouse tissues along with gastric organoids and in vitro cell models. Using quantitative real-time RT-PCR, we detected significant overexpression of TIMP1 in the human gastric cancer samples, as compared to normal stomach samples (P < 0.01). We also detected overexpression of Timp1 in neoplastic gastric lesions of the Tff1-knockout (KO) mice, as compared to normal stomach tissues. Reconstitution of TFF1 in human gastric cancer cell lines led to a significant decrease in the mRNA expression level of TIMP1 (P < 0.05). In vitro analysis demonstrated that TIMP1 mRNA expression is induced by TNF-α and activation of NF-κB whereas inhibition of NF-κB using BAY11-7082 led to inhibition of NF-κB and downregulation of TIMP1. Western blot analysis confirmed the decrease in TIMP1 protein level following reconstitution of TFF1. By using immunofluorescence, we showed nuclear localization of NF-κB and expression of TIMP1 in gastric organoids established from the Tff1-KO stomach where reconstitution of Tff1 using recombinant protein led to a notable reduction in the expression of both NF-κB and TIMP1. Using EDU assay, as a measure of proliferating cells, we found that TIMP1 promotes cellular proliferation whereas TFF1 reconstitution leads to a significant decrease in cellular proliferation (P < 0.05). In summary, our findings demonstrate overexpression of TIMP1 in mouse and human gastric cancers through NF-kB-dependent mechanism. We also show that TFF1 suppresses NF-κB and inhibits TIMP1-mediated proliferative potential in gastric cancer.

Huang Z, Yang Q, Huang Z
Identification of Critical Genes and Five Prognostic Biomarkers Associated with Colorectal Cancer.
Med Sci Monit. 2018; 24:4625-4633 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
BACKGROUND Colorectal cancer (CRC) is a common malignant tumor with high incidence and mortality worldwide. The aim of this study was to evaluate the association between differentially expressed genes (DEGs), which may function as biomarkers for CRC prognosis and therapies, and the clinical outcome in patients with CRC. MATERIAL AND METHODS A total of 116 normal mucous tissue and 930 CRC tissue datasets were downloaded from the Gene Expression Omnibus database (GEO) and The Cancer Genome Atlas (TCGA). After screening DEGs based on limma package in R. Gene Ontology (GO) and KEGG enrichment analysis as well as the protein-protein interaction (PPI) networks were performed to predict the function of these DEGs. Meanwhile, Cox proportional hazards regression was used to build a prognostic model of these DEGs. Then, Kaplan-Meier risk analysis was used to test the model in TCGA datasets and validation datasets. RESULTS In the present study, 300 DEGs with 100 upregulated genes and 200 downregulated genes were identified. The PPI networks including 162 DEGs and 256 nodes were constructed and 2 modules with high degree were selected. Moreover, 5 genes (MMP1, ACSL6, SMPD1, PPARGC1A, and HEPACAM2) were identified using the Cox proportional hazards stepwise regression. Kaplan-Meier risk curve in the TCGA and validation cohorts showed that high-risk group had significantly poor overall survival than the low-risk group. CONCLUSIONS Our study provided insights into the mechanisms of CRC formation and found 5 prognostic genes, which could potentially inform further studies and clinical therapies.

Liao CH, Wu HC, Hu PS, et al.
The Association of Matrix Metalloproteinase-1 Promoter Polymorphisms with Prostate Cancer in Taiwanese Patients.
Anticancer Res. 2018; 38(7):3907-3911 [PubMed] Related Publications
BACKGROUND/AIM: The family of matrix metalloproteinases (MMPs) is responsible for the maintenance of extracellular matrix component homeostasis and the association of MMP-1 genetic polymorphisms with personal susceptibility to prostate cancer has only been investigated in Turkish and Japan populations and never in Taiwan. In the current study, we aimed to examine the contribution of a polymorphism in the promoter region of MMP-1 to Taiwan prostate cancer.
MATERIALS AND METHODS: The MMP-1 rs1799705 polymorphic genotypes were genotyped among 218 prostate cancer patients and 436 healthy controls by the typical polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology.
RESULTS: The percentages of 2G/2G, 1G/2G, and 1G/1G for MMP-1 -1607 genotypes were 36.2, 40.4 and 23.4% in the prostate cancer group and 33.7, 44.3, and 22.0% in the healthy control group (p trend=0.6362), respectively. The odds ratios (ORs) after adjusting for age and smoking status for those carrying 1G/2G and 1G/1G genotypes at MMP-1 -1607 were 0.84 (95%CI=0.55-1.21, p=0.3862) and 0.94 (95%CI=0.67-1.53, p=0.9586), respectively, compared to those carrying the wild-type 2G/2G genotype. Supporting these findings, the adjusted OR for those carrying the 1G allele at MMP-1 -1607 was 1.03 (95%CI=0.71-1.45, p=0.6910), compared to those carrying the wild-type 2G allele.
CONCLUSION: Our findings suggest that the polymorphic genotypes at MMP-1 promoter -1607 may play a major role in determining personal cancer susceptibility for prostate cancer in Taiwan.

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.

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