胃癌细胞中ING5基因表达调控及抑癌分子机理解析

Gastric cancer is one of the commonest gastrointestinal cancers risking human health all over the world, but the molecular mechanisms of its tumorigenesis and progression remain elusive. In our previous work, there was up-regulated expression and nucleocytoplasmic translocation of ING5 protein in gastric cancer. ING5 overexpression suppressed aggressive phenotypes, tumor growth and metastasis of gastric cancer cells. To realize the target and chemosensitive therapy of ING5, we plan to clarify the molecular mechanisms of ING5 expression from the transcriptional and translational modulation of nuclear proteins and miRNAs respectively. We will observe the effects of ING5 mutants on the aggressive phenotypes of gastric cancer cells to determine the key domains of ING5 for its biological functions. Subsequently, the domains of ING5 protein are being analyzed for the transcriptional regulation of down-stream genes at the aspect of protein-protein/DNA interaction, which combines the transcriptomic data to establish the signal pathway. Finally, the inhibitory effects of ING5 on gastric carcinogenesis, its growth and metastasis will be evaluated using xenograft model of nude mice and conditional ING5 knockout mode. The effects of miRNA and transcriptional factors on the growth were analyzed in nude mice bearing gastric cancer cells. If possible, the study would enrich the etiology of gastric cancer, clarify tumor-inhibiting effects and related molecular mechanisms of ING5, and provide a novel target molecule for early diagnosis and gene therapy of gastric cancer.

胃癌是严重威胁人类健康的常见消化道肿瘤之一,但是其发生和演进分子机制有待阐明。前期工作提示，胃癌中抑癌基因ING5表达上调且核浆移动，体内外实验结果提示ING5表达可以逆转胃癌细胞恶性表型并抑制肿瘤生长和转移。为了实现ING5的靶向和增敏治疗，本研究拟在核蛋白的转录和miRNA的翻译水平探讨ING5基因表达调控，观察ING5截断蛋白的生物学功能，通过蛋白-蛋白/DNA相互作用分析ING5结构域对下游靶基因的转录调控，结合转录组测序建立ING5信号传导通路，研究裸鼠体内ING5突变体以及调控因素(miRNA和转录因子)对胃癌细胞生长和血道转移的影响及分子机制，最后观察ING5表达缺陷对胃粘膜上皮细胞生物学行为及化学诱癌的影响。此研究项目的顺利实施，可极大推动胃癌病因学的发展，丰富胃癌细胞中ING5基因的肿瘤抑制作用及分子机理研究，为胃癌早期诊断和晚期基因治疗提供一个新的分子靶标。

胃癌是严重威胁人类健康的常见消化道肿瘤之一,但是其发生和演进分子机制有待阐明。前期工作提示，胃癌中抑癌基因ING5表达上调且核浆移动，体内外实验结果提示ING5表达可以逆转胃癌细胞恶性表型并抑制肿瘤生长和转移。为了实现ING5的靶向和增敏治疗，本研究拟在核蛋白的转录和miRNA的翻译水平探讨ING5基因表达调控，观察ING5截断蛋白的生物学功能，通过蛋白-蛋白/DNA相互作用分析ING5结构域对下游靶基因的转录调控，结合转录组测序建立ING5信号传导通路，研究裸鼠体内ING5突变体以及调控因素(miRNA和转录因子)对胃癌细胞生长和血道转移的影响及分子机制，最后观察ING5表达缺陷对胃粘膜上皮细胞生物学行为及化学诱癌的影响。此研究项目的顺利实施，可极大推动胃癌病因学的发展，丰富胃癌细胞中ING5基因的肿瘤抑制作用及分子机理研究，为胃癌早期诊断和晚期基因治疗提供一个新的分子靶标。