TY - JOUR
T1 - VILIP-1 downregulation in non-small cell lung carcinomas
T2 - Mechanisms and prediction of survival
AU - Fu, Jian
AU - Fong, Kathryn
AU - Bellacosa, Alfonso
AU - Ross, Eric
AU - Apostolou, Sinoula
AU - Bassi, Daniel E.
AU - Jin, Fang
AU - Zhang, Jirong
AU - Cairns, Paul
AU - de Caceres, Inmaculada Ibañez
AU - Braunewell, Karl Heinz
AU - Klein-Szanto, Andres J.
PY - 2008/2/27
Y1 - 2008/2/27
N2 - 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 ceil 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. Copyright:
AB - 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 ceil 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. Copyright:
KW - Carcinoma, Non-Small-Cell Lung/diagnosis
KW - DNA Methylation
KW - Down-Regulation/genetics
KW - Gene Expression Regulation, Neoplastic
KW - Gene Silencing
KW - Histones/metabolism
KW - Humans
KW - Neurocalcin/genetics
KW - Promoter Regions, Genetic
KW - RNA, Messenger/genetics
KW - Survival Rate
UR - http://www.scopus.com/inward/record.url?scp=45949096014&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000260586500042&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1371/journal.pone.0001698
DO - 10.1371/journal.pone.0001698
M3 - Article
C2 - 18301774
SN - 1932-6203
VL - 3
SP - e1698
JO - PLoS ONE
JF - PLoS ONE
IS - 2
M1 - e1698
ER -