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Concordant repression and aberrant methylation of transforming growth factor-beta signaling pathway genes occurs early in gastric cardia adenocarcinoma

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Abstract

The loss of transforming growth factor-β (TGF-β) response due to the dysregulation of TGF-β receptor type I (TGFBR1), type II (TGFBR2) and Smad4 is well known for its contribution to oncogenesis, although the role of the genes of TGF-β/Smad signalling pathway in gastric cardia adenocarcinoma (GCA) is poorly understood. In the present study, the methylation status and expression of TGF-β receptor type I (TGFBR1), type II (TGFBR2), and Smad4 was investigated in GCA and dysplasia. MSP approach was used to detect the methylation status of TGFBR1, TGFBR2, and Smad4. Immunohistochemistry and quantitative RT-PCR methods were used respectively to examine the protein and mRNA expression of them in tissues. The methylation frequency of TGFBR1 and TGFBR2 in the tissues of high grade dysplasia and GCA was significantly higher than that in corresponding normal tissues (p < 0.01) and was significantly associated with mRNA and protein expression of the two genes (p < 0.05). The methylation frequency of Smad4 in the 30 ~ 171 sites was higher than that in the −248 ~ 26 sites and was associated with the loss of Smad4 expression. The decreased expression of TGFBR1, TGFBR2 and Smad4 was correlated with increased expression of TGF-β1 in GCA. In all, these data suggest that methylation of TGFBR1, TGFBR2 and Smad4 may exist in the gastric cardia dysplasia stages and plays an important role in these genes silencing and subsequently affect the TGF-β/Smad signaling pathway.

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Acknowledgments

We thank the patients and control individuals for taking part in this study. Supported by Grants from the important medical subjects foundation of Hebei province.

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Authors and Affiliations

  1. Department of Laboratory of Pathology, Hebei Cancer Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China

    Wei Guo, Zhiming Dong, Yanli Guo, Gang Kuang & Zhibin Yang

  2. Department of Research Center, Hebei Cancer Institute, The Fourth Hospital of Hebei Medical University, Jiankanglu 12, Shijiazhuang, 050011, Hebei, China

    Baoen Shan

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  1. Wei Guo
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  2. Zhiming Dong
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  3. Yanli Guo
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  4. Gang Kuang
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  6. Baoen Shan
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Correspondence to Baoen Shan.

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Wei Guo and Zhiming Dong contributed equally to this work.

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Guo, W., Dong, Z., Guo, Y. et al. Concordant repression and aberrant methylation of transforming growth factor-beta signaling pathway genes occurs early in gastric cardia adenocarcinoma. Mol Biol Rep 39, 9453–9462 (2012). https://doi.org/10.1007/s11033-012-1810-x

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  • DOI: https://doi.org/10.1007/s11033-012-1810-x

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