Metastasis-associated Protein 1 Protein Expression Research Articles

Nicotinic Acid-Mediated Modulation of Metastasis-Associated Protein 1 Methylation and Inflammation in Brain Arteriovenous Malformation.

We explored metastasis-associated protein 1 (MTA1) promoter methylation in the development of brain arteriovenous malformation (BAVM). The clinical data of 148 sex- and age-matched BAVMs and controls were collected, and the MTA1 DNA methylation in peripheral white blood cells (WBC) was assessed by bisulfite pyrosequencing. Among them, 18 pairs of case-control samples were used for WBC mRNA detection, 32 pairs were used for WBC MTA1 protein measurement, and 50 pairs were used for plasma inflammatory factor analysis. Lipopolysaccharide (LPS) treatment was used to induce an inflammatory injury cell model of human brain microvascular endothelial cells (BMECS). 5-Aza-2'-deoxycytidine (5-AZA), nicotinic acid (NA), and MTA1 siRNAs were used in functional experiments to examine BMECS behaviors. RT-qPCR, Western blot, and ELISA or cytometric bead arrays were used to measure the expression levels of MTA1, cytokines, and signaling pathway proteins in human blood or BMECS. The degree of MTA1 promoter methylation was reduced in BAVM compared with the control group and was inversely proportional to MTA1 expression. Plasma ApoA concentrations in BAVM patients were significantly lower than those in controls and correlated positively with MTA1 promoter methylation and negatively with MTA1 expression. The expression of cytokine was markedly higher in BAVM than in controls. Cell experiments showed that 5-AZA decreased the methylation level of MTA1 and increased the expression of MTA1 protein. LPS treatment significantly increased cytokine concentrations (p < 0.05). NA and MTA1 silencing could effectively reverse the LPS-mediated increase in IL-6 and TNF-α expression through the NF-κB pathway. Our study indicated that NA may regulate MTA1 expression by affecting promoter DNA methylation, improve vascular inflammation through the NF-κB pathway, and alleviate the pathological development of BAVM.

Clinicopathological and prognostic significance of metastasis-associated protein 1 expression and its correlation with angiogenesis in lung invasive adenocarcinomas, based on the 2011 IASLC/ATS/ERS classification.

Based on previous findings regarding the angiogenic activities and prognostic roles of metastasis-associated protein 1 (MTA1) in early-stage non-small cell lung cancer, the clinicopathological and prognostic significance of MTA1 protein expression, and its correlation with angiogenesis in lung invasive adenocarcinoma, were further assessed in the present study, according to the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. High protein expression levels of MTA1 were commonly observed in patients with lung invasive adenocarcinoma, and were significantly correlated with tumor size (P=0.030), lymph node metastasis (P=0.021) and microvessel density (P=0.015). Survival analysis demonstrated that patients with high protein expression levels of MTA1 exhibited significantly shorter five-year disease-free and overall survival than those patients whose protein expression levels of MTA1 were low (24.5% vs. 48.7%, P=0.001, and 34.7% vs. 59.2%, P=0.005, respectively). In addition, Cox regression multivariate analysis demonstrated that high protein expression levels of MTA1 significantly correlated with unfavorable five-year disease-free survival (P=0.024). These findings indicate that MTA1 protein expression may possess clinical potential as an indicator of progressive phenotype. Therefore, MTA1 is a promising prognostic predictor to identify subgroups of patients with high risk of relapse, and a potentially novel therapeutic target for antiangiogenesis in patients with lung invasive adenocarcinoma.

Metastasis-associated protein 1 expression in oral squamous cell carcinomas: correlation with metastasis and angiogenesis.

Metastasis-associated protein 1 (MTA1) has been associated with poor prognosis in several carcinomas. Recent investigation has found that in different tumors, MTA1 protein significantly correlates with tumor angiogenesis, suggesting that MTA1 may be a possible angiogenesis-promoting molecule in malignant tumors. Thus, the current study was performed to determine the role of MTA1 protein in the biological behavior of oral squamous cell carcinoma and its relation with tumor angiogenesis. In this study, 44 oral squamous cell carcinomas and 15 normal epitheliums were reviewed by IHC staining for MTA1 and CD105. Frequency of MTA1 expression in SCCs was recorded as 97.7%, which was significantly higher than that of the control group (33.3%). Mean percentage of MTA1 expression in oral squamous cell carcinomas was 76.88 ± 25.33% which was significantly higher than that of the control group (22.81 ± 10.83). Our data showed a correlation between MTA1 expression with lymph node metastasis, tumor size and, stage. Evaluation of the correlation between MTA1 protein expression and micro vessel density showed that high micro vessel density was detected more frequently in tumors with MTA1 protein overexpression than in those without overexpression. In the present study, high expression of the MTA1 protein was seen in oral squamous cell carcinoma, and was closely associated with tumor progression and increased tumor angiogenesis. The findings may indicate that MTA1 protein has clinical potentials as a useful indicator of progressive phenotype, a promising prognostic predictor to identify patients with poor prognosis and may be a potential novel therapeutic target of anti-angiogenesis for patients with oral squamous cell carcinoma.

Effects of antioxidants on drugs used against testicular cancer-induced alterations in metastasis-associated protein 1 signaling in the rat testis

Metastasis-associated protein 1 (MTA1) is involved in tumor growth and metastasis of cancers. Being a component of nucleosome remodeling and histone deacetylase complex, the protein is also associated with DNA damage response pathway. Since the protein is involved in cancer pathology, we first investigated the effects of bleomycin, etoposide, and cisplatin (BEP) on MTA1 signaling in the testis. Second, since the antioxidants (AOs) have protective effects, we further investigated whether or not an AO cocktail modulates the effects of the drugs. Adult male Sprague Dawley rats (N = 4) were treated either with saline, or AO (α-tocopherol, l-ascorbic acid, zinc, and selenium), or therapeutic dose levels of etoposide (15 mg/kg) and cisplatin (3 mg/kg) from day 1-4 of the week and B (1.5 mg/kg) on the second day of the week, or BEP + AO. The real-time polymerase chain reaction showed that MTA1 and MTA1s (short form) gene expression was downregulated in AO (100% and 100%), BEP (86% and 71%), and BEP + AO (97% and 93%) groups. Western blotting and immunohistochemistry results showed that unnormalized MTA1 protein expression was upregulated in AO (38%) and BEP + AO (34%) groups; however, the MTA1/β-actin ratio was upregulated in all treated groups (21, 19, and 15%, respectively). In conclusion, the results indicate that both BEP and AO suppress MTA1 and MTA1s transcription, which may render the germ cells to be more prone to apoptosis. However, upregulation of MTA1 protein expression may be related to induced DNA damage. Modulation of MTA1 signaling is a novel mechanism of action of BEP and AO, which may be useful in developing newer anticancer drugs.

Down-regulation of MTA1 protein leads to the inhibition of migration, invasion, and angiogenesis of non-small-cell lung cancer cell line

Metastasis-associated protein 1 (MTA1) high expression has been detected in a wide variety of human aggressive tumors and plays important roles in the malignant biological behaviors such as invasion, metastasis, and angiogenesis. However, the specific roles and mechanisms of MTA1 protein in regulating the malignant behaviors of non-small-cell lung cancer (NSCLC) cells still remain unclear. To elucidate the detailed functions of MTA1 protein, we down-regulated the MTA1 protein expression in NSCLC cell line by RNA interference (RNAi) in vitro, and found that down-regulation of MTA1 protein significantly inhibited the migration and invasion potentials of 95D cells. Further research revealed that down-regulation of MTA1 protein significantly decreased the activity of matrix metalloproteinase-9, which could be the mechanism responsible for the inhibition of 95D cells migration and invasion. In addition, the tube formation assay demonstrated that the number of complete tubes induced by the conditioned medium of MTA1-siRNA 95D cells was significantly smaller than that of 95D cells. These findings demonstrate that MTA1 protein plays important roles in regulating the migration, invasion, and angiogenesis potentials of 95D cells, suggesting that MTA1 protein down-regulation by RNAi might be a novel therapeutic approach to inhibit the progression of NSCLC.

Close Association of Metastasis‐Associated Protein 1 Overexpression with Increased Angiogenesis and Poor Survival in Patients with Histologically Node‐Negative Gastric Cancer

Although metastasis-associated protein 1 (MTA1) has been recently demonstrated as a potent angiogenesis-promoting factor in various malignant tumors, its angiogenic property in gastric cancer (GC) remains unclear. This study has detected the expression of MTA1 protein in surgically resected tissues of pathologic N0 (pN0) GC and further investigated its relation with other clinicopathologic factors and tumor angiogenesis and prognosis. MTA1 protein expression was detected immunohistochemically in 111 pN0 GC specimens. Its correlations with clinicopathologic factors and tumor prognosis were evaluated. The intratumoral microvessel density (MVD) was assessed based on CD105 antigen immunoreactivity and analyzed for correlation with MTA1 protein expression. Overexpression of MTA1 was detected in 36.04 % of patients and exhibited a significant association with tumor size and MVD. Survival analysis demonstrated that both overall (OS) and disease-free (DFS) survivals in patients overexpressing MTA1 were significantly poorer than those without MTA1 overexpression 5 years after the operation (both p < 0.001). Multivariate survival analysis demonstrated that MTA1 overexpression was an independent prognosticator for unfavorable OS and DFS (p < 0.001, respectively). MTA1 overexpression is frequently observed in pN0 GC patients and is significantly associated with increased angiogenesis and poor prognosis. Detection of MTA1 protein expression may help predict the relapse and prognosis of pN0 GC. Also, MTA1 protein may form a novel target for antiangiogenic therapy.

Metastasis‐associated Protein 1 Nuclear Expression is Closely Associated with Tumor Progression and Angiogenesis in Patients with Esophageal Squamous Cell Cancer

The purposes of the present study were to detect the expression of metastasis-associated protein 1 (MTA1) in patients with esophageal squamous cell cancer (ESCC), and to evaluate the relevance of MTA1 protein expression to the tumor progression, angiogenesis, and prognosis. Both MTA1 protein and intratumoral microvessels were examined by immunohistochemical staining in 131 ESCC patients who successfully underwent subtotal esophagectomy and esophagogastric anastomosis at Qilu Hospital between Jan 2004 and Dec 2005. Intratumoral microvessel density (MVD) was recorded by counting CD-34 positive immunostained endothelial cells. All statistical analyses were performed with SPSS 13.0 statistical software. High expression of MTA1 protein was detected in 57 cases and significantly correlated with tumor invasion depth (P = 0.041), lymph node metastasis (P = 0.021), pathologic stage (P = 0.003), and MVD (P = 0.044). Survival analysis showed that patients with MTA1 protein high expression had significantly poor overall 5-year survival (P = 0.002), and the factor found on multivariate analysis to significantly affect overall survival was only pathologic stage (P = 0.040). Further stratified survival analysis split by pathologic stage demonstrated that MTA1 protein high expression significantly predicted unfavorable prognosis among patients with pathologic stage II disease (P = 0.006). High expression of the MTA1 protein is common in ESCC, and is closely associated with tumor progression, increased tumor angiogenesis, and poor survival. These findings indicate that MTA1 protein has clinical potentials as a useful indicator of progressive phenotype, a promising prognostic predictor to identify patients with poor prognosis, and a potential novel therapeutic target of antiangiogenesis for patients with ESCC.

Localization and Androgen Regulation of Metastasis-Associated Protein 1 in Mouse Epididymis

BackgroundMetastasis-associated protein 1 (MTA1), the founding member of the MTA family of genes, can modulate transcription by influencing the status of chromatin remodeling. Despite its strong correlation with the metastatic potential of cancer cells, MTA1 can also regulate crucial cellular pathways by modifying the acetylation status. We have previously reported the presence of MTA1/MTA1 in human and mouse testes, providing the evidence for its involvement in the regulation of testicular function during murine spermatogenesis. The objective of present study was to further assess the localization of MTA1 in mouse epididymis on both transcriptional and translational level, and then to explore whether MTA1 expression is regulated by androgens and postnatal epididymal development.Methodology/Principal FindingsMice were deprived of circulating androgen by bilaterally castration and were then supplemented with exogenous testosterone propionate for one week. MTA1 was immunolocalized in the epithelium of the entire epididymis with the maximal expression in the nuclei of principal cells and of clear cells in proximal region. Its expression decreased gradually after castration, whereas testosterone treatment could restore the expression, indicating that the expression of this gene is dependent on androgen. During postnatal development, the protein expression in the epididymis began to appear from day 7 to day 14, increased dramatically from postnatal day 28, and peaked at adulthood onwards, coinciding with both the well differentiated status of epididymis and the mature levels of circulating androgens. This region- and cell-specific pattern was also conservative in normal human epididymis.ConclusionsOur data suggest that the expression of MTA1 protein could be regulated by androgen pathway and its expression level is closely associated with the postnatal development of the epididymis, giving rise to the possibility that this gene plays a potential role in sperm maturation and fertility.

Metastasis-Associated Protein 1 Nuclear Expression is Associated with Tumor Progression and Clinical Outcome in Patients with Non-small Cell Lung Cancer

Little research has been done to test the usefulness of metastasis-associated protein 1 (MTA1) as a prognostic marker for non-small cell lung cancer (NSCLC). In this study, we investigated MTA1 expression and its prognostic value for NSCLC. NSCLC surgical tissue samples were taken from 100 patients with NSCLC who had been followed up for more than 2 years. The expression of MTA1 protein was evaluated by immunohistochemistry, and the correlations between the expression of MTA1 and clinical features and the prognosis were analyzed. The difference of MTA1 protein expression between NSCLCs and their adjacent nonneoplastic lung tissues was analyzed in a tissue microarray. The change of MTA1 mRNA expression and protein expression after RNA interference (RNAi) was detected by real-time polymerase chain reaction, Western blot, and immunocytochemistry in NSCLC cell line 95D. Overexpression of MTA1 (immunoreactivity scoring >4) was shown in 61.0% of the NSCLC cases but only in 9.4% of their adjacent nonneoplastic lung tissues (p < 0.001). The MTA1 expression level was correlated with lymph node metastasis (p = 0.013) and clinical stage (p = 0.002). Survival analysis showed that the MTA1 overexpression group had a significantly shorter overall survival time than the MTA1 downexpression group (p = 0.003). However, multivariate analysis showed that MTA1 expression was not a significant and independent prognostic parameter for patients with NSCLC. After RNAi, the 95D cells exhibit consistent reduction in MTA1 mRNA expression and MTA1 protein expression. MTA1 protein expression is associated with tumor progression and clinical outcome in patients with NSCLC. Further molecular, cellular, and animal model studies on MTA1 gene will provide new clues for exploring the mechanism of carcinogenesis and tumor progression in patients with NSCLC.

Overexpression of metastasis-associated MTA1 in oral squamous cell carcinomas: correlation with metastasis and invasion

Metastasis-associated protein 1 (MTA1) is physiologically expressed at low levels in human tissues. Its expression is associated with progression of solid cancers and is common in cancer cell lines. This study investigated whether MTA1 was expressed in squamous cell carcinoma (SCC) and would be a useful metastatic marker. Specimens from 38 patients with oral SCC were stained using the avidin-biotin-peroxidase technique with polyclonal antibodies against MTA1. Human SCC cell lines SAS, HSC2, OSC19 and OSC20 were analysed for MTA1 mRNA expression. MTA1 expression in control tissues was significantly lower than in carcinomas. MTA1 protein expression was detected in 33 of 38 SCC tissues from patients. Histologically, MTA1 protein production was strongly associated with cancer cell invasion, and clinically there was a correlation between lymph node metastasis and MTA1 protein production. Among the cancer cell lines, HSC2 showed the lowest mRNA expression, and OSC20 showed the highest MTA1 mRNA expression. In the Matrigel invasion assay, the HSC2 cell line showed the lowest invasion and the OSC20 cell line showed the highest invasion. RNAi-mediated MTA1 silencing in the OSC20 cells decreased the invasion index. MTA1 expression in oral SCC may be associated with increased invasive ability, which may cause lymph node metastasis.

Poster 057: Metastasis-Associated MTA1 Expression in Oral Squamous Cell Carcinoma: Relationship With Lymph Node Metastasis

Metastasis-associated protein 1 (MTA1) is physiologically expressed at only lowlevels in human tissue, except testis. Its expression has been found to be associated with progression in solid cancers of various organs and cancer cell lines with high invasive potential and thus is believed to play a role in cancer progression to the metastatic state. Functional studies supported this by showing that experimental overexpression of MTA1 in keratinocytes is associated with increase in migration and invasion and survival in the anchorage-independent state. However, few reports have examined the role of MTA1 in oral squamous cell carcinoma. To determine the relationship between clinicopathologic factors and MTA1 expression in patients with oral squamous cell carcinoma, we investigated MTA1 gene expression and protein production. 38 oral squamous cell carcinomas (tongue carcinoma) were enrolled in this study. The expression of MTA1 was assayed immunohistochemically using polyclonal antibodies, and the expression of PCNA was assayed immunohistochemically using monoclonal antibody. The human oral squamous cell carcinoma cell lines, SAS, HSC-2, OSC19 and OSC20 were obtained from the Human Science Research Resource Bank. For PCR analysis, cDNA was amplified by Taq DNA polymerase. BioCoat Matrigel invasion chambers were used to assess cell invasion. Briefly, cells were seeded in the upper chamber. Cells on the reverse side of the insert were fixed and stained with DiffQuick. To investigate the correlation of MTA1 with cancer invasion, the effect of MTA1 inhibition was examined by RNA interference (RNAi). Significance was assessed by means of Student T test and Pearsons correlation coefficient. MTA1 protein expression was detected in 33 of 38 SCCs. There was no correlation between MTA1 expression and T category. There was correlation between MTA1 expression and N category and clinical stage. Immunohistochemical expression of MTA1 had no correlation with tumor cell growth factor (PCNA) and WHO histological malignancy grade. MTA1 protein production was strongly associated with cancer cell invasion (p<0.05), and there was significant correlation with lymph node metastasis and MTA1 protein production. HSC2 revealed low mRNA expression and OSC 20 revealed highest mRNA expression. In matrigel invasion assay, the HSC2 cell line revealed lowest invasion and the OSC20 cell line revealed highest invasion. RNAi-mediated MTA1 reduction decreased the invasion index (p<0.01). MTA1 may be a useful marker for lymph node metastasis, and MTA1 expression may be associated with increased invasive ability in oral squamous cell carcinomas.

The role of metastasis-associated protein 1 in prostate cancer progression.

Distinguishing aggressive prostate cancer from indolent disease represents an important clinical challenge, as current therapy requires over treating men with prostate cancer to prevent the progression of a few cases. Expression of the metastasis-associated protein 1 (MTA1) has previously been found to be associated with progression to the metastatic state in various cancers. Analyzing DNA microarray data, we found MTA1 to be selectively overexpressed in metastatic prostate cancer compared with clinically localized prostate cancer and benign prostate tissue. These results were validated by demonstrating overexpression of MTA1 in metastatic prostate cancer by immunoblot analysis. MTA1 protein expression was evaluated by immunohistochemistry in a broad spectrum of prostate tumors with tissue microarrays containing 1940 tissue cores from 300 cases. Metastatic prostate cancer demonstrated significantly higher mean MTA1 protein expression intensity (score = 3.4/4) and percentage of tissue cores staining positive for MTA1 (83%) compared with clinically localized prostate cancer (score = 2.8/4, 63% positive cores) or benign prostate tissue (score = 1.5/4, 25% positive cores) with a mean difference of 0.54 and 1.84, respectively (P < 0.00001 for both). Paradoxically, for localized disease, higher MTA1 protein expression was associated with lower rates of prostate specific antigen recurrence after radical prostatectomy for localized disease. In summary, this study identified an association of MTA1 expression and prostate cancer progression.