A whole-genome SNP association study of NCI60 cell line panel indicates a role of Ca2+ signaling in selenium resistance.
A whole-genome SNP association study of NCI60 cell line panel indicates a role of Ca2+ signaling in selenium resistance.
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DOI：
10.1371/journal.pone.0012601
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发表时间：
2010-09-07
期刊：
影响因子：
3.7
通讯作者：
Ozcelik H
中科院分区：
文献类型：
--
作者：
Savas S;Briollais L;Ibrahim-zada I;Jarjanazi H;Choi YH;Musquera M;Fleshner N;Venkateswaran V;Ozcelik H
流行病学研究表明，摄入硒和预防多种癌症之间存在关联。考虑到硒的临床重要性，我们的目标是找出与硒治疗耐药相关的基因。我们应用了我们团队之前开发的一种方法，该方法基于NCI60癌症细胞系小组公开获得的遗传和药理学数据。简而言之，我们根据NCI60细胞系的生长抑制(GI50)数据将其归类为耐硒和敏感细胞系。然后，我们利用现有的Affymetrix 125K SNP芯片数据，对硒敏感和耐药的NCI60细胞株进行了全基因组病例对照关联研究。结果显示，位于5q33-34、10q11.2、10q22.3和14q13.1的4个SNP与硒抵抗显著相关。这些SNP位于编码蛋白支架蛋白(AKAP6)、膜蛋白(SGCD)、通道蛋白(KCNMA1)和蛋白激酶(PRKG1)的基因内含子。SiRNA下调KCNMA1基因后，LNCaP和PC3细胞对硒的敏感性均增强。此外，SNP-SNP互作(上位性)分析表明，AKAP6中的SNP与SGCD以及AKAP6中的SNP与KCNMA1之间存在相互作用，符合加性遗传模型。这些基因也都参与了钙离子信号转导，具有直接诱导肿瘤细胞凋亡的作用，与硒的化学预防作用相一致。一旦我们的发现得到进一步验证，这一知识就可以转化为临床，在那里，通过简单的DNA分析，可以很容易地识别哪些人可以从补硒的化学预防特性中受益。
Epidemiological studies have suggested an association between selenium intake and protection from a variety of cancer. Considering this clinical importance of selenium, we aimed to identify the genes associated with resistance to selenium treatment. We have applied a previous methodology developed by our group, which is based on the genetic and pharmacological data publicly available for the NCI60 cancer cell line panel. In short, we have categorized the NCI60 cell lines as selenium resistant and sensitive based on their growth inhibition (GI50) data. Then, we have utilized the Affymetrix 125K SNP chip data available and carried out a genome-wide case-control association study for the selenium sensitive and resistant NCI60 cell lines. Our results showed statistically significant association of four SNPs in 5q33–34, 10q11.2, 10q22.3 and 14q13.1 with selenium resistance. These SNPs were located in introns of the genes encoding for a kinase-scaffolding protein (AKAP6), a membrane protein (SGCD), a channel protein (KCNMA1), and a protein kinase (PRKG1). The knock-down of KCNMA1 by siRNA showed increased sensitivity to selenium in both LNCaP and PC3 cell lines. Furthermore, SNP-SNP interaction (epistasis) analysis indicated the interactions of the SNPs in AKAP6 with SGCD as well as SNPs in AKAP6 with KCNMA1 with each other, assuming additive genetic model. These genes were also all involved in the Ca2+ signaling, which has a direct role in induction of apoptosis and induction of apoptosis in tumor cells is consistent with the chemopreventive action of selenium. Once our findings are further validated, this knowledge can be translated into clinics where individuals who can benefit from the chemopreventive characteristics of the selenium supplementation will be easily identified using a simple DNA analysis.
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影响因子：
3.8
作者：
Khaitan D;Sankpal UT;Weksler B;Meister EA;Romero IA;Couraud PO;Ningaraj NS
通讯作者：
Ningaraj NS
影响因子：
64.8
作者：
Frazer, Kelly A.;Ballinger, Dennis G.;Cox, David R.;Hinds, David A.;Stuve, Laura L.;Gibbs, Richard A.;Belmont, John W.;Boudreau, Andrew;Hardenbol, Paul;Leal, Suzanne M.;Pasternak, Shiran;Wheeler, David A.;Willis, Thomas D.;Yu, Fuli;Yang, Huanming;Zeng, Changqing;Gao, Yang;Hu, Haoran;Hu, Weitao;Li, Chaohua;Lin, Wei;Liu, Siqi;Pan, Hao;Tang, Xiaoli;Wang, Jian;Wang, Wei;Yu, Jun;Zhang, Bo;Zhang, Qingrun;Zhao, Hongbin;Zhao, Hui;Zhou, Jun;Gabriel, Stacey B.;Barry, Rachel;Blumenstiel, Brendan;Camargo, Amy;Defelice, Matthew;Faggart, Maura;Goyette, Mary;Gupta, Supriya;Moore, Jamie;Nguyen, Huy;Onofrio, Robert C.;Parkin, Melissa;Roy, Jessica;Stahl, Erich;Winchester, Ellen;Ziaugra, Liuda;Altshuler, David;Shen, Yan;Yao, Zhijian;Huang, Wei;Chu, Xun;He, Yungang;Jin, Li;Liu, Yangfan;Shen, Yayun;Sun, Weiwei;Wang, Haifeng;Wang, Yi;Wang, Ying;Xiong, Xiaoyan;Xu, Liang;Waye, Mary M. Y.;Tsui, Stephen K. W.;Wong, J. Tze-Fei;Galver, Luana M.;Fan, Jian-Bing;Gunderson, Kevin;Murray, Sarah S.;Oliphant, Arnold R.;Chee, Mark S.;Montpetit, Alexandre;Chagnon, Fanny;Ferretti, Vincent;Leboeuf, Martin;Olivier, Jean-Franccois;Phillips, Michael S.;Roumy, Stephanie;Sallee, Clementine;Verner, Andrei;Hudson, Thomas J.;Kwok, Pui-Yan;Cai, Dongmei;Koboldt, Daniel C.;Miller, Raymond D.;Pawlikowska, Ludmila;Taillon-Miller, Patricia;Xiao, Ming;Tsui, Lap-Chee;Mak, William;Song, You Qiang;Tam, Paul K. H.;Nakamura, Yusuke;Kawaguchi, Takahisa;Kitamoto, Takuya;Morizono, Takashi;Nagashima, Atsushi;Ohnishi, Yozo;Sekine, Akihiro;Tanaka, Toshihiro;Tsunoda, Tatsuhiko;Deloukas, Panos;Bird, Christine P.;Delgado, Marcos;Dermitzakis, Emmanouil T.;Gwilliam, Rhian;Hunt, Sarah;Morrison, Jonathan;Powell, Don;Stranger, Barbara E.;Whittaker, Pamela;Bentley, David R.;Daly, Mark J.;de Bakker, Paul I. W.;Barrett, Jeff;Chretien, Yves R.;Maller, Julian;McCarroll, Steve;Patterson, Nick;Pe'er, Itsik;Price, Alkes;Purcell, Shaun;Richter, Daniel J.;Sabeti, Pardis;Saxena, Richa;Schaffner, Stephen F.;Sham, Pak C.;Varilly, Patrick;Altshuler, David;Stein, Lincoln D.;Krishnan, Lalitha;Smith, Albert Vernon;Tello-Ruiz, Marcela K.;Thorisson, Gudmundur A.;Chakravarti, Aravinda;Chen, Peter E.;Cutler, David J.;Kashuk, Carl S.;Lin, Shin;Abecasis, Goncalo R.;Guan, Weihua;Li, Yun;Munro, Heather M.;Qin, Zhaohui Steve;Thomas, Daryl J.;McVean, Gilean;Auton, Adam;Bottolo, Leonardo;Cardin, Niall;Eyheramendy, Susana;Freeman, Colin;Marchini, Jonathan;Myers, Simon;Spencer, Chris;Stephens, Matthew;Donnelly, Peter;Cardon, Lon R.;Clarke, Geraldine;Evans, David M.;Morris, Andrew P.;Weir, Bruce S.;Tsunoda, Tatsuhiko;Johnson, Todd A.;Mullikin, James C.;Sherry, Stephen T.;Feolo, Michael;Skol, Andrew
通讯作者：
Skol, Andrew
影响因子：
15.9
作者：
Amberg, GC;Bonev, AD;Santana, LF
通讯作者：
Santana, LF
影响因子：
3.9
作者：
Jarjanazi, Hamdi;Kiefer, Jeffrey;Ozcelik, Hilmi
通讯作者：
Ozcelik, Hilmi
影响因子：
8
作者：
Bloch, M.;Ousingsawat, J.;Bubendorf, L.
通讯作者：
Bubendorf, L.