Identification of novel subregions of LOH in gastric cancer and analysis of the HIC1 and TOB1 tumor suppressor genes in these subregions.
Identification of novel subregions of LOH in gastric cancer and analysis of the HIC1 and TOB1 tumor suppressor genes in these subregions.
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DOI：
10.1007/s10059-011-2316-4
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发表时间：
2011-07
影响因子：
3.8
通讯作者：
Fu, Songbin
中科院分区：
文献类型：
--
作者：
Yu, Jingcui;Liu, Peng;Cui, Xiaobo;Sui, Yu;Ji, Guohua;Guan, Rongwei;Sun, Donglin;Ji, Wei;Liu, Fangli;Liu, An;Zhao, Yuzhen;Yu, Yang;Jin, Yan;Bai, Jing;Geng, Jingshu;Xue, Yingwei;Qi, Jiping;Lee, Ki-Young;Fu, Songbin
在此之前，我们在45例原发胃癌(GC)的17号染色体上发现了3个杂合性缺失的重叠区域(11-30 cM的R1-R3)。提示17号染色体上存在与胃癌相关的肿瘤抑制基因(TSGs)。在这些区域推定的TSG中，HIC1(在SR1中)和Tob1(在SR3中)仍有待GC检测。采用免疫组织化学(IHC)、甲基化特异性聚合酶链式反应(MSP)和免疫印迹法检测HIC1和Tob1蛋白在胃癌组织中的表达及调控状态。我们缩小了17号染色体上的缺失区间，并在GC中定义了5个较小的LOH亚区，SR1-SR5(0.54~3.42 cM)。我们发现HIC1在86%(91/106)的原发GC中表达下调，在87%(26/30)的原发GC中发生甲基化。在HIC1蛋白表达下调的原发GCs中，75%(18/24)存在HIC1基因甲基化。在75%(73/97)的胃癌组织中，TAB1基因不表达或表达降低。此外，在分化的GC细胞系中，总的非磷酸化和磷酸化的Tob1蛋白水平普遍降低。进一步分析发现，HIC1和Tob1蛋白在胃癌组织芯片样本(67%，52/78)和原发胃癌(65%，11/17)中同时显著下调。这些结果表明，HIC1和Tob1的表达沉默在GC中是一种常见的现象，可能与疾病的发生发展有关。
Previously, we identified 3 overlapping regions showing loss of heterozygosity (LOH, R1-R3 from 11 to 30 cM) on chromosome 17 in 45 primary gastric cancers (GCs). The data indicated the presence of tumor suppressor genes (TSGs) on chromosome 17 involved in GC. Among the putative TSGs in these regions, HIC1 (in SR1) and TOB1 (in SR3) remain to be examined in GC. By immunohistochemistry (IHC), methylation-specific PCR (MSP) and western blot, we evaluated the expression and regulation status for HIC1 and TOB1 protein in GC. We narrowed down the deletion intervals on chromosome 17 and defined five smaller LOH subregions, SR1-SR5 (0.54 to 3.42 cM), in GC. We found that HIC1 had downregulated expression in 86% (91/106) and was methylated in 87% (26/30) of primary GCs. Of the primary GCs showing downregulation of HIC1 protein, 75% (18/24) had methylated HIC1 gene. TOB1 was either absent or expressed at reduced levels in 75% (73/97) of the GC samples. In addition, a general reduction was found in total and the ratio of unphosphorylated to phosphorylated TOB1 protein levels in the differentiated GC cell lines. Further analysis revealed significant simultaneous downregulation of both HIC1 and TOB1 protein in GC tissue microarray samples (67%, 52/78) and in primary GCs (65%, 11/17). These results indicate that silencing of HIC1 and TOB1 expression is a common occurrence in GC and may contribute to the development and progression of the disease.
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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：
9.7
作者：
Ito, Y;Suzuki, T;Miyauchi, A
通讯作者：
Miyauchi, A
影响因子：
9.7
作者：
Iwanaga, K;Sueoka, N;Sueoka, E
通讯作者：
Sueoka, E
影响因子：
10.5
作者：
Yoshida, Y;Nakamura, T;Yamamoto, T
通讯作者：
Yamamoto, T
影响因子：
2.1
作者：
Suzuki, T;Matsuda, S;Yamamoto, T
通讯作者：
Yamamoto, T