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Methylation status of CpG island of Smad4 gene in esophageal squamous cell carcinoma
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Abstract:
Objective : To investigate the methylation status in promoter and exon1 CpG island of Smad4 (mothers against decapentaplegic homolog 4) gene and its correlation with protein expressions of Smad4 and TGF-β1 in esophageal squamous cell carcinoma (ESCC). Methods: Totally 128 ESCC samples and the corresponding adjacent normal tissues were obtained from Fourth Hospital of Hebei Medical University (2004-2008) in the present study. Methylation specific PCR (MSP), RT-PCR and immunohistochemistry assays were used to examine the methylation status of 5′ CpG island, mRNA and protein expression of Smad4 in ESCC and the corresponding adjacent normal tissues. Immunohistochemistry method was used to detect the protein expression of TGF-β1 in ESCC and the corresponding adjacent normal tissues. Results: For the CpG island of promoter site, Smad4 was methylated in 7/128 (5.5%) ESCC tissues; for the CpG island of 5′ UTR of exon1, Smad4 was methylated in 39/128 (30.5%) ESCC tissues; the numbers were all significantly higher than those in the corresponding adjacent normal tissues (P<0.05). Smad4 mRNA and protein expressions in ESCC tissues were significantly lower than those in the corresponding adjacent normal tissues (P<0.05) and were correlated with Smad4 methylation status. TGF-β1 expression rate was 66.4% in ESCC tissues, which was significantly higher than that in the corresponding adjacent normal tissues (P<0.01), and TGF-β1 expression rate was increased with the increase of MNT stage and the decrease of differentiation stage of ESCC (P<0.05). The protein expression of Smad4 was inversely correlated with TGF-β1 expression in ESCC. Conclusion: Methylation of CpG island in Smad4 gene and TGF-β1 overexpression might play important roles in the development of ESCC, and CpG island in 5′ UTR of exon1 in Smad4 gene is more likely to be hypermethylated than the promoter region and results in Smad4 gene silence.
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Project Supported:
Project supported by the Key Medical Science Research Foundation of Hebei Province (No. 20090465)
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