Differential expression of angiogenesis-related genes in human gastric cancers with and those without high-frequency microsatellite instability
Differential expression of angiogenesis-related genes in human gastric cancers with and those without high-frequency microsatellite instability
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DOI：
10.1016/j.canlet.2007.02.004
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发表时间：
2007-08-28
期刊：
影响因子：
9.7
通讯作者：
Shinomura, Yasuhisa
中科院分区：
文献类型：
--
作者：
Miyamoto, Nobuki;Yamamoto, Hiroyuki;Shinomura, Yasuhisa
具有和不具有高频微卫星不稳定性（MSI-H）的胃癌代表了不同的致癌途径。本研究的目的是澄清参与血管生成的p53相关基因的表达是否在这些癌症之间受到差异调节。我们系统分析了血管内皮生长因子A（VEGFA）、成纤维细胞生长因子2（FGF 2）、血小板反应蛋白1（THBS 1）和脑特异性血管生成抑制因子1（BAI 1）的表达，并将结果与胃癌中的微血管计数（MVC）、MSI状态、p53突变和胰高血糖素-内过氧化物合酶2（PTGS 2）表达相关。200例癌组织中VEGFA阳性表达率为46%。VEGFA阳性与MVC、血管浸润、淋巴结转移、远处转移及肿瘤分期有关。FGF 2阳性与低分化、浸润深度和高MVC显著相关。MSI-H组VEGFA和FGF 2阳性率及MVC均低于MSI-L组和MSS组。VEGFA表达与p53突变和PTGS 2表达相关。THBS 1基因甲基化在11个癌细胞系中的6个中检测到，在200个病例中的44%中检测到。THBS 1甲基化与远端位置、血管浸润、远处转移、MSI-H、野生型p53和较高MVC显著相关。VEGF阳性和THBS 1甲基化阳性的癌症患者预后最差。MSI-H胃癌的特征是MVC较低，VEGFA、FGF 2和PTGS 2过表达频率低，THBS 1甲基化频率高。我们的研究结果表明，胃癌和那些没有MSI-H代表不同的致癌途径，包括异常表达的因子调节血管生成。这种差异可能与这些具有MSI-H的癌症的侵袭性较低的表型相关，并影响未来的分子靶向治疗。(c)2007爱思唯尔爱尔兰有限公司保留所有权利。
Gastric cancers with and those without high-frequency microsatellite instability (MSI-H) represent distinctive pathways of carcinogenesis. The aim of this study was to clarify if expression of p53 related genes involved in angiogenesis is differentially regulated between these cancers. We systematically analyzed the expression of vascular endothelial growth factor A (VEGFA), fibroblast growth factor 2 (FGF2), thrombospondin 1 (THBS1), and brain-specific angiogenesis inhibitor 1 (BAI1), and we correlated the results with microvessel count (MVC), MSI status, p53 mutations, and prostaglandin-endoperoxide synthase 2 (PTGS2) expression in gastric cancers. Expression of VEGFA in carcinoma cells was immunohistochemically seen in 46% of 200 cases. VEGFA positivity was significantly associated with higher MVC, vascular invasion, lymph node and distant metastasis, and advanced tumor stage. FGF2 positivity was significantly associated with poor differentiation, depth of invasion, and higher MVC. VEGFA and FGF2 positivities and MVC were lower in MSI-H cancers than in MSI-L or MSS cancers. VEGFA expression was associated with both p53 mutations and PTGS2 expression. Methylation of the THBS1 gene was detected in 6 of 11 cancer cell lines and in 44% of 200 cases. THBS1 methylation was significantly associated with distal location, vascular invasion, distant metastasis, MSI-H, wild-type p53, and higher MVC. The prognosis was worst in patients with cancers that were VEGFA-positive and THBS1 methylation-positive. Gastric cancers with MSI-H were characterized by lower MVC, low frequency of VEGFA, FGF2, and PTGS2 overexpression, and high frequency of THBS1 methylation. Our results suggest that gastric cancers with and those without MSI-H represent distinctive pathways of carcinogenesis, including aberrant expression of factors regulating angiogenesis. The difference may be associated with less aggressive phenotype of these cancers with MSI-H and affect future molecular targeted therapeutics. (c) 2007 Elsevier Ireland Ltd. All rights reserved.