RPL22L1调控S6K2及其介导的蛋白质翻译系统促进结直肠癌转移的机制

Metastasis is the main cause of death in patients with colorectal cancer. Due to insufficient understanding of the metastatic mechanism, clinical treatment still lacks effective targets. Protein translation is an upstream event of cellular activity and plays an important role in the regulation of the overall biological behavior of cells. Our previous study found that the ribosomal protein analogue RPL22L1 is not only highly related to the metastasis of colorectal cancer patients, but also regulates several metastasis-related steps such as cell migration, invasion, adhesion, cytokine secretion, and EMT of colorectal cancer. In addition, RPL22L1 can regulate the S6K2 expression which is a pivotal protein in protein translation process. We proposed the hypothesis that "RPL22L1 promotes metastasis of colorectal cancer through regulation of S6K2 and its mediated protein translation system." This project intends to analyze the role of RPL22L1 in the regulation of S6K2 and its mediated protein translation system through a variety of colorectal cancer cells and animal models. Clarify a new mechanism about the activation of the RPL22L1-S6K2-translational regulatory pathway through analysis of clinical colorectal cancer cases. The project will enrich our understanding of the function of ribosome-like proteins, deepen the understanding of the mechanism of tumor metastasis, and provide a potential new upstream target for the targeted treatment of colorectal cancer.

转移是结直肠癌患者死亡的主要原因，由于对转移机制的深入认知不足，临床治疗仍缺乏有效靶点。蛋白质翻译是细胞生命活动的上游事件，对于细胞整体生物学行为调控具有重要作用。我们前期研究发现类核糖体蛋白RPL22L1不仅与结直肠癌患者的转移发生高度相关，还可调控结直肠癌细胞迁移、侵袭、粘附、细胞因子分泌以及EMT等多个转移相关步骤。此外，RPL22L1可以调控蛋白质翻译过程中枢纽蛋白S6K2表达，因此提出“RPL22L1通过调控S6K2及其介导的蛋白质翻译系统促进结直肠癌转移”的假说。本项目拟通过多种结直肠癌细胞和动物模型分析RPL22L1对S6K2及其介导的蛋白翻译系统的调控作用，并通过临床结直肠癌病例分析明确RPL22L1-S6K2-翻译调控通路活化的新机制，该项目将丰富我们对类核糖体蛋白功能的认识，加深对肿瘤转移发生机制的理解，为结直肠癌的靶向治疗提供潜在上游新靶点。

蛋白质翻译作为细胞生命活动的上游事件，对细胞整体生物学行为调控具有重要的作用。本项目前期研究已发现一新的候选癌基因RPL22L1对于结直肠癌转移具有重要促进作用，且可调控蛋白翻译过程枢纽蛋白S6K2表达。在本项目中进一步通过细胞模型、动物模型、临床样本充分探究RPL22L1与S6K2及其下游蛋白翻译相关通路的关系；通过不同节点因子靶向抑制探究RPL22L1对S6K2的调控关系；并探究RPL22L1与S6K2相关因子调控在临床结直肠癌中的意义。结果表明，RPL22L1对S6K2及相应蛋白翻译通路具有促进作用，这种作用在低氧条件下尤为突出；RPL22L1通过mTOR途径调控S6K2，雷帕霉素可抑制RPL22L1带来的促癌作用；RPL22L1可作为结直肠癌预后的独立指标。此外，通过研究还发现RPL22L1可能对血管生成具有调控作用，影响西妥昔单抗对结直肠癌细胞的作用，RPL22L1对蛋白质翻译的调控在低氧条件下尤为特殊需要进行进一步的挖掘和探索。拓展研究发现，RPL22L1在肝细胞癌、胶质瘤中同样具有重要的作用，对于RPL22L1高表达的肝细胞癌患者或可考虑联用ERK靶向药物，对于RPL22L1高表达的胶质瘤患者联用STAT3靶向药物会取得更好的治疗效果。