Putative tumour suppressor gene necdin is hypermethylated and mutated in human cancer.
Putative tumour suppressor gene necdin is hypermethylated and mutated in human cancer.
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DOI：
10.1038/bjc.2013.104
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发表时间：
2013-04-02
影响因子：
8.8
通讯作者：
Chapman, E. J.
中科院分区：
文献类型：
--
作者：
De Faveri, L. E.;Hurst, C. D.;Platt, F. M.;Taylor, C. F.;Roulson, J-A;Sanchez-Carbayo, M.;Knowles, M. A.;Chapman, E. J.
关键词：
Necdin（NDN）表达下调端粒酶永生化正常人尿路上皮细胞。端粒酶永生化的正常人尿路上皮细胞没有检测到遗传改变。因此，许多在永生化后表达改变的基因是报道了表观遗传沉默的基因。通过实时定量PCR和免疫印迹检测正常组织和肿瘤细胞系中NDN的表达。对尿路上皮癌（UC）进行免疫组化。对尿路上皮癌和UC细胞系进行基于HumanMethylation 27 BeadChip Array的甲基化分析。进行突变筛选。通过逆转录病毒介导的下调或过表达研究了NDN表达的功能意义。NDN蛋白在正常组织中广泛表达。在44个UC细胞系中的38个（86%）和25个非UC细胞系中的19个（76%）中观察到表达缺失。在大多数原发性UC中发现NDN蛋白的缺失。Oncomine分析表明在多种肿瘤类型中表达下调。在UC中，确定了NDN和关键CpG位点的肿瘤特异性高甲基化，其中高甲基化与表达降低相关。在结直肠癌和卵巢癌细胞系中发现了六种新的突变，包括一些预测的功能意义。功能研究表明，NDN在体外可抑制低密度下的集落形成，影响非贴壁生长和失巢凋亡。NDN是一种新的肿瘤抑制候选物，在癌症中下调和高甲基化或突变。
Necdin (NDN) expression is downregulated in telomerase-immortalised normal human urothelial cells. Telomerase-immortalised normal human urothelial cells have no detected genetic alterations. Accordingly, many of the genes whose expression is altered following immortalisation are those for which epigenetic silencing is reported. NDN expression was examined in normal tissues and tumour cell lines by quantitative real-time PCR and immunoblotting. Immunohistochemistry was performed on urothelial carcinoma (UC). Urothelial carcinoma and UC cell lines were subject to HumanMethylation27 BeadChip Array-based methylation analyses. Mutation screening was performed. The functional significance of NDN expression was investigated using retroviral-mediated downregulation or overexpression. NDN protein was widely expressed in normal tissues. Loss of expression was observed in 38 out of 44 (86%) of UC cell lines and 19 out of 25 (76%) of non-UC cell lines. Loss of NDN protein was found in the majority of primary UC. Oncomine analysis demonstrated downregulation of expression in multiple tumour types. In UC, tumour-specific hypermethylation of NDN and key CpG sites where hypermethylation correlated with reduced expression were identified. Six novel mutations, including some of predicted functional significance, were identified in colorectal and ovarian cancer cell lines. Functional studies showed that NDN could suppress colony formation at low cell density and affect anchorage-independent growth and anoikis in vitro. NDN is a novel tumour suppressor candidate that is downregulated and hypermethylated or mutated in cancer.
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影响因子：
23.9
作者：
Liu Y;Elf SE;Miyata Y;Sashida G;Liu Y;Huang G;Di Giandomenico S;Lee JM;Deblasio A;Menendez S;Antipin J;Reva B;Koff A;Nimer SD
通讯作者：
Nimer SD
影响因子：
30.8
作者：
Jay, P;Rougeulle, C;Muscatelli, F
通讯作者：
Muscatelli, F
影响因子：
50.3
作者：
Richardson, AL;Wang, ZGC;Ganesan, S
通讯作者：
Ganesan, S
影响因子：
6.4
作者：
Santegoets, Lindy A. M.;van Seters, Manon;Blok, Leen J.
通讯作者：
Blok, Leen J.
影响因子：
6.4
作者：
BEAN, MA;PEES, H;OETTGEN, HF
通讯作者：
OETTGEN, HF