系统性干预RNA翻译起始对肺癌癌症干细胞的作用机制研究

Heterogeneity is one of the main causes of targeted therapy failure in lung cancer. While lung cancer cells have common characteristics in terms of highly active translation initiation behaviors and translation initiation efficiency (translation ratio, TR), which is strongly relevant to phenotypes. This implies that systematic interference on translation initiation can safely contain the malignant phenotypes of lung cancer cells. The cancer stem cell (CSC) model proposes that the growth and progression of many cancers are driven by small subpopulations of CSCs. We found that the up-regulated proteins in side population (SP) cells which represents an enrichment of CSCs were targeting translation initiation according to our preliminary experiment result. This suggests that the highly active translation initiation is mechanistically relevant to CSC. As there is no published to date focusing on the translatome (RNC-mRNA) of CSC, such a mechanism remains unaddressed. We have recently finished multi-omics experiment of proteome, transcriptome and translatome on SP and non-SP cells. In this project, we will research whether high translation initiation gens closely related to CSC’s generation and differentiation? This implication will be validated with human lung cancer cell lines and nude mouse. This investigation has its potentials to reveal new theories on lung cancer research focusing on systematic interference translation initiation can safely contain growth and metastasis that leads to novel strategies on the therapy of lung cancer.

异质性是导致肺癌治疗失败的主要原因之一。在我们的前期研究中发现：虽然肺癌细胞有很高的异质性，但也有着共同的规律，即均因翻译失控而具有高度活跃的翻译起始行为。因此，全局干预肺癌的翻译起始则可能安全降低肺癌的恶性表型。我们前期研究发现肺癌A549细胞中富含癌症干细胞（CSC）的侧群细胞（SP）其上调蛋白质集中靶向翻译起始，提示翻译起始活跃可能与CSC存在机制联系，但目前因尚无研究者报道CSC的翻译组相关内容，因此其具体机制仍不明。在本项目中，我们完成了A549细胞中SP与non-SP的蛋白质组、转录组和翻译组的多组学测定工作，接下来我们将研究高翻译起始的基因是否与肺癌CSC的生长和分化密切相关？进一步在细胞水平和动物实验中进行机制研究，并探索干预这些机制对肺癌的影响和生物学意义。本项目将有望为肺癌研究领域提供新的理论依据和新的研究方向，并为肺癌治疗提供潜在的新策略。

本项目对肺癌高翻译模态进行表征，利用多组学的方法发现肺癌癌症干细胞（CSC）的高翻译起始效率特征，通过开发翻译起始抑制药物金精三羧酸（ATCA）对肺癌细胞翻译起始进行系统性压制，达到降低肺癌细胞干性、增殖、转移等恶性表型目的。通过在细胞和小鼠实验发现ATCA不仅可以抑制肺癌癌细胞增殖、迁移和干性，还可以抑制多种癌症细胞，包括肝癌、卵巢癌细胞株，说明干预翻译起始可能对癌症具有广谱抑制效果，加大了ATCA作为癌症治疗理论和临床研究意义。结合我们论证了肺癌细胞翻译起始异常活跃，且有规律性和表型特异性，我们认为ATCA一方面可有效降低肺癌恶性表型，另一方面具临床应用的潜力。