Title |
VILIP-1 Downregulation in Non-Small Cell Lung Carcinomas: Mechanisms and Prediction of Survival
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Published in |
PLOS ONE, February 2008
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DOI | 10.1371/journal.pone.0001698 |
Pubmed ID | |
Authors |
Jian Fu, Kathryn Fong, Alfonso Bellacosa, Eric Ross, Sinoula Apostolou, Daniel E. Bassi, Fang Jin, Jirong Zhang, Paul Cairns, Inmaculada Ibañez de Caceres, Karl-Heinz Braunewell, Andres J. Klein-Szanto |
Abstract |
VILIP-1, a member of the neuronal Ca++ sensor protein family, acts as a tumor suppressor gene in an experimental animal model by inhibiting cell proliferation, adhesion and invasiveness of squamous cell carcinoma cells. Western Blot analysis of human tumor cells showed that VILIP-1 expression was undetectable in several types of human tumor cells, including 11 out of 12 non-small cell lung carcinoma (NSCLC) cell lines. The down-regulation of VILIP-1 was due to loss of VILIP-1 mRNA transcripts. Rearrangements, large gene deletions or mutations were not found. Hypermethylation of the VILIP-1 promoter played an important role in gene silencing. In most VILIP-1-silent cells the VILIP-1 promoter was methylated. In vitro methylation of the VILIP-1 promoter reduced its activity in a promoter-reporter assay. Transcriptional activity of endogenous VILIP-1 promoter was recovered by treatment with 5'-aza-2'-deoxycytidine (5'-Aza-dC). Trichostatin A (TSA), a histone deacetylase inhibitor, potently induced VILIP-1 expression, indicating that histone deacetylation is an additional mechanism of VILIP-1 silencing. TSA increased histone H3 and H4 acetylation in the region of the VILIP-1 promoter. Furthermore, statistical analysis of expression and promoter methylation (n = 150 primary NSCLC samples) showed a significant relationship between promoter methylation and protein expression downregulation as well as between survival and decreased or absent VILIP-1 expression in lung cancer tissues (p<0.0001). VILIP-1 expression is silenced by promoter hypermethylation and histone deacetylation in aggressive NSCLC cell lines and primary tumors and its clinical evaluation could have a role as a predictor of short-term survival in lung cancer patients. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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India | 1 | 4% |
France | 1 | 4% |
Unknown | 25 | 93% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Master | 5 | 19% |
Researcher | 4 | 15% |
Student > Bachelor | 2 | 7% |
Student > Postgraduate | 2 | 7% |
Student > Ph. D. Student | 2 | 7% |
Other | 4 | 15% |
Unknown | 8 | 30% |
Readers by discipline | Count | As % |
---|---|---|
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Agricultural and Biological Sciences | 5 | 19% |
Neuroscience | 2 | 7% |
Pharmacology, Toxicology and Pharmaceutical Science | 1 | 4% |
Unspecified | 1 | 4% |
Other | 3 | 11% |
Unknown | 9 | 33% |