肿瘤抑制性基因修饰的系统筛选及作用机制研究

肿瘤的发生同基因的关系错综复杂。通过修饰基因表达水平来抑制肿瘤生长的策略拥有充分理论可行性，但目标基因及其作用机制迄今未获系统研究。本项目拟开创性应用秀丽线虫（Caenorhabditis elegans）模式系统进行全基因组高通量筛选，以此定位有广泛克制多种肿瘤潜力的基因修饰。具体而言，通过RNA干扰依次抑制各基因表达，观察其对罹患两种由完全不同分子机制导致的生殖腺肿瘤的线虫的生存期的影响，我们已经鉴定出了nhx-2及sgk-1等基因的下调显著抑制肿瘤的危害。进一步的，本项目将对nhx-2等基因抑制的作用从细胞学层面染色观察，并将对sgk-1等基因抑制的效果应用转录组、代谢组学方法搜寻及遗传学方法确认，最终明确其分子机制。本项目除了将在理论上增加对肿瘤病理机制的认知外，也将为医疗实践提供治疗多种癌症的潜在靶标，拥有巨大的转化价值。

The relationships between tumor onset and individual genes are complex, thus the strategy of tumor suppression via modified gene expression is theoretically sound. However, to date, no systemic studies on these genes have been conducted to reveal their identities or mechanisms. We propose to use a model organism, the nematode Caenorhabditis elegans, to conduct this high throughput genome-wide screen in order to identify all genetic modifications effective in universally antagonizing various tumors. Briefly, we will inactivate each individual gene using RNA interference and then determine its influences on survival of two germline tumorous strains caused by distinct mechanisms. Our preliminary screen has already led to identification of several genes whose downregulation remarkably alleviate tumor pathologies, including the nhx-2 gene and the sgk-1 gene. Moreover, we aim at revealing the detailed molecular mechanism of the nhx-2 gene using cellular staining, and that of the sgk-1 gene using transcriptomic and metabolomic analyses followed by epistatic approaches. This study will not only help understand the mechanisms of tumor progression, but also provide potential targets for curing various cancers, therefore exhibiting enormous potential of medical translation.