Integrative genomics identifies RAB23 as an invasion mediator gene in diffuse-type gastric cancer
Integrative genomics identifies RAB23 as an invasion mediator gene in diffuse-type gastric cancer
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DOI：
10.1158/0008-5472.can-07-5870
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发表时间：
2008-06-15
期刊：
影响因子：
11.2
通讯作者：
Tan, Patrick
中科院分区：
文献类型：
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作者：
Hou, Qingsong;Wu, Yong Hui;Tan, Patrick
复发性基因组扩增和缺失在原发性胃癌（GC）中经常观察到。然而，在这些区域内识别特定的癌基因和肿瘤抑制基因可能具有挑战性，因为它们通常覆盖数十至数百个基因。在这里，我们结合了高分辨率阵列为基础的比较基因组杂交（aCGH）与基因表达谱的目标基因在局灶性高水平扩增的GC细胞系，并确定RAB 23作为一个扩增和过表达的Chr 6p11p12基因在Hs746T细胞。在一些缺乏RAB 23扩增的品系中也观察到高RAB 23蛋白表达，这表明除了基因扩增之外，上调RAB 23的另外机制。siRNA沉默RAB23显著降低了Hs746T细胞的细胞侵袭和迁移，而过表达RAB23增强了AGS细胞的细胞侵袭。通过荧光原位杂交和基因组qPCR证实了原发性胃肿瘤中的RAB 23扩增，并且在来自香港和英国的两个独立患者队列中，RAB 23表达与弥漫型GC（dGC）相比与胃肠道型GC（iGC）显著相关。这些结果提供了进一步的证据，dGC和iGC可能代表两种分子上不同的肿瘤类型，并表明通过将高分辨率aCGH与表达谱相结合来研究局灶性染色体扩增是在复发性染色体畸变区域中鉴定新型癌症基因的有力策略。
Recurrent genomic amplifications and deletions are frequently observed in primary gastric cancers (GC). However, identifying specific oncogenes and tumor suppressor genes within these regions can be challenging, as they often cover tens to hundreds of genes. Here, we combined high-resolution array-based comparative genomic hybridization (aCGH) with gene expression profiling to target genes within focal high-level amplifications in GC cell lines, and identified RAB23 as an amplified and overexpressed Chr 6p11p12 gene in Hs746T cells. High RAB23 protein expression was also observed in some lines lacking RAB23 amplification, suggesting additional mechanisms for up-regulating RAB23 besides gene amplification. siRNA silencing of RAB23 significantly reduced cellular invasion and migration in Hs746T cells, whereas overexpression of RAB23 enhanced cellular invasion in AGS cells. RAB23 amplifications in primary gastric tumors were confirmed by both fluorescence in situ hybridization and genomic qPCR, and in two independent patient cohorts from Hong Kong and the United Kingdom RAB23 expression was significantly associated with diffuse-type GC (dGC) compared with intestinal-type GC (iGC). These results provide further evidence that dGC and iGC likely represent two molecularly distinct tumor types, and show that investigating focal chromosomal amplifications by combining high-resolution aCGH with expression profiling is a powerful strategy for identifying novel cancer genes in regions of recurrent chromosomal aberration.