Expression Level Of Metastasis-associated Protein 1 Research Articles

Metastasis-associated protein 1, modulated by miR-30c, promotes endometrial cancer progression through AKT/mTOR/4E-BP1 pathway

ObjectiveThough metastasis-associated protein 1 (MTA1) is widely overexpressed in human cancers and is associated with advanced clinicopathological characteristics and survival in related diseases, the association between MTA1 and endometrial cancer (EC) is little known and needs to be studied. MethodsWestern blot and immunohistochemistry were used to analyze protein expression level of cells and tissues, while real-time PCR was used for RNA detection. Bioinformatics tool analysis revealed the relationship between MTA1 and clinicopathological characteristics and survival. CCK-8 assay, colony-formation assay, cell scratch assay, and Transwell assay were performed to determine cell proliferation, migration and invasion abilities, respectively. ResultsThe expression level of MTA1 was significantly higher in human EC tissues than in normal endometrium. MTA1 expression was correlated positively with lymph nodes metastasis and poor survival rate in EC. Experimentally overexpressed MTA1 could promote cell proliferation, migration and invasion abilities of EC cell lines Ishikawa, HEC-1B, and RL-952, while reduction of MTA1 inhibited these cell biological behaviors. Moreover, MTA1 could also reverse the negative effect of miR-30c, a direct modulator of MTA1, on EC cells. Our research also revealed that overexpression of MTA1 contributed to EC tumor growth, while knockdown of MTA1 resulted in tumor growth inhibition. Additionally, the phosphorylation levels of mTOR (S2448) and 4E-BP1 (T37/46) changed significantly along with AKT (T308) under regulation of MTA1, both in vivo and vitro. ConclusionOur results showed that MTA1, as a downstream target of miR-30c, might promote EC progression via AKT/mTOR/4E-BP1 pathway, which indicated the potential therapy target of MTA1 in EC.

Relationship between MTA1 and spread through air space and their joint influence on prognosis of patients with stage I-III lung adenocarcinoma

ObjectiveTo characterize the relationship between metastasis-associated protein 1 (MTA1) and spread through air spaces (STAS), and to investigate the joint prognostic value of MTA1 and STAS in resected lung adenocarcinomas. MethodsWe retrospectively reviewed 208 operated patients with stage I–III lung adenocarcinoma from January 2009 to December 2014. STAS was identified by H&E staining. Expression level of MTA1 was determined by immunohistochemistry. The relationship between MTA1 and STAS was determined by using a logistic regression model. The synergistic effects of MTA1 and STAS on prognosis were analyzed using a Cox proportional hazards regression model. ResultsPatients with either STAS or high expression of MTA1 had significantly worse overall survival (OS) and shorter recurrence-free survival (RFS) than those without STAS or with low expression of MTA1 (p < 0.001). Among 107 patients with STAS presence in lung adenocarcinomas, 57 (53.3%) cases had high expression of MTA1. High expression of MTA1 was positively associated with the increased frequency of STAS presence (p < 0.01). Subgroup analysis showed that the patients with both high expression of MTA1 and STAS-positive presence had significantly worst OS and shortest RFS compared with the others (p < 0.001), while the patients with high expression of MTA1 /STAS-negative presence shared similar RFS with those with high expression of MTA1 /STAS-positive presence. Furthermore, high MTA1 levels in STAS-positive patients was associated with a higher risk of postoperative metastasis and recurrence (p < 0.001). ConclusionsSTAS was more frequently observed in adenocarcinomas with high MTA1 expression levels. MTA1 was associated with a higher risk of worse overall survival among patients with STAS and could provide helpful prognostic information in STAS-positive patients with stage I–III lung adenocarcinoma.2pTis classified based on pathological tumor diameter and pN is classified based on lymph node metastasis according to the eighth edition of the TNM classification

MicroRNA-183 suppresses the vitality, invasion and migration of human osteosarcoma cells by targeting metastasis-associated protein 1.

The aim of the present study was to investigate the effects of microRNA (miR)-183 on vitality, invasion, metastasis and apoptosis in osteosarcoma (OS) cells, mediated by its binding to metastasis-associated protein 1 (MTA1). A dual luciferase reporter assay was performed to determine whether MTA1 was a direct target of miR-183. Cell Counting Kit-8, Transwell, scratch-wound healing, fluorescence-activated cell sorting andterminal deoxynucleotidyl transferase dUTP nick end labeling assays were also performed to investigate the effects of miR-183 expression on the proliferation, invasion, migration and apoptosis of MG63 cells. It was demonstrated that that MTA1 expression levels were significantly higher in OS tissues and MG63 cells compared with corresponding adjacent noncancerous tissues and normal cells, respectively, while miR-183 expression levels were significantly lower (both P<0.05). Furthermore, miR-183 overexpression downregulated MTA1 levels and inhibited cell proliferation (P<0.05), migration (P<0.05) and invasion (P<0.01), as well as promoting apoptosis (P<0.01) by binding to the 3'-untranslated region of MTA1. These results indicate that miR-183 inhibits the vitality, invasion, migration and apoptosis of the OS cell line MG63 by targeting MTA1. These findings may contribute to the development of novel clinical therapeutic approaches for the treatment of OS.

Mechanism of pterostilbene inhibiting growth of hepatocellular carcinoma by regulating metastasis-associated protein 1 expression

Objective To explore the action mechanism of pterostilbene inhibiting growth of hepatocellular carcinoma (HCC) by regulating metastasis-associated protein 1 (MTA1) expression. Methods The expression of MTA1 mRNA was detected by real-time quantitative polymerase chain reaction (Real-time PCR) in 78 cases of human HCC tissues and the counterparts from 78 cases of paracarcinoma tissues. The relationship between the expression of MTA1 with clinicopathological features of HCC was evaluated. The SSMC-7721 cells were cultured in the presence of pterostilbene for 24 h. The cell viability was measured by methyl thiazol tetrazolium (MTT) assay, and the protein expression of MTA1 was detected by Western blotting. Results The expression of MTA1 was significantly higher in HCC tissues than in matched paracarcinoma tissues. The expression of MTA1 was significantly higher in TMN Ⅲ-Ⅳ HCC tissues than in TMN Ⅰ-Ⅱ HCC tissues (P=0.000). The expression level of MTA1 in HCC tissues was related to intrahepatic metastasis and portal vein infiltration. There was down-regulation of MTA1, histone deacetylase (HDAC)1 and HDAC2 expression in pterostilbene-treated SSMC-7721 cells compared to vehicle-treated cells. The ratio of Acp53/total p53 was higher in HCC cells after treatment. The cell viability was decreased with increasing pterostilbene dose (P=0.000). Conclusion The expression of MTA1 may relate to the proliferation, metastasis and clinical stages of HCC. The expression of MTA1 in HCC tissues may be positively correlated with the TMN stages. Key words: Metastasis-associated protein 1; Pterostilbene; Carcinoma, hepatocellular

MiR-30c-2* negative regulated MTA-1 expression involved in metastasis and drug resistance of HPV-infected non-small cell lung cancer

MiR-30c-2* is considered to be a tumor suppressor microRNA in various cancers and is associated with gemcitabine sensitivity of lung cancer cells. Downregulation of miR-30c-2* promotes tumor invasion via increased expression of metastasis-associated protein-1. We hypothesized that downregulated expression of miR-30c-2* was involved in human papillomavirus-associated lung tumorigenesis and drug resistance. We examined whether expression of human papillomavirus 16/18 oncoprotein and miR-30c-2*-associated genes could be linked to patient outcome by collecting 319 lung tumors from patients with non-small cell lung cancer to determine expression of human papillomavirus 16/18 E6 protein, miR-30c-2*, and miR-30c-2* downstream metastasis-associated protein-1 mRNA by immunohistochemical and real-time polymerase chain reaction analysis. Our results showed that miR-30C-2* levels were increased 45-fold in the E6-knockdown TL-1cells when compared with levels in the parental cells. More interestingly, metastasis-associated protein-1 expression correlated negatively with miR-30C-2* and positively with human papillomavirus 16 E6 protein expression in lung tumors from lung cancer patients. Metastasis-associated protein-1 expression levels in the tumor tissues correlated positively with tumor stage and nodal metastasis. Patients with high metastasis-associated protein-1 expression, and especially patients infected with human papillomavirus, experienced a poor clinical outcome, tumor recurrence, and a poor therapeutic response compared with those with low metastasis-associated protein-1 expression. These results showed that miR-30C-2* and levels of downstream metastasis-associated protein-1 gene expression in the tumor tissues of patients could be useful in predicting clinical outcome and therapeutic response and in selecting useful therapeutic drugs for lung cancer patients, especially patients with human papillomavirus infection.

Expression of histone deacetylase 1 and metastasis-associated protein 1 as prognostic factors in colon cancer

Histone deacetylase 1 (HDAC1) and metastasis-associated protein 1 (MTA1) form the nucleosome remodeling and histone deacetylation (NuRD) complex and may possibly play a central role in cancer development. However, limited data has been reported regarding the expression of both HDAC1 and MTA1. The aim of the present study was to clarify the clinical role of HDAC1 and MTA1 expression in colon cancer. Seventy-four patients with colon cancer, who underwent colectomy at our institution, were enrolled in this study. Expression of HDAC1 and MTA1 was examined immunohistochemically. The patients were divided into four groups: HDAC1-positive group (n=58), HDAC1-negative group (n=16), MTA1-positive group (n=38) and MTA1-negative group (n=36). Clinicopathological factors and survival rates were compared between the groups. Regarding the clinicopathological factors, the depth of tumor invasion and stage correlated significantly with HDAC1 expression (p<0.05). Age, depth of tumor invasion and vascular invasion tended to correlate with MTA1 expression. The 5-year survival rate in the HDAC1-positive group (55.1%) was significantly worse compared to the HDAC1-negative group (86.5%) (p<0.05), and the 5-year survival rate of the MTA1-positive group (50.5%) was significantly worse than that of the MTA1-negative group (73.1%) (p=0.05). In patients with stages II-IV and curability A, B, the survival rate in those with HDAC1-positive expression was significantly worse than those with HDAC1-negative expression (p<0.05), and the survival rate of the MTA1-positive group tended to be worse than that of the MTA1-negative group (p=0.07). Overall survival in both the HDAC1 and MTA1-positive groups was significantly worse than overall survival of the other groups (p<0.05). Disease-free survival in both the HDAC1- and MTA1-positive groups, among patients with stages II-IV and curability A, B, was also significantly worse than that of the other groups (p<0.05). HDAC1 and MTA1 expression levels were significantly related to poorer prognosis. Therefore, HDAC1 and MTA1 expression levels are potential prognostic indicators for colon cancer.

Abstract 210: Metastasis-associated protein 1 is a transcriptional target of the tumor suppressor p53

Abstract Although metastasis-associated protein 1 (MTA1) is known to play roles in angiogenesis and metastasis in various human cancers, the molecular mechanism of regulation of MTA1 gene expression remains unclear. Therefore, we searched potential regulators of MTA1 expression in this study. Treatment of 5-fluorouracil (5-FU), a traditional anti-cancer drug in HepG2, MCF7 and LNCaP cells, expressing wild-type p53, decreased the protein and mRNA expression of MTA1. However, the MTA1 expression levels were not altered in response to 5-FU treatment in Hep3B, MDA-MB-231 and PC3 cells which lack functional p53. The specific knockdown of p53 in HepG2 and MCF7 cells recovered the level of MTA1 after 5-FU treatment. This observation indicates that p53 mediates the repression of MTA1. Next, we virtually analyzed the promoter region of the human MTA1 gene and identified several potential consensus binding sequences of p53. Indeed, chromatin immunoprecipitation and pull-down assays showed that p53 directly bound to the MTA1 promoter region. These findings suggest that p53 is transcriptionally associated with regulation of MTA1 gene expression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 210. doi:10.1158/1538-7445.AM2011-210

Metastasis-associated protein 1 induces VEGF-C and facilitates lymphangiogenesis in colorectal cancer

To study the correlation between high metastasis-associated protein 1 (MTA1) expression and lymphangiogenesis in colorectal cancer (CRC) and its role in production of vascular endothelial growth factor-C(VEGF-C). Impact of high MTA1 and VEGF-C expression levels on disease progression and lymphovascular density (LVD, D2-40-immunolabeled) in 81 cases of human CRC was evaluated by immunohistochemistry. VEGF-C mRNA and protein expressions in human LoVo and HCT116 cell lines were detected by real-time polymerase chain reaction and Western blotting, respectively, with a stable expression vector or siRNA. The elevated MTA1 and VEGF-C expression levels were correlated with lymph node metastasis and Dukes stages (P < 0.05). Additionally, high MTA1 expression level was correlated with a large tumor size (P < 0.05). A significant correlation was found between MTA1 and VEGF-C protein expressions in tumor cells (r = 0.371, P < 0.05). Similar to the VEGF-C expression level, high MTA1 expression level was correlated with high LVD in CRC (P < 0.05). Furthermore, over-expression of MTA1 significantly enhanced the VEGF-C mRNA and protein expression levels, whereas siRNAs - knocked down MTA1 decreased the VEGF-C expression level. MTA1, as a regulator of tumor-associated lymphangiogenesis, promotes lymphangiogenesis in CRC by mediating the VEGF-C expression.

Expression of Hypoxia-Inducible Factor-1α, Histone Deacetylase 1, and Metastasis-Associated Protein 1 in Pancreatic Carcinoma

Hypoxia-inducible factor 1alpha (HIF-1alpha) is a transcription factor that plays an important role in tumor growth and metastasis. Inhibition of histone deacetylase shows a marked inhibition of HIF-1alpha expression; however, the association between HIF-1alpha and histone deacetylase 1 (HDAC1), metastasis-associated protein 1 (MTA1) is not fully understood. Hypoxia-inducible factor 1alpha, HDAC1, and MTA1 expressions were detected by immunohistochemistry in 39 pancreatic carcinoma patients. The correlations between the expression of HIF-1alpha, HDAC1, or MTA1 and clinical features and the prognosis were analyzed. Hypoxia-inducible factor 1alpha, HDAC1, and MTA1 positive stainings were found in 41%, 56%, and 31%, respectively. There was no correlation between HIF-1alpha, HDAC1, or MTA1 expression levels and any clinical parameters. The survival rate for patients with HIF-1alpha and HDAC1-positive stainings were significantly lower than for patients with HIF-1alpha and HDAC1-negative stainings. The MTA1 overexpression group did not have a significantly lower prognosis than the MTA1 underexpression group. The survival rate for the HDAC1(+)/MTA1(2-3) group was significantly lower than for the other groups. These results suggest that HIF-1alpha expression may be regulated through HDAC1/MTA1, which is associated with a poor prognosis for pancreatic carcinoma and indicates that HIF-1alpha and HDAC1/MTA1 are a promising therapeutic target in pancreatic carcinoma treatment.

Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells

Expression level of metastasis-associated protein 1 (MTA1) is closely related to tumor growth and metastasis in various cancers. Although increased expression level of MTA1 was observed in hepatocellular carcinoma (HCC), role of MTA1 complex containing histone deacetylase (HDAC) in hepatitis B virus (HBV)-associated hepatocarcinogenesis has not been studied. Here, we demonstrated that HBx strongly induced the expression of MTA1 and HDAC1 genes at transcription level. MTA1 and HDAC1/2 physically associated with hypoxia-inducible factor-1 alpha (HIF-1 alpha) in vivo in the presence of HBx, which was abolished by knockdown of MTA1 by short interfering RNA (siRNA). HBx induced deacetylation of the oxygen-dependent degradation domain of HIF-1 alpha, which was accompanied with dissociation of prolyl hydroxylases and von Hippel-Lindau tumor suppressor from HIF-1 alpha. These results indicate that HBx-induced deacetylation is important for proteasomal degradation of HIF-1 alpha. Further, we observed that protein levels of MTA1 and HDAC1 were increased in the liver of HBx-transgenic mice. Also, there was a higher expression of HDAC1 in HCC than in the adjacent non-tumorous cirrhotic nodules in 10 out of 12 human HBV-associated HCC specimens. Together, our data indicate a positive cross talk between HBx and the MTA1/HDAC complex in stabilizing HIF-1 alpha, which may play a critical role in angiogenesis and metastasis of HBV-associated HCC.

Correlation between the expression of hypoxia-inducible factor-1α or histone deacetylase 1/metastasis-associated protein 1 complex and poor prognosis on human pancreatic carcinoma

21012 Background: Hypoxia-inducible factor-1a (HIF-1a) is a transcription factor that plays an important role in tumor growth and metastasis by regulating energy metabolism and inducing angiogenesis. Inhibition of histone deacetylase shows a marked inhibition of HIF-1a expression, however, the association between HIF-1a and histone deacetylase 1 (HDAC1) / metastasis-associated protein 1 (MTA1) is not fully understood. Here, we explored the involvement of HIF-1a and HDAC1/MTA1 in human pancreatic carcinoma. Methods: HIF-1a, HDAC1 and MTA1 expressions were detected by immunohistochemistry in surgical specimens obtained from 39 patients with pancreatic carcinoma. The correlations between the expression of HIF-1a, HDAC1 or MTA1 and clinical features, and the prognosis of patients with pancreatic carcinoma were then analyzed. Results: HIF-1a, HDAC1 and MTA1 positive stainings were found in 16 of 39 cases (41%), 22 of 39 cases (56%) and 12 of 39 cases (31%), respectively. There was no correlation between HIF-1a, HDAC1 or MTA1 expression levels and any of the clinical parameters examined. The five-year survival rate for pancreatic carcinoma patients with HIF-1a and HDAC1 positive stainings were significantly lower than for those patients with HIF-1a and HDAC1 negative stainings (P = 0.0243 and 0.0433). The MTA1 positive stainings group did not have a significantly worse prognosis than the MTA1 negative stainings group (P = 0.9694). In addition, the five-year survival rate for the HDAC1/MTA1 positive stainings group was statistically significantly worse than for the other groups (P = 0.0386). Conclusions: These results suggest that HIF-1a expression may be regulated through HDAC1/MTA1, which is associated with a poor prognosis on human pancreatic carcinoma, and indicate that HIF-1a and HDAC1/MTA1 is a promising therapeutic target in pancreatic carcinoma treatment. No significant financial relationships to disclose.