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The metastasis-associated gene MTA3, a component of the Mi-2/NuRD transcriptional repression complex, predicts prognosis of gastroesophageal junction adenocarcinoma.

Dong H, Guo H, Xie L, Wang G, Zhong X, Khoury T, Tan D, Zhang H - PLoS ONE (2013)

Bottom Line: The metastasis-associated gene MTA3, a novel component of the Mi-2/NuRD transcriptional repression complex, was identified as master regulator of EMT through inhibition of Snail to increase E-cadherin expression in breast cancer.MTA3 expression was decreased at both protein and mRNA levels in tumor tissues compared to the non-tumorous and lowed MTA3 levels were noted in tumor cell lines with stronger metastatic potential.Combined misexpression of MTA3, Snail and E-cadherin had stronger correlation with malignant properties.

View Article: PubMed Central - PubMed

Affiliation: Department of Integrative Oncology, Affiliated Cancer Hospital of Shantou University Medical College, Shantou, China.

ABSTRACT
Gastroesophageal junction (GEJ) adenocarcinoma carries a poor prognosis that is largely attributable to early and frequent metastasis. The acquisition of metastatic potential in cancer involves epithelial-to-mesenchymal transition (EMT). The metastasis-associated gene MTA3, a novel component of the Mi-2/NuRD transcriptional repression complex, was identified as master regulator of EMT through inhibition of Snail to increase E-cadherin expression in breast cancer. Here, we evaluated the expression pattern of the components of MTA3 pathway and the corresponding prognostic significance in GEJ adenocarcinoma. MTA3 expression was decreased at both protein and mRNA levels in tumor tissues compared to the non-tumorous and lowed MTA3 levels were noted in tumor cell lines with stronger metastatic potential. Immunohistochemical analysis of a cohort of 128 cases exhibited that patients with lower expression of MTA3 had poorer outcomes. Combined misexpression of MTA3, Snail and E-cadherin had stronger correlation with malignant properties. Collectively, results suggest that the MTA3-regulated EMT pathway is altered to favor EMT and, therefore, disease progression and that MTA3 expression was an independent prognostic factor in patients with GEJ adenocarcinoma.

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MTA3 is down-regulated in GEJ adenocarcinoma tissue and in high metastatic potential cancer cell lines.(A) MTA3 protein is down-regulated in human GEJ adenocarcinoma tissues as determined by immunoblot analysis. N, adjacent noncancerous tissues; C, cancerous tissues. (B) MTA3 transcript is significantly decreased in esophageal and gastric adenocarcinoma tissues, relative to the corresponding normal tissue. The data were from the analysis in Oncomine database. NE, normal esophagus (n = 28); EAC, esophageal adenocarcinoma (n = 75); NG, normal gastric (n = 29); GC, gastric cancer (n = 20). (C) MTA3 mRNA level is decreased in high metastatic potential cell lines of gastric adenocarcinoma and esophageal adenocarcinoma. Gene expression data for MTA3 were extracted from “CCLE Expression Entrez 2012-04-06”. (D) In all 39 tumor cell lines, the exclusively available GEJ adenocarcinoma cell line OE-19 (arrow), which has high metastatic potential, fell into the decreased-MTA3 group composed of 9 cell lines, 7 of which are more invasive. *P<0.05, **P<0.01, ***P<0.001.
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pone-0062986-g001: MTA3 is down-regulated in GEJ adenocarcinoma tissue and in high metastatic potential cancer cell lines.(A) MTA3 protein is down-regulated in human GEJ adenocarcinoma tissues as determined by immunoblot analysis. N, adjacent noncancerous tissues; C, cancerous tissues. (B) MTA3 transcript is significantly decreased in esophageal and gastric adenocarcinoma tissues, relative to the corresponding normal tissue. The data were from the analysis in Oncomine database. NE, normal esophagus (n = 28); EAC, esophageal adenocarcinoma (n = 75); NG, normal gastric (n = 29); GC, gastric cancer (n = 20). (C) MTA3 mRNA level is decreased in high metastatic potential cell lines of gastric adenocarcinoma and esophageal adenocarcinoma. Gene expression data for MTA3 were extracted from “CCLE Expression Entrez 2012-04-06”. (D) In all 39 tumor cell lines, the exclusively available GEJ adenocarcinoma cell line OE-19 (arrow), which has high metastatic potential, fell into the decreased-MTA3 group composed of 9 cell lines, 7 of which are more invasive. *P<0.05, **P<0.01, ***P<0.001.

Mentions: Given that evidenced functions of MTA3 as a transcriptional corepressor and tumor suppressor, we determine if MTA3 is downregulated in GEJ adenocarcinoma. We examined MTA3 expression at protein level in a cohort of GEJ adenocarcinoma specimen (n = 25) by immunoblot analysis, and transcript level of MTA3 on microarray database. Immunoblot assay revealed that 72% tumor specimen had lower MTA3 protein expression than the paired adjacent noncancerous tissues (P<0.001; Figure 1A). In support of above findings, we analyzed MTA3 mRNA level in the human cancer microarray database Oncomine. Since there are no array data available for GEJ adenocarcinoma, we mined data from esophageal adenocarcinoma and gastric adenocarcinoma, both of which are closely relevant to GEJ adenocarcinoma. Higher MTA3 levels were noted in normal esophagus relative to esophageal adenocarcinoma (P<0.001; Figure 1B) [27], and in normal gastric mucosa than in mixed-type gastric cancer or diffuse-type gastric cancer (P = 0.008 and P = 0.025; Figure 1B) [28]. Moreover, mRNA expression data for MTA3 in 39 gastric and esophageal adenocarcinoma cell lines were extracted from CCLE (http://www.broadinstitute.org/ccle/home) [29]. MTA3 mRNA expression appeared more common in low metastatic cell lines than in cell lines with high metastatic potential (P = 0.035; Figure 1C). Interestingly, OE-19, the exclusive GEJ adenocarcinoma cell line which has high metastatic potential, had lower levels of MTA3 mRNA expression compared to most other gastric and esophageal adenocarcinoma cell lines (Figure 1D arrow). Accordingly, these results consistently indicate that MTA3 is downregulated in tumorous tissues, and underexpression of MTA3 is related with stronger metastasis tendency in tumor cells, supporting the hypothesis that MTA3 may act as a tumor suppressor and metastasis inhibitor in GEJ adenocarcinoma.


The metastasis-associated gene MTA3, a component of the Mi-2/NuRD transcriptional repression complex, predicts prognosis of gastroesophageal junction adenocarcinoma.

Dong H, Guo H, Xie L, Wang G, Zhong X, Khoury T, Tan D, Zhang H - PLoS ONE (2013)

MTA3 is down-regulated in GEJ adenocarcinoma tissue and in high metastatic potential cancer cell lines.(A) MTA3 protein is down-regulated in human GEJ adenocarcinoma tissues as determined by immunoblot analysis. N, adjacent noncancerous tissues; C, cancerous tissues. (B) MTA3 transcript is significantly decreased in esophageal and gastric adenocarcinoma tissues, relative to the corresponding normal tissue. The data were from the analysis in Oncomine database. NE, normal esophagus (n = 28); EAC, esophageal adenocarcinoma (n = 75); NG, normal gastric (n = 29); GC, gastric cancer (n = 20). (C) MTA3 mRNA level is decreased in high metastatic potential cell lines of gastric adenocarcinoma and esophageal adenocarcinoma. Gene expression data for MTA3 were extracted from “CCLE Expression Entrez 2012-04-06”. (D) In all 39 tumor cell lines, the exclusively available GEJ adenocarcinoma cell line OE-19 (arrow), which has high metastatic potential, fell into the decreased-MTA3 group composed of 9 cell lines, 7 of which are more invasive. *P<0.05, **P<0.01, ***P<0.001.
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pone-0062986-g001: MTA3 is down-regulated in GEJ adenocarcinoma tissue and in high metastatic potential cancer cell lines.(A) MTA3 protein is down-regulated in human GEJ adenocarcinoma tissues as determined by immunoblot analysis. N, adjacent noncancerous tissues; C, cancerous tissues. (B) MTA3 transcript is significantly decreased in esophageal and gastric adenocarcinoma tissues, relative to the corresponding normal tissue. The data were from the analysis in Oncomine database. NE, normal esophagus (n = 28); EAC, esophageal adenocarcinoma (n = 75); NG, normal gastric (n = 29); GC, gastric cancer (n = 20). (C) MTA3 mRNA level is decreased in high metastatic potential cell lines of gastric adenocarcinoma and esophageal adenocarcinoma. Gene expression data for MTA3 were extracted from “CCLE Expression Entrez 2012-04-06”. (D) In all 39 tumor cell lines, the exclusively available GEJ adenocarcinoma cell line OE-19 (arrow), which has high metastatic potential, fell into the decreased-MTA3 group composed of 9 cell lines, 7 of which are more invasive. *P<0.05, **P<0.01, ***P<0.001.
Mentions: Given that evidenced functions of MTA3 as a transcriptional corepressor and tumor suppressor, we determine if MTA3 is downregulated in GEJ adenocarcinoma. We examined MTA3 expression at protein level in a cohort of GEJ adenocarcinoma specimen (n = 25) by immunoblot analysis, and transcript level of MTA3 on microarray database. Immunoblot assay revealed that 72% tumor specimen had lower MTA3 protein expression than the paired adjacent noncancerous tissues (P<0.001; Figure 1A). In support of above findings, we analyzed MTA3 mRNA level in the human cancer microarray database Oncomine. Since there are no array data available for GEJ adenocarcinoma, we mined data from esophageal adenocarcinoma and gastric adenocarcinoma, both of which are closely relevant to GEJ adenocarcinoma. Higher MTA3 levels were noted in normal esophagus relative to esophageal adenocarcinoma (P<0.001; Figure 1B) [27], and in normal gastric mucosa than in mixed-type gastric cancer or diffuse-type gastric cancer (P = 0.008 and P = 0.025; Figure 1B) [28]. Moreover, mRNA expression data for MTA3 in 39 gastric and esophageal adenocarcinoma cell lines were extracted from CCLE (http://www.broadinstitute.org/ccle/home) [29]. MTA3 mRNA expression appeared more common in low metastatic cell lines than in cell lines with high metastatic potential (P = 0.035; Figure 1C). Interestingly, OE-19, the exclusive GEJ adenocarcinoma cell line which has high metastatic potential, had lower levels of MTA3 mRNA expression compared to most other gastric and esophageal adenocarcinoma cell lines (Figure 1D arrow). Accordingly, these results consistently indicate that MTA3 is downregulated in tumorous tissues, and underexpression of MTA3 is related with stronger metastasis tendency in tumor cells, supporting the hypothesis that MTA3 may act as a tumor suppressor and metastasis inhibitor in GEJ adenocarcinoma.

Bottom Line: The metastasis-associated gene MTA3, a novel component of the Mi-2/NuRD transcriptional repression complex, was identified as master regulator of EMT through inhibition of Snail to increase E-cadherin expression in breast cancer.MTA3 expression was decreased at both protein and mRNA levels in tumor tissues compared to the non-tumorous and lowed MTA3 levels were noted in tumor cell lines with stronger metastatic potential.Combined misexpression of MTA3, Snail and E-cadherin had stronger correlation with malignant properties.

View Article: PubMed Central - PubMed

Affiliation: Department of Integrative Oncology, Affiliated Cancer Hospital of Shantou University Medical College, Shantou, China.

ABSTRACT
Gastroesophageal junction (GEJ) adenocarcinoma carries a poor prognosis that is largely attributable to early and frequent metastasis. The acquisition of metastatic potential in cancer involves epithelial-to-mesenchymal transition (EMT). The metastasis-associated gene MTA3, a novel component of the Mi-2/NuRD transcriptional repression complex, was identified as master regulator of EMT through inhibition of Snail to increase E-cadherin expression in breast cancer. Here, we evaluated the expression pattern of the components of MTA3 pathway and the corresponding prognostic significance in GEJ adenocarcinoma. MTA3 expression was decreased at both protein and mRNA levels in tumor tissues compared to the non-tumorous and lowed MTA3 levels were noted in tumor cell lines with stronger metastatic potential. Immunohistochemical analysis of a cohort of 128 cases exhibited that patients with lower expression of MTA3 had poorer outcomes. Combined misexpression of MTA3, Snail and E-cadherin had stronger correlation with malignant properties. Collectively, results suggest that the MTA3-regulated EMT pathway is altered to favor EMT and, therefore, disease progression and that MTA3 expression was an independent prognostic factor in patients with GEJ adenocarcinoma.

Show MeSH
Related in: MedlinePlus