类泛素蛋白UBL3通过调控与信号传导相关的氨酰tRNA合成酶来抑制肺癌的作用机制

Lung cancer is one of the most prevalent and deadly cancers in the world, with no effective treatment strategy. Ubiquitin-like proteins are abnormally expressed during tumorigenesis, but their function in cancer remains unclear. Our previous study shows that, compared to the normal tissue, the expression of UBL3, an ubiquitin-like protein, is significantly down-regulated in non-small cell lung cancer, while DNA methylation of its gene promoter is significantly enhanced. In addition, low expression of UBL3 is significantly associated with poor prognosis in patients with lung adenocarcinoma. UBL3 overexpression not only inhibits tumor growth both in vitro and in vivo, but also inhibits the phosphorylation of protein kinases of EGFR and ERK signaling pathways. We also found that UBL3 binds to several aminoacyl tRNA synthetases. We hypothesize that UBL3 may regulates several aminoacyl tRNA synthetases to exert its anti-tumor activity. At the molecular, cellular, animal, and clinical samples levels, the proposed study will elucidate: 1) the interaction between UBL3 and aminoacyl tRNA synthetases and its effect on lung cancer; 2) the effect of UBL3 on the localization and stability of aminoacyl tRNA synthetases; This study will help to identify new therapeutic targets for lung cancer treatment.

肺癌是目前世界范围内发病率和致死率最高的癌症之一，但缺乏有效的治疗策略。类泛素蛋白在肿瘤发生发展中表达异常，但其作用尚不清楚。我们前期工作发现：与正常组织相比，类泛素蛋白UBL3在非小细胞肺癌中的表达明显下调，其基因启动子的DNA甲基化增强。此外，UBL3的低表达与肺腺癌患者的不良预后显著相关。UBL3过表达不仅抑制肺癌细胞在体外和体内的成瘤能力，还会抑制EGFR，ERK等信号通路中激酶的磷酸化。此外，与UBL3结合的蛋白包括多种氨酰tRNA合成酶。我们推测UBL3通过调控氨酰tRNA合成酶来发挥其抑癌作用。本研究将从分子，细胞，动物，临床样本等水平上阐明：1)UBL3和氨酰tRNA合成酶之间的相互作用及其对肺癌的影响; 2)UBL3对氨酰tRNA合成酶的定位和稳定性的影响。本研究将为发现新的肺癌治疗靶点提供帮助。

类泛素蛋白在肿瘤的发生和发展中发挥重要的调控作用，通常类泛素蛋白在肿瘤发生发展中表达异常，但其作用尚不清楚。我们前期工作发现：与正常组织相比，类泛素蛋白UBL3在非小细胞肺癌中的表达明显下调，其基因启动子的DNA甲基化增强。此外，UBL3的低表达与肺腺癌患者的不良预后显著相关。在后续研究中本项目主要从 1) 明确 UBL3 和氨酰 tRNA 合成酶的相互作用；2) 阐明 UBL3 和氨酰 tRNA 合成酶的相互作用对肺癌的影响；3) 确定氨酰 tRNA 合成酶在肺癌中的作用；4) 研究 UBL3 对氨酰 tRNA 合成酶定位和稳定性的影响等方面探索类泛素蛋白UBL3调控非小细胞肺癌的具体作用机制。研究结果提示UBL3通过调控氨酰tRNA合成酶来发挥其抑癌作用，本研究将为发现新的肺癌治疗靶点提供帮助。