VILIP-1 downregulation in non-small cell lung carcinomas: mechanisms and prediction of survival.
VILIP-1 downregulation in non-small cell lung carcinomas: mechanisms and prediction of survival.
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DOI：
10.1371/journal.pone.0001698
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发表时间：
2008-02-27
期刊：
影响因子：
3.7
通讯作者：
Klein-Szanto, Andres J.
中科院分区：
文献类型：
--
作者：
Fu, Jian;Fong, Kathryn;Bellacosa, Alfonso;Ross, Eric;Apostolou, Sinoula;Bassi, Daniel E.;Jin, Fang;Zhang, Jirong;Cairns, Paul;Ibanez de Caceres, Immaculada;Braunewell, Karl-Heinz;Klein-Szanto, Andres J.
VILIP-1是神经元Ca++传感器蛋白家族的成员，在实验动物模型中作为肿瘤抑制基因，通过抑制鳞状细胞癌细胞的细胞增殖、粘附和侵袭。人肿瘤细胞的Western印迹分析显示，VILIP-1表达在几种类型的人肿瘤细胞中检测不到，包括12种非小细胞肺癌（NSCLC）细胞系中的11种。VILIP-1的下调是由于VILIP-1 mRNA转录物的丢失。未发现VILIP-1基因重排、大片段缺失或突变，VILIP-1基因启动子区甲基化在基因沉默中起重要作用。在大多数VILIP-1沉默细胞中，VILIP-1启动子被甲基化。VILIP-1启动子的体外甲基化在启动子-报告基因测定中降低了其活性。用5′-氮杂-2 ′-脱氧胞苷（5′-Aza-dC）处理内源性VILIP-1启动子可恢复其转录活性。曲古抑菌素A（TSA），一种组蛋白去乙酰化酶抑制剂，有效地诱导VILIP-1表达，表明组蛋白去乙酰化是VILIP-1沉默的另一种机制。TSA增加了VILIP-1启动子区域的组蛋白H3和H4乙酰化。此外，表达和启动子甲基化的统计学分析（n = 150个原发性NSCLC样品）显示在肺癌组织中启动子甲基化和蛋白质表达下调之间以及存活和VILIP-1表达降低或缺失之间存在显著关系（p<0.0001）。 VILIP-1表达在侵袭性NSCLC细胞系和原发性肿瘤中通过启动子超甲基化和组蛋白去乙酰化而沉默，其临床评价可能作为肺癌患者短期生存的预测因子。
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.
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DOI：
10.1073/pnas.93.18.9821
发表时间：
1996-09-03
影响因子：
11.1
作者：
Herman, JG;Graff, JR;Baylin, SB
通讯作者：
Baylin, SB
影响因子：
15.9
作者：
Alikhani-Koopaei, R;Fouladkou, F;Frey, BM
通讯作者：
Frey, BM
影响因子：
64.5
作者：
Luo, RX;Postigo, AA;Dean, DC
通讯作者：
Dean, DC
影响因子：
45.3
作者：
Harvey, JM;Clark, GM;Allred, DC
通讯作者：
Allred, DC
影响因子：
5.6
作者：
PRESTRIDGE, DS
通讯作者：
PRESTRIDGE, DS