Gene Summary

Gene:MMP12; matrix metallopeptidase 12
Aliases: ME, HME, MME, MMP-12
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 protease degrades soluble and insoluble elastin. This gene may play a role in aneurysm formation and mutations in this gene are associated with lung function and chronic obstructive pulmonary disease (COPD). This gene is part of a cluster of MMP genes on chromosome 11. [provided by RefSeq, Jan 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:macrophage metalloelastase
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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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.

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

Specific Cancers (4)

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: MMP12 (cancer-related)

Liu L, Shi M, Wang Z, et al.
A molecular and staging model predicts survival in patients with resected non-small cell lung cancer.
BMC Cancer. 2018; 18(1):966 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The current TNM staging system is far from perfect in predicting the survival of individual non-small cell lung cancer (NSCLC) patients. In this study, we aim to combine clinical variables and molecular biomarkers to develop a prognostic model for patients with NSCLC.
METHODS: Candidate molecular biomarkers were extracted from the Gene Expression Omnibus (GEO), and Cox regression analysis was performed to determine significant prognostic factors. The survival prediction model was constructed based on multivariable Cox regression analysis in a cohort of 152 NSCLC patients. The predictive performance of the model was assessed by the Area under the Receiver Operating Characteristic Curve (AUC) and Kaplan-Meier survival analysis.
RESULTS: The survival prediction model consisting of two genes (TPX2 and MMP12) and two clinicopathological factors (tumor stage and grade) was developed. The patients could be divided into either high-risk group or low-risk group. Both disease-free survival and overall survival were significantly different among the diverse groups (P < 0.05). The AUC of the prognostic model was higher than that of the TNM staging system for predicting survival.
CONCLUSIONS: We developed a novel prognostic model which can accurately predict outcomes for patients with NSCLC after surgery.

Huang EY, Chang JC, Chen HH, et al.
Carcinoembryonic antigen as a marker of radioresistance in colorectal cancer: a potential role of macrophages.
BMC Cancer. 2018; 18(1):321 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: We sought to identify the carcinoembryonic antigen (CEA) as a marker of radioresistance in rectal cancer.
METHODS: From July 1997 to January 2008, 104 patients with stage II or III rectal cancer who were treated with post-operative radiotherapy (PORT) were included in this study. The doses of radiotherapy ranged from 45 to 54.6 Gy. The CEA levels were measured before surgery. We analyzed the actuarial rates of overall survival (OS), distant metastasis (DM), and local recurrence (LR) using Kaplan-Meier curves. Multivariate analyses were performed with Cox regression models. We used THP-1 monocyte cell lines for macrophage differentiation (M0, M1 or M2). The RNA extracted from the macrophages was analyzed via a genomic method in the core laboratory. The radiosensitivities of CEA-rich LS1034 cells were compared between cells with and without the conditioned media from CEA-stimulated macrophages.
RESULTS: Preoperative CEA levels ≥10 ng/mL were independent predictive factors for OS (p = 0.005), DM (p = 0.026), and LR (p = 0.004). The OS rates among the patients with pretreatment CEA levels < 10 ng/mL and ≥10 ng/mL were 64.5% and 35.9% (p = 0.004), respectively. The corresponding rates of DM were 40.6% and 73.1% (p = 0.024). The corresponding rates of LR were 6.6% and 33.9% (p = 0.002). In the M0 macrophages, exogenous CEA elicited a dose-response relationship with M2 differentiation. In the CEA-stimulated M0 cells, some mRNAs were upregulated by as much as 5-fold, including MMP12, GDF15, and JAG1. In the CEA-stimulated M2 cells, a 4-fold up-regulation of GADD45G mRNA was noted. The conditioned media from the CEA-stimulated M2 cells elicited an increase in the numbers of LS180, SW620, and LS1034 cells after irradiation. CEA caused the M2 differentiation of the macrophages.
CONCLUSION: Pretreatment CEA levels ≥10 ng/mL are a significant risk factor for OS, DM, and LR following PORT for rectal cancer. CEA causes radioresistance in the presence of M2 macrophages. More comprehensive examinations prior to surgery and intensive adjuvant therapy are suggested for patients with CEA levels ≥10 ng/mL. Further studies of these mechanisms are needed.

Li J, Zhang X, Liu Q, et al.
Myeloid-derived suppressor cells accumulate among myeloid cells contributing to tumor growth in matrix metalloproteinase 12 knockout mice.
Cell Immunol. 2018; 327:1-12 [PubMed] Related Publications
Myeloid-derived suppressor cells (MDSCs) are found frequently in patients and mice bearing tumors, which derived from immature myeloid cells. In healthy individuals, immature myeloid cells formed in the bone marrow differentiating to dendritic cells, macrophages and neutrophils. However, it is unclear whether some gene deficiency will lead to MDSCs accumulation in mice without bearing tumor. Here, we observed that MDSCs accumulated in the bone marrow of matrix metalloproteinase 12 knockout mice (MMP12

Cao W, Wei W, Zhan Z, et al.
Regulation of drug resistance and metastasis of gastric cancer cells via the microRNA647-ANK2 axis.
Int J Mol Med. 2018; 41(4):1958-1966 [PubMed] Free Access to Full Article Related Publications
Due to a lack of effective methods for early diagnosis, the majority of patients with gastric cancer (GC) are diagnosed during the late stages of the disease, which are often accompanied by metastasis. For these patients, despite being considered an important therapeutic modality in the treatment of cancer, chemotherapy is usually not effective due to multidrug resistance (MDR). The expression levels of MDR/metastasis‑associated genes are regulated by numerous microRNAs (miRNAs/miRs). The expression of miR-647 in GC tissues and SGC7901/VCR cell line (drug resistance to vincristine) was detected by qRT-PCR. The effect of overexpression of miR-647 on drug resistance was evaluated by measuring the half maximal inhibitory concentration (IC50) value of SGC-7901/VCR to vincristine and tumor growth in vivo. Moreover, drug-induced cell apoptosis and cell cycle were evaluated by flow cytometry, as well as the ability of cell migration and invasiveness detected by wound healing and transwell assay. Furthermore, underlying targets of miR-647 were predicted by TargetScan and MicroRNA; meanwhile, the expression of ANK2, FAK, MMP2, MMP12,CD44,SNAIL1 were observed by qRT-PCR and western blot analysis. The present study established that the expression levels of miR‑647 were downregulated in GC tissues from patients with metastasis and in the vincristine‑resistant SGC7901 (SGC‑7901/VCR) GC cell line. The IC50 value for vincristine was significantly decreased, whereas the proportion of cells in G0/G1 phase and the drug‑induced apoptotic rate were significantly increased following upregulation of miR‑647. Furthermore, the results demonstrated that miR‑647 overexpression led to decreased migration and invasion of SGC‑7901/VCR cells. Overexpression of miR‑647 was also demonstrated to sensitize tumors to chemotherapy in vivo. In addition, miR‑647 overexpression was able to reduce the expression levels of ankyrin‑B, focal adhesion kinase, matrix metalloproteinase (MMP)2, MMP12, cluster of differentiation 44 and snail family transcriptional repressor 1. In conclusion, these findings demonstrated that miR‑647 may function as a novel target to ameliorate drug resistance and metastasis of GC cells.

Xie Y, Sun W, Deng Z, et al.
MiR-302b Suppresses Osteosarcoma Cell Migration and Invasion by Targeting Runx2.
Sci Rep. 2017; 7(1):13388 [PubMed] Free Access to Full Article Related Publications
Osteosarcoma patients with lung metastasis and local invasion remain challenging to treat despite the significant contribution of the combination of surgery and neo-adjuvant chemotherapy. Our previous microarray study demonstrated that miR-302b had significantly lower expression in osteosarcoma cell lines than in osteoblast cell lines. In the present study, we further elucidated the role of miR-302b in regulating the migration and invasiveness of osteosarcoma. MiR-302b expression was markedly down-regulated in osteosarcoma cell lines and clinical tumour tissues. Lower levels of miR-302b expression were significantly associated with metastasis and high pathological grades. A functional study demonstrated that over-expression of miR-302b suppressed tumour cell proliferation, invasion and migration in vitro and in vivo. Runx2 was identified as a direct target gene for miR-302b by bioinformatics analysis and dual-luciferase reporter gene assay. Moreover, over-expression of miR-302b induced down-regulation of Runx2, OPN, MMP-2, MMP-9, MMP-12, MMP-14, and VEGF in 143B cells. Exogenous expression of Runx2 partially rescued the inhibitory effect of miR-302b on the invasion and migration activity of 143B osteosarcoma cells. Taken together, our results indicate that miR-302b functions as a tumour repressor in the invasion and migration of osteosarcoma by directly downregulating Runx2 expression and may be a potential therapeutic target for osteosarcoma.

Fujimura T, Kakizaki A, Sato Y, et al.
The Immunological Roles of Periostin/Tumor-Associated Macrophage Axis in Development of Dermatofibrosarcoma Protuberans.
Anticancer Res. 2017; 37(6):2867-2873 [PubMed] Related Publications
BACKGROUND/AIM: Dermatofibrosarcoma protuberance (DFSP) is a fibrohistiocytic tumor of intermediate malignancy characterized by slow infiltrative growth and a high tendency to recur locally. Periostin is involved in modulating cell function and inducing the production of proinflammatory cytokines, chemokines, and matrix metalloproteinases (MMPs) from tumor-associated macrophages (TAMs) to promote fibrosis and tumor growth. This study aimed to examine the cancer stroma of DFSP, focusing on TAMs-related proteins and MMPs.
PATIENTS AND METHODS: Using immunohistochemical staining and DNA microarray database, we evaluated periostin, CD163, CD206, MMP1 and MMP12 in 10 cases of DFSP and dermatofibroma.
RESULTS: Dense deposits of periostin as well as a substantial number of CD163
CONCLUSION: Increased levels of MMP1 and MMP12 on TAMs in the peripheral areas of DFSP might contribute to local invasion.

Zuurbier L, Rahman A, Cordes M, et al.
Apelin: A putative novel predictive biomarker for bevacizumab response in colorectal cancer.
Oncotarget. 2017; 8(26):42949-42961 [PubMed] Free Access to Full Article Related Publications
Bevacizumab (bvz) is currently employed as an anti-angiogenic therapy across several cancer indications. Bvz response heterogeneity has been well documented, with only 10-15% of colorectal cancer (CRC) patients benefitting in general. For other patients, clinical efficacy is limited and side effects are significant. This reinforces the need for a robust predictive biomarker of response. To identify such a biomarker, we performed a DNA microarray-based transcriptional profiling screen with primary endothelial cells (ECs) isolated from normal and tumour colon tissues. Thirteen separate populations of tumour-associated ECs and 10 of normal ECs were isolated using fluorescence-activated cell sorting. We hypothesised that VEGF-induced genes were overexpressed in tumour ECs; these genes could relate to bvz response and serve as potential predictive biomarkers. Transcriptional profiling revealed a total of 2,610 differentially expressed genes when tumour and normal ECs were compared. To explore their relation to bvz response, the mRNA expression levels of top-ranked genes were examined using quantitative PCR in 30 independent tumour tissues from CRC patients that received bvz in the adjuvant setting. These analyses revealed that the expression of MMP12 and APLN mRNA was significantly higher in bvz non-responders compared to responders. At the protein level, high APLN expression was correlated with poor progression-free survival in bvz-treated patients. Thus, high APLN expression may represent a novel predictive biomarker for bvz unresponsiveness.

Wang Z, Shao M, Liu Y
Promotion of Wilms' tumor cells migration and invasion by mono-2-ethyhexyl phthalate (MEHP) via activation of NF-κB signals.
Chem Biol Interact. 2017; 270:1-8 [PubMed] Related Publications
Wilms tumor is a pediatric kidney cancer associated with inactivation of the WT1 tumor-suppressor gene in 5-10% of cases. There is an urgent need to illustrate risk factors which can trigger the motility of Wilms tumor cells. Our present study revealed that mono-(2-ethylhexyl) phthalate (MEHP) exposure can significantly increase the in vitro migration and invasion of G401 and WiT49 cells. Real time PCR and western blot analysis revealed that MEHP treatment can increase the expression of metalloproteinase-2 (MMP-2) and MMP-9, while had no effect on the expression of MMP-1, MMP-3, or MMP-12. The si-MMP-2 and si-MMP-9 can reverse MEHP induced migration and invasion of G401 cells. MEHP can activate both ERK1/2 and p65 in WT cells, while had no obvious effect on Akt or PKA. However, only BAY 11-7082, the inhibitor of NF-κB, while not ERK1/2 (PD 98059), can reverse MEHP induced migration and invasion of WT cells. BAY 11-7082 also can attenuate MEHP induced up regulation of MMP-2 and MMP-9. The inhibitor of estrogen receptor reversed MEHP induced activation of NF-κB and up regulation of MMP-2/-9. In addition, MEHP also increased the mRNA and protein expression, nuclear translocation, and transcriptional activities of NF-κB in WT cells. Collectively, our study found that MEHP stimulated the Wilms' tumor progression via NF-κB signals.

Dandachi N, Kelly NJ, Wood JP, et al.
Macrophage Elastase Induces TRAIL-mediated Tumor Cell Death through Its Carboxy-Terminal Domain.
Am J Respir Crit Care Med. 2017; 196(3):353-363 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Macrophage elastase (matrix metalloproteinase [MMP]-12) is a potent protease that contributes to the lung destruction that accompanies cigarette smoking; it simultaneously inhibits lung tumor angiogenesis and metastasis by catalyzing the formation of antiangiogenic peptides. Recent studies have revealed novel nonproteolytic functions of MMP12, including antimicrobial activity through a peptide within its C-terminal domain (CTD).
OBJECTIVES: To determine whether the MMP12 CTD contributes to its antitumor activity in lung cancer.
METHODS: We used recombinant MMP12 peptide fragments, including its catalytic domain, CTD, and a 20 amino acid peptide within the CTD (SR20), in an in vitro system to delineate their effects on non-small cell lung cancer cell proliferation and apoptosis. We translated our findings to two murine models of lung cancer, including orthotopic human xenograft and Kras
MEASUREMENTS AND MAIN RESULTS: We show that SR20 triggers tumor apoptosis by up-regulation of gene expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptor, death receptor 4, sensitizing cells to an autocrine loop of TRAIL-mediated cell death. We then demonstrate the therapeutic efficacy of SR20 against two murine models of lung cancer.
CONCLUSIONS: The MMP12 CTD initiates TRAIL-mediated tumor cell death through its conserved SR20 peptide.

Chen Z, Soutto M, Rahman B, et al.
Integrated expression analysis identifies transcription networks in mouse and human gastric neoplasia.
Genes Chromosomes Cancer. 2017; 56(7):535-547 [PubMed] Free Access to Full Article Related Publications
Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide. The Tff1 knockout (KO) mouse model develops gastric lesions that include low-grade dysplasia (LGD), high-grade dysplasia (HGD), and adenocarcinomas. In this study, we used Affymetrix microarrays gene expression platforms for analysis of molecular signatures in the mouse stomach [Tff1-KO (LGD) and Tff1 wild-type (normal)] and human gastric cancer tissues and their adjacent normal tissue samples. Combined integrated bioinformatics analysis of mouse and human datasets indicated that 172 genes were consistently deregulated in both human gastric cancer samples and Tff1-KO LGD lesions (P < .05). Using Ingenuity pathway analysis, these genes mapped to important transcription networks that include MYC, STAT3, β-catenin, RELA, NFATC2, HIF1A, and ETS1 in both human and mouse. Further analysis demonstrated activation of FOXM1 and inhibition of TP53 transcription networks in human gastric cancers but not in Tff1-KO LGD lesions. Using real-time RT-PCR, we validated the deregulated expression of several genes (VCAM1, BGN, CLDN2, COL1A1, COL1A2, COL3A1, EpCAM, IFITM1, MMP9, MMP12, MMP14, PDGFRB, PLAU, and TIMP1) that map to altered transcription networks in both mouse and human gastric neoplasia. Our study demonstrates significant similarities in deregulated transcription networks in human gastric cancer and gastric tumorigenesis in the Tff1-KO mouse model. The data also suggest that activation of MYC, STAT3, RELA, and β-catenin transcription networks could be an early molecular step in gastric carcinogenesis.

Kuasne H, Barros-Filho MC, Busso-Lopes A, et al.
Integrative miRNA and mRNA analysis in penile carcinomas reveals markers and pathways with potential clinical impact.
Oncotarget. 2017; 8(9):15294-15306 [PubMed] Free Access to Full Article Related Publications
Penile carcinoma (PeCa) is an important public health issue in poor and developing countries, and has only recently been explored in terms of genetic and epigenetic studies. Integrative data analysis is a powerful method for the identification of molecular drivers involved in cancer development and progression. miRNA and mRNA expression profiles followed by integrative analysis were investigated in 23 PeCa and 12 non-neoplastic penile tissues (NPT). Expression levels of eight miRNAs and 10 mRNAs were evaluated in the same set of samples used for microarray and in a validation set of cases (PeCa = 36; NPT = 27). Eighty-one miRNAs and 2,697 mRNAs were identified as differentially expressed in PeCa. Integrative data analysis revealed 255 mRNAs potentially regulated by 68 miRNAs. Using RT-qPCR, eight miRNAs and nine transcripts were confirmed as altered in PeCa. We identified that MMP1, MMP12 and PPARG and hsa-miR-31-5p, hsa-miR-224-5p, and hsa-miR-223-3p were able to distinguish tumors from NPT with high sensitivity and specificity. Higher MMP1 expression was detected as a better predictor of lymph node metastasis than the clinical-pathological data. In addition, PPARG and EGFR were highlighted as potential pathways for targeted therapy in PeCa. The analysis based on HPV positivity (7 of 23 cases) revealed five miRNA and 13 mRNA differentially expressed. Although in a limited number of cases, HPV positive PeCa presented less aggressive phenotype in comparison with negative cases. Overall, an integrative analysis using mRNA and miRNA profiles revealed markers related with tumor development and progression. Furthermore, MMP1 expression level was a predictive marker for lymph node metastasis in patients with PeCa.

Cao W, Wei W, Zhan Z, et al.
Role of miR-647 in human gastric cancer suppression.
Oncol Rep. 2017; 37(3):1401-1411 [PubMed] Free Access to Full Article Related Publications
MicroRNAs (miRNAs) regulate various oncogenes concomitantly, resulting in tumor suppression. They regulate proliferation and migration pathways in tumor development, suggesting a potential therapeutic role. In the present study, we found that miR-647 was markedly downregulated in gastric cancer (GC), and was significantly correlated with reduced tumor size and metastasis. In addition, miR-647 was also reduced in GC cell lines. Furthermore, overexpression of miR-647 in the GC cell lines inhibited cell proliferation, promoted cell cycle arrest at the G0/G1 phase and induced cell apoptosis. miR-647 also significantly inhibited tumor growth in vivo. Notably, we found that miR-647 overexpression suppressed the migration and invasion of the cancer cells, particularly liver metastasis in nude mice. miR-647 also reduced the expression levels of genes associated with proliferation and metastasis in tumors, including ANK2, FAK, MMP2, MMP12, CD44 and SNAIL1. Overall, our findings demonstrated that miR-647 exerts powerful antitumorigenic effects in vitro and in vivo, and may represent a promising therapeutic agent against GC.

Hass HG, Vogel U, Scheurlen M, Jobst J
Gene-expression Analysis Identifies Specific Patterns of Dysregulated Molecular Pathways and Genetic Subgroups of Human Hepatocellular Carcinoma.
Anticancer Res. 2016; 36(10):5087-5095 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma comprises of a group of heterogeneous tumors of different etiologies. The multistep process of liver carcinogenesis involves various genetic and phenotypic alterations. The molecular pathways and driver mutations involved are still under investigation.
MATERIALS AND METHODS: DNA micorarray technology was used to identify differentially expressed genes between human hepatocarcinoma and non-tumorous liver tissues to establish a unique specific gene-expression profile independent of the underlying liver disease. The validity of this global gene-expression profile was tested for its robustness against biopsies from other liver entities (cirrhotic and non-cirrhotic liver) by diagnosing HCC in blinded samples.
RESULTS: Most of the consistently and strongly overexpressed genes were related to cell-cycle regulation and DNA replication [27 genes, e.g. cyclin B1, karyopherin alpha 2 (KPNA2), cyclin-dependent kinase 2 (CDC2)], G-protein depending signaling [e.g. Rac GTPase activating protein 1 (RACGAP1), Rab GTPase YPT1 homolog (RAB1), and ADP-ribosylation factor-like 2 (ARL2)] and extracellular matrix re-modelling or cytoskeleton structure [22 genes, e.g. serine proteinase inhibitor 1 kazal-type (SPINK1), osteopontin (OPN), secreted protein acidic and rich in cysteine (SPARC), collagen type 1 alpha2 (COL1A2), integrin alpha6 (ITGA6), and metalloproteinase 12 (MMP12)]. Furthermore, significantly differentially expressed genes (e.g. calcium-binding proteins, G-proteins, oncofetal proteins) in relation to tumor differentiation were detected using gene-expression analysis.
CONCLUSION: It is suggested that these significantly dysregulated genes are highly specific and potentially utilizable as prognostic markers and may lead to a better understanding of human hepatocarcinogenesis.

Shang D, Zheng T, Zhang J, et al.
Profiling of mRNA and long non-coding RNA of urothelial cancer in recipients after renal transplantation.
Tumour Biol. 2016; 37(9):12673-12684 [PubMed] Related Publications
The molecular mechanism and signal transduction pathways involved in urothelial cancer (UC) after renal transplantation (RTx) remain unknown. In this study, we investigated the profiling of messenger RNA (mRNA) and long non-coding RNA (lncRNA) in RTx recipients with UC. The mRNA and lncRNA of six pairs of UC and corresponding normal urothelial tissues in RTx recipients were profiled using Arraystar Human lncRNA Microarray V3.0, which is designed for the global profiling of 26,109 coding transcripts and 30,586 lncRNAs. Quantitative real-time PCR (qRT-PCR) was used to validate the differentially expressed mRNAs and lncRNAs. Molecular function classification and biological process classification for the differentially expressed mRNAs were analyzed with Gene Ontology. The key pathways that were associated with UC after RTx were analyzed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Compared to normal urothelial tissues, 1597 mRNAs were upregulated and 1032 mRNAs were downregulated in UC; 2107 lncRNAs were upregulated and 1794 lncRNAs were downregulated (greater than twofold). Further qRT-PCR analysis of mRNA and lncRNA expression showed well consistency with the data of microarray analysis. The expression of matrix metalloprotease (MMP)-3, MMP-10, MMP-12, and MMP-13 was significantly increased, while the expression of CD36 was decreased in UC after RTx. Co-expression analysis of lncRNAs and their nearby coding genes showed that lncRNAs may play critical roles in regulating nearby genes in the carcinogenesis of UC. Our results also suggest that peroxisome proliferator-activated receptor (PPAR) signaling may be involved in UC after RTx. Moreover, several cytokines and their receptors were also significantly upregulated in UC after RTx, suggesting that cytokines might be modulated and participated in the carcinogenesis of UC after RTx. We analyzed the potential molecular mechanism and pathways involved in the UC of RTx recipients. Our results revealed that several key regulatory pathways and lncRNAs play critical roles in the carcinogenesis of UC, and suggest that UC in RTx recipients may be more likely to invade and metastasis. However, the detailed functional analysis of these mechanisms should be further performed in the future.

Yu PF, Huang Y, Han YY, et al.
TNFα-activated mesenchymal stromal cells promote breast cancer metastasis by recruiting CXCR2
Oncogene. 2017; 36(4):482-490 [PubMed] Free Access to Full Article Related Publications
Mesenchymal stromal cells (MSCs) tend to infiltrate into tumors and form a major component of the tumor microenvironment. Our previous work demonstrated that tumor necrosis factor α (TNFα)-activated MSCs significantly promoted tumor growth. However, the role of TNFα-treated MSCs in tumor metastasis remains elusive. Employing a lung metastasis model of murine breast cancer, we found that TNFα-activated MSCs strikingly enhanced tumor metastasis compared with normal MSCs. We analyzed the chemokine profiles and found that the expression of CCL5, CCR2 and CXCR2 ligands were enhanced in TNFα-activated MSCs. Using genetic or pharmacological strategies to inhibit CCL5 or CCR2, we demonstrated that CCL5 and CCR2 ligands were indispensable in supporting TNFα-activated MSCs to promote tumor metastasis. Analysis of immune cells revealed that CXCR2 ligands (CXCL1, CXCL 2 and CXCL5) expressed by TNFα-activated MSCs efficiently recruited CXCR2

Wan Z, Jiang D, Chen S, et al.
T-box transcription factor brachyury promotes tumor cell invasion and metastasis in non-small cell lung cancer via upregulation of matrix metalloproteinase 12.
Oncol Rep. 2016; 36(1):306-14 [PubMed] Related Publications
T-box transcription factor brachyury and matrix metalloproteinases (MMPs) play important roles in non-small cell lung cancer (NSCLC) cell invasion and metastasis. However, the association between Brachyury and the MMP family has not yet been fully investigated. The present study aimed to assess the influence of Brachyury on the expression of 23 MMP members and to further explore the mechanisms involved in the promotion of NSCLC cell invasion by Brachyury and MMPs in the H460 and H1299 stable cell lines. The protein expression levels and correlations between the brachyury transcription factor and the targeted MMPs were also validated in 52 NSCLC patient tissue samples. We observed that brachyury significantly upregulated MMP12 expression to promote NSCLC cell invasion. We also found a potential binding site for the brachyury transcription factor in the MMP12 promoter.

Xiao X, He Z, Cao W, et al.
Oridonin inhibits gefitinib-resistant lung cancer cells by suppressing EGFR/ERK/MMP-12 and CIP2A/Akt signaling pathways.
Int J Oncol. 2016; 48(6):2608-18 [PubMed] Related Publications
Oridonin (Ori), a diterpenoid compound extracted from traditional medicinal herbs, elicits antitumor effects on many cancer types. However, whether Ori can be used in gefitinib-resistant non-small cell lung cancer (NSCLC) cells remains unclear. This study investigated the antitumor activity and underlying mechanisms of Ori. Results demonstrated that this compound dose-dependently inhibited the proliferation, invasion, and migration of the gefitinib-resistant NSCLC cells in vitro. Ori also significantly downregulated the phosphorylation of EGFR, ERK, Akt, expression levels of matrix metalloproteinase-12 (MMP-12), and the cancerous inhibitor of protein phosphatase 2A (CIP2A). In addition, Ori upregulated protein phosphatase 2A (PP2A) activity of gefitinib-resistant NSCLC cells. Ori combined with docetaxel synergistically inhibited these cells. Ori also inhibited tumor growth in murine models. Immunohistochemistry results further revealed that Ori downregulated phospho-EGFR, MMP-12, and CIP2A in vivo. These findings indicated that Ori can inhibit the proliferation, invasion, and migration of gefitinib-resistant NSCLC cells by suppressing EGFR/ERK/MMP-12 and CIP2A/PP2A/Akt signaling pathways. Thus, Ori may be a novel effective candidate to treat gefitinib-resistant NSCLC.

Bradford JR, Wappett M, Beran G, et al.
Whole transcriptome profiling of patient-derived xenograft models as a tool to identify both tumor and stromal specific biomarkers.
Oncotarget. 2016; 7(15):20773-87 [PubMed] Free Access to Full Article Related Publications
The tumor microenvironment is emerging as a key regulator of cancer growth and progression, however the exact mechanisms of interaction with the tumor are poorly understood. Whilst the majority of genomic profiling efforts thus far have focused on the tumor, here we investigate RNA-Seq as a hypothesis-free tool to generate independent tumor and stromal biomarkers, and explore tumor-stroma interactions by exploiting the human-murine compartment specificity of patient-derived xenografts (PDX).Across a pan-cancer cohort of 79 PDX models, we determine that mouse stroma can be separated into distinct clusters, each corresponding to a specific stromal cell type. This implies heterogeneous recruitment of mouse stroma to the xenograft independent of tumor type. We then generate cross-species expression networks to recapitulate a known association between tumor epithelial cells and fibroblast activation, and propose a potentially novel relationship between two hypoxia-associated genes, human MIF and mouse Ddx6. Assessment of disease subtype also reveals MMP12 as a putative stromal marker of triple-negative breast cancer. Finally, we establish that our ability to dissect recruited stroma from trans-differentiated tumor cells is crucial to identifying stem-like poor-prognosis signatures in the tumor compartment.In conclusion, RNA-Seq is a powerful, cost-effective solution to global analysis of human tumor and mouse stroma simultaneously, providing new insights into mouse stromal heterogeneity and compartment-specific disease markers that are otherwise overlooked by alternative technologies. The study represents the first comprehensive analysis of its kind across multiple PDX models, and supports adoption of the approach in pre-clinical drug efficacy studies, and compartment-specific biomarker discovery.

Cao W, Wei W, Zhan Z, et al.
MiR-1284 modulates multidrug resistance of gastric cancer cells by targeting EIF4A1.
Oncol Rep. 2016; 35(5):2583-91 [PubMed] Related Publications
Routine chemotherapy as an important treatment mode often can not be effective because of multidrug resistance (MDR). MicroRNA (miRNA) modulates the expression of a great number of genes, including MDR. In this study, the expression of miR-1284 was reduced in gastric cancer (GC) tissue specimens with metastasis and in vincristine-resistant (VCR) GC SGC7901 cells (SGC-7901/VCR) compared to that in the controls. Recombinant lentiviral vectors with miR-1284 led to the overexpression of miR-1284 mRNA and reversed the chemoresistance of SGC7901/VCR cells, promoted cell cycle arrested at the G0/G1 phase, accelerated drug-induced apoptosis, and decreased migration and invasiveness of SGC-7901/VCR. In addition, the overexpression of miR-1284 sensitized tumors to chemotherapy in vivo. Our data provide combined evidence that miR-1284 can heighten the expression of MYC and reduce the expression of JUN, MMP12, and EIF4A1 that was the direct target. In conclusion, miR-1284 can function as a new regulator to reduce GC MDR cells by targeting EIF4A1.

Niu H, Hu Z, Liu H, et al.
Long non-coding RNA AK027294 involves in the process of proliferation, migration, and apoptosis of colorectal cancer cells.
Tumour Biol. 2016; 37(8):10097-105 [PubMed] Free Access to Full Article Related Publications
This study is aimed to investigate the differentially expressed long non-coding RNAs (lncRNAs) in colorectal cancer and its potential biological function. Colorectal adenoma is the precancerous lesions of colorectal cancer, so in this study, we used colorectal adenoma as negative control. The global lncRNA expression profile in colorectal cancer and adenoma was evaluated by bioinformatics. The biological functions and potential mechanism of AK027294 were investigated in HCT116, HCT8, and SW480 colorectal cancer cells. A total of 135 lncRNAs were found to be differentially expressed in colorectal cancer and adenoma tissues. Among them, 71 lncRNAs were up-regulated and 64 lncRNAs were down-regulated. Especially, AK027294 was found to be highly expressed in colorectal cancer tissues compared with colorectal adenoma tissues (fold change is 184.5). Our results indicated that AK027294 down-regulation significantly inhibited colorectal cancer cells proliferation and migration, but promoted cell apoptosis (P < 0.05). The potential mechanism of AK027294 might be associated with the regulation of caspase-3, caspase-8, Bcl-2, MMP12, MMP9, and TWIST. The lncRNA expression profile in colorectal cancer suggests lncRNAs may play important roles in the occurrence and progression of colorectal cancer. AK027294 is highly expressed in colorectal cancer and closely correlates with colorectal cells proliferation, migration, and apoptosis.

Warnecke-Eberz U, Metzger R, Hölscher AH, et al.
Diagnostic marker signature for esophageal cancer from transcriptome analysis.
Tumour Biol. 2016; 37(5):6349-58 [PubMed] Related Publications
Esophageal cancer is often diagnosed at an advanced stage. Diagnostic markers are needed for achieving a cure in esophageal cancer detecting and treating tumor cells earlier. In patients with locally advanced squamous cell carcinoma of the esophagus (ESCC), we profiled the gene expression of ESCC compared to corresponding normal biopsies for diagnostic markers by genome microarrays. Profiling of gene expression identified 4844 genes differentially expressed, 2122 upregulated and 2722 downregulated in ESCC. Twenty-three overexpressed candidates with best scores from significance analysis have been selected for further analysis by TaqMan low-density array-technique using a validation cohort of 40 patients. The verification rate was 100 % for ESCC. Twenty-two markers were additionally overexpressed in adenocarcinoma of the esophagus (EAC). The markers significantly overexpressed already in earlier tumor stages (pT1-2) of both histological subtypes (n = 19) have been clustered in a "diagnostic signature": PLA2G7, PRAME, MMP1, MMP3, MMP12, LIlRB2, TREM2, CHST2, IGFBP2, IGFBP7, KCNJ8, EMILIN2, CTHRC1, EMR2, WDR72, LPCAT1, COL4A2, CCL4, and SNX10. The marker signature will be translated to clinical practice to prove its diagnostic impact. This diagnostic signature may contribute to the earlier detection of tumor cells, with the aim to complement clinical techniques resulting in the development of better detection of concepts of esophageal cancer for earlier therapy and more favorite prognosis.

Agostini M, Janssen KP, Kim IJ, et al.
An integrative approach for the identification of prognostic and predictive biomarkers in rectal cancer.
Oncotarget. 2015; 6(32):32561-74 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Colorectal cancer is the third most common cancer in the world, a small fraction of which is represented by locally advanced rectal cancer (LARC). If not medically contraindicated, preoperative chemoradiotherapy, represent the standard of care for LARC patients. Unfortunately, patients shows a wide range of response rates in which approximately 20% has a complete pathological response, whereas in 20 to 40% the response is poor or absent.
RESULTS: The following specific gene signature, able to discriminate responders' patients from non-responders, were founded: AKR1C3, CXCL11, CXCL10, IDO1, CXCL9, MMP12 and HLA-DRA. These genes are mainly involved in immune system pathways and interact with drugs traditionally used in the adjuvant treatment of rectal cancer.
DISCUSSION: The present study suggests that new ideas for therapy could be found not only limited to studying genes differentially expressed between the two groups of patients but deepening the mechanisms, associated to response, in which they are involved.
METHODS: Gene expression studies performed by: Agostini et al., Rimkus et al. and Kim et al. have been merged through a meta-analysis of the raw data. Gene expression data-sets have been processed using A-MADMAN. Common differentially expressed gene (DEG) were identified through SAM analysis. To further characterize the identified DEG we deeply investigated its biological role using an integrative computational biology approach.

Yang S, Long M, Tachado SD, Seng S
Cigarette smoke modulates PC3 prostate cancer cell migration by altering adhesion molecules and the extracellular matrix.
Mol Med Rep. 2015; 12(5):6990-6 [PubMed] Free Access to Full Article Related Publications
Prostate cancer (PCa) is the second leading cause of cancer‑related mortality among American males. Studies suggest that cigarette smoking is associated with the progression of PCa; however, the molecular mechanisms underlying this process have not been extensively investigated. PCa progression is characterized by increased cell migration and alterations in extracellular matrix (ECM)‑ and cell adhesion molecule (CAM)‑related gene expression. In the present study, the influence of cigarette smoke medium (SM) on cell migration and on the expression of ECM‑ and CAM‑related genes in PC3 prostate adenocarcinoma cells was investigated. According to a wound‑healing assay, SM treatment promoted PC3 cell migration. RNA expression levels from SM‑treated and control cells were analyzed using a polymerase chain reaction (PCR) array. Of 84 genes analyzed, 27.38% (23/84) exhibited a ≥2‑fold change in threshold cycle in PC3 cells following 0.5% SM treatment. Functional gene grouping analysis demonstrated that SM treatment modulated the RNA transcription of approximately 18.4% of CAMs and 33.93% of ECM‑related genes. Quantitative PCR analysis showed that SM treatment led to a significant decrease in transcription levels of the following genes: Collagen 5 α‑1(V), connective tissue growth factor, integrin β‑2, kallmann syndrome 1, laminin α 3, matrix metallopeptidase 7 (MMP7), MMP13, secreted protein acidic cysteine‑rich, thrombospondin‑2 and versican; and that SM significantly increased the transcription levels of MMP2 and MMP12. Furthermore, MMP2 knockdown significantly reduced the migration of SM‑treated PC3 cells. The present study provides novel insights into the association of cigarette smoking with PCa progression, via the alteration of ECM/CAM interactions.

Bonnefont-Rebeix C, Fournel-Fleury C, Ponce F, et al.
Characterization of a novel canine T-cell line established from a spontaneously occurring aggressive T-cell lymphoma with large granular cell morphology.
Immunobiology. 2016; 221(1):12-22 [PubMed] Related Publications
Dogs with lymphoma are established as good model for human non-Hodgkin lymphoma studies. Canine cell lines derived from lymphomas may be valuable tools for testing new therapeutic drugs. In this context, we established a canine T-cell line, PER-VAS, from a primary aggressive T-cell lymphoma with large granular morphology. Flow cytometric analysis revealed a stable immunophenotype: PER-VAS cells were positively labelled for CD5, CD45, MHC II and TLR3, and were negative for CD3, CD4 and CD8 expression. Although unstable along the culture process, IL-17 and MMP12 proteins were detectable as late as at passages 280 and 325i.e. respectively 24 and 29 months post isolation. At passage 325, PER-VAS cells maintained the expression of IL-17, CD3, CD56, IFNγ and TNFα mRNAs as shown by RT-PCR analysis. Stable rearrangement of the TCRγ gene has been evidenced by PCR. PER-VAS cells have a high proliferation index with a doubling time of 16.5h and were tumorigenic in Nude mice. Compared to the canine cell lines already reported, PER-VAS cells display an original expression pattern, close to NKT cells, which makes them valuable tools for in vitro comparative research on lymphomas.

Zhang Z, Zhu S, Yang Y, et al.
Matrix metalloproteinase-12 expression is increased in cutaneous melanoma and associated with tumor aggressiveness.
Tumour Biol. 2015; 36(11):8593-600 [PubMed] Related Publications
Cutaneous melanoma is the most malignant form of skin cancer characterized by aggressive invasion. Matrix metalloproteinases play essential roles in tumor invasion due to their ECM degrading capacity. However, the clinical significance of matrix metalloproteinasis (MMP)-12 in human cutaneous melanoma has not been addressed yet. In the present study, we investigated MMP-12 expression level in 298 patients with cutaneous melanoma and 60 normal skin tissue specimens by immunohistochemistry assay. Appropriate statistical analysis was utilized to determine the association of MMP-12 with clinical features and prognosis of melanoma. Results showed that MMP-12 expression was increased in cutaneous melanoma compared with that in normal skin. It was also found that MMP-12 expression in melanoma was significantly associated with tumor invasion and metastasis. Univariate survival analysis indicated that patients with melanoma of high MMP-12 expression had unfavorable overall survival compared with those of low MMP-12 expression. Cox's proportional hazards analysis showed that MMP-12 expression was an independent prognostic marker of overall survival for patients with cutaneous melanoma. These results proved that MMP-12 expression was increased in cutaneous melanoma and associated with tumor progression. It also provided the first evidence that MMP-12 level could be an independent prognostic marker for patients with cutaneous melanoma.

Gump JM, Donson AM, Birks DK, et al.
Identification of targets for rational pharmacological therapy in childhood craniopharyngioma.
Acta Neuropathol Commun. 2015; 3:30 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Pediatric adamantinomatous craniopharyngioma (ACP) is a histologically benign but clinically aggressive brain tumor that arises from the sellar/suprasellar region. Despite a high survival rate with current surgical and radiation therapy (75-95 % at 10 years), ACP is associated with debilitating visual, endocrine, neurocognitive and psychological morbidity, resulting in excheptionally poor quality of life for survivors. Identification of an effective pharmacological therapy could drastically decrease morbidity and improve long term outcomes for children with ACP.
RESULTS: Using mRNA microarray gene expression analysis of 15 ACP patient samples, we have found several pharmaceutical targets that are significantly and consistently overexpressed in our panel of ACP relative to other pediatric brain tumors, pituitary tumors, normal pituitary and normal brain tissue. Among the most highly expressed are several targets of the kinase inhibitor dasatinib - LCK, EPHA2 and SRC; EGFR pathway targets - AREG, EGFR and ERBB3; and other potentially actionable cancer targets - SHH, MMP9 and MMP12. We confirm by western blot that a subset of these targets is highly expressed in ACP primary tumor samples.
CONCLUSIONS: We report here the first published transcriptome for ACP and the identification of targets for rational therapy. Experimental drugs targeting each of these gene products are currently being tested clinically and pre-clinically for the treatment of other tumor types. This study provides a rationale for further pre-clinical and clinical studies of novel pharmacological treatments for ACP. Development of mouse and cell culture models for ACP will further enable the translation of these targets from the lab to the clinic, potentially ushering in a new era in the treatment of ACP.

Tian ZQ, Li ZH, Wen SW, et al.
Identification of Commonly Dysregulated Genes in Non-small-cell Lung Cancer by Integrated Analysis of Microarray Data and qRT-PCR Validation.
Lung. 2015; 193(4):583-92 [PubMed] Related Publications
BACKGROUND: Non-small-cell lung cancer (NSCLC), the most common lung cancer, leads to the largest number of cancer-related deaths worldwide. There are many studies to identify the differentially expressed genes (DEGs) between NSCLC and normal control (NC) tissues by means of microarray technology. Because of the inconsistency of the microarray data sets, we performed an integrated analysis to identify DEGs and analyzed their biological function.
METHODS AND RESULTS: We combined 15 microarray data sets and identified 1063 DEGs between NSCLC and NC tissues; in addition, we found that the DEGs were enriched in regulation of cell proliferation process and focal adhesion signaling pathway. The protein-protein interaction network analysis for the top 20 significantly DEGs revealed that CAV1, COL1A1, and ADRB2 were the significant hub proteins. Finally, we employed qRT-PCR to validate the meta-analysis approach by determining the expression of the top 10 most significantly DEGs and found that the expression of these genes were significantly different between tumor and NC tissues, in accordance with the results of meta-analysis.
CONCLUSION: qRT-PCR results indicated that the meta-analysis approach in our study was acceptable. Our data suggested that some of the DEGs, including MMP12, COL11A1, THBS2, FAP, and CAV1, may participate in the pathology of NSCLC and could be applied as potential markers or therapeutic targets for NSCLC.

Lv FZ, Wang JL, Wu Y, et al.
Knockdown of MMP12 inhibits the growth and invasion of lung adenocarcinoma cells.
Int J Immunopathol Pharmacol. 2015; 28(1):77-84 [PubMed] Related Publications
Matrix metalloproteinase-12 (MMP12) is involved in many pathological processes including cancer. The expression and function of MMP12 in lung adenocarcinoma (LAC) remain unclear. The present study aimed to investigate the correlation of MMP12 expression with LAC patients and clarify its role in growth and invasion of LAC cells. The expression of MMP12 in human LAC was examined by immunohistochemical assay using a tissue microarray procedure. A loss-of-function experiment was used for observing the effects of lentiviral vector-mediated MMP12 shRNA (shMMP12) on cell growth and invasion in LAC cell lines (A549), indicated by MTT and Transwell assays. We found that the expression of MMP12 protein was significantly increased in LAC tissues compared with that in adjacent non-cancerous tissues (ANCT) (57.69% vs. 32.69%, P = 0.019), and was closely correlated with the pathological stage and lymph node metastasis of LAC patients (P = 0.01; P = 0.003). Knockdown of MMP12 inhibited proliferation and invasion of LAC cells followed by the downregulation of proliferating cell nuclear antigen (PCNA) and vascular endothelial growth factor (VEGF). In conclusion, our findings show that high expression of MMP12 is correlated with the pathological stage and tumor metastasis of LAC patients, and knockdown of MMP12 suppresses the development of LAC cells, suggesting that MMP12 may be a promising therapeutic target for the treatment of LAC.

Litvinov IV, Netchiporouk E, Cordeiro B, et al.
The Use of Transcriptional Profiling to Improve Personalized Diagnosis and Management of Cutaneous T-cell Lymphoma (CTCL).
Clin Cancer Res. 2015; 21(12):2820-9 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Although many patients with mycosis fungoides presenting with stage I disease enjoy an indolent disease course and normal life expectancy, about 15% to 20% of them progress to higher stages and most ultimately succumb to their disease. Currently, it is not possible to predict which patients will progress and which patients will have a stable disease. Previously, we conducted microarray analyses with RT-PCR validation of gene expression in biopsy specimens from 60 patients with stage I-IV cutaneous T-cell lymphoma (CTCL), identified three distinct clusters based upon transcription profile, and correlated our molecular findings with 6 years of clinical follow-up.
EXPERIMENTAL DESIGN: We test by RT-PCR within our prediction model the expression of about 240 genes that were previously reported to play an important role in CTCL carcinogenesis. We further extend the clinical follow-up of our patients to 11 years. We compare the expression of selected genes between mycosis fungoides/Sézary syndrome and benign inflammatory dermatoses that often mimic this cancer.
RESULTS: Our findings demonstrate that 52 of the about 240 genes can be classified into cluster 1-3 expression patterns and such expression is consistent with their suggested biologic roles. Moreover, we determined that 17 genes (CCL18, CCL26, FYB, T3JAM, MMP12, LEF1, LCK, ITK, GNLY, IL2RA, IL26, IL22, CCR4, GTSF1, SYCP1, STAT5A, and TOX) are able to both identify patients who are at risk of progression and also distinguish mycosis fungoides/Sézary syndrome from benign mimickers.
CONCLUSIONS: This study, combined with other gene expression analyses, prepares the foundation for the development of personalized molecular approach toward diagnosis and treatment of CTCL.

Ford CA, Petrova S, Pound JD, et al.
Oncogenic properties of apoptotic tumor cells in aggressive B cell lymphoma.
Curr Biol. 2015; 25(5):577-88 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. We hypothesized that, in progression of malignant disease, constitutive loss of a fraction of the tumor cell population through apoptosis could yield tumor-promoting effects.
RESULTS: Here, we demonstrate that apoptotic tumor cells promote coordinated tumor growth, angiogenesis, and accumulation of TAMs in aggressive B cell lymphomas. Through unbiased "in situ transcriptomics" analysis-gene expression profiling of laser-captured TAMs to establish their activation signature in situ-we show that these cells are activated to signal via multiple tumor-promoting reparatory, trophic, angiogenic, tissue remodeling, and anti-inflammatory pathways. Our results also suggest that apoptotic lymphoma cells help drive this signature. Furthermore, we demonstrate that, upon induction of apoptosis, lymphoma cells not only activate expression of the tumor-promoting matrix metalloproteinases MMP2 and MMP12 in macrophages but also express and process these MMPs directly. Finally, using a model of malignant melanoma, we show that the oncogenic potential of apoptotic tumor cells extends beyond lymphoma.
CONCLUSIONS: In addition to its profound tumor-suppressive role, apoptosis can potentiate cancer progression. These results have important implications for understanding the fundamental biology of cell death, its roles in malignant disease, and the broader consequences of apoptosis-inducing anti-cancer therapy.

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