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Methylation adjacent to negatively regulating AP-1 site reactivates TrkA gene expression during cancer progression

Oncogene volume 24, pages 5108–5118 (2005)Cite this article

Abstract

Nerve growth factor and its high-affinity receptor TrkA are thought to be involved in the progression of various cancers. This study investigated the mechanism that regulates aberrant or increased TrkA expression in various cancer cell lines and in the course of pancreatic cancer progression. We found that the negative cis-acting AP-1-like sequence TGAGCGA was located in the 5′-untranslated region of the TrkA gene. Sodium bisulfite mapping revealed that steady-state TrkA expression correlated positively with the accumulation of methylated CpG around the AP-1-like site. Electrophoretic mobility shift assay showed that the AP-1-like site was bound mainly by c-Jun homodimers; the binding was directly blocked by Sss I methylase-induced methylation or by an excess of oligonucleotides containing consensus AP-1 sequences. Consequently, activation of TrkA gene expression by methylation was considered to be caused by the direct interference of c-Jun binding to the negatively regulating AP-1-like site. Furthermore, the accumulation of methylated CpG around the AP-1-like site was also observed with increased TrkA immunohistochemical staining in cases of advanced pancreatic adenocarcinoma with extensive perineural invasion. Unlike global methylation at CpG islands that leads to gene silencing, specific methylation at non-CpG islands would play a crucial epigenetic role in the versatility and plasticity of TrkA expression during cancer progression.

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Acknowledgements

We thank Dr Luis F Parada (Center for Developmental Biology, UT Southwestern Medical Center) and Dr Yasuhiro Indo (Department of Pediatrics, Kumamoto University School of Medicine, Japan) for kindly providing TrkA cDNA. We also thank Dr Ushijima (Carcinogenesis Division, National Cancer Center Research Institute) for helpful suggestions. We thank Shuichi Matsuda for excellent technical assistance. This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Health and Welfare, Japan (to SK) and by a Grant-in-Aid for Scientific Research (to SK, No. 16590278, and to RK, No. 16590313), and for 21st Century COE Program, ‘Center of Excellence for Signal Transduction Disease: Diabetes Mellitus as Model’ from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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  1. Division of Molecular Pathology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, 650-0017, Kobe, Japan

    Masayo Fujimoto, Riko Kitazawa, Sakan Maeda & Sohei Kitazawa

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  1. Masayo Fujimoto
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  2. Riko Kitazawa
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Correspondence to Sohei Kitazawa.

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Fujimoto, M., Kitazawa, R., Maeda, S. et al. Methylation adjacent to negatively regulating AP-1 site reactivates TrkA gene expression during cancer progression. Oncogene 24, 5108–5118 (2005). https://doi.org/10.1038/sj.onc.1208697

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