Abstract 88: Promoter hypermethylation leads to loss of Wnt7a in NSCLC
| Autor: | Michelle Vanscoyk, Scott N. Freeman, Meredith A. Tennis, Robert A. Winn |
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| Rok vydání: | 2011 |
| Předmět: | |
| Zdroj: | Cancer Research. 71:88-88 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | The Wnt signaling pathway is critical to normal development but the involvement of the pathway in lung tumorigenesis has not been clearly established. Wnt7a, with its receptor Fzd9, is required for maintenance of epithelial differentiation and inhibits transformed growth. Wnt7a has been shown to be frequently lost in NSCLC cell lines and tumors. We demonstrate that loss of Wnt7a in a non-transformed lung epithelial cell line leads to increased proliferation. Using pyrosequencing, 58 of 81 (72%) of NSCLC tumors we tested had higher methylation in the Wnt7a promoter region compared to adjacent normal lung tissue. We also tested 10 pairs of human NSCLC tumor and normal adjacent lung samples with known loss of expression of Wnt7a in the tumor and 6 (60%) had increased methylation of the Wnt7a promoter region in the tumors. Two NSCLC cell lines demonstrated to have methylated Wnt7a and loss of Wnt7a expression, H157 and H1299, were used to investigate methylation of the Wnt7a promoter. Treatment of these cell lines with 5-aza-2deoxycytidine resulted in increased expression of Wnt7a and increased downstream activity of known targets of Wnt7a-Fzd9 signaling. Methylation of a Wnt7a promoter luciferase resulted in decreased activity of the luciferase compared to an untreated Wnt7a luciferase. NNK is a tobacco carcinogen known to attenuate DNMT1 degradation, leading to increased promoter methylation. Treatment of a non-transformed lung epithelial cell line with NNK resulted in decreased expression of Wnt7a and increased clonogenicity. Together, these results indicate that Wnt7a is frequently lost by methylation in NSCLC and that methylation of Wnt7a leads to decreased expression. Wnt7a could be methylated by exposure to tobacco carcinogens, leading to loss of expression and increased transformed lung cell growth. The clinical use of demethylating agents could restore Wnt7a activity, helping to decrease growth of NSCLC. 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 88. doi:10.1158/1538-7445.AM2011-88 |
| Databáze: | OpenAIRE |
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