MAGOH通过circSRPK1调控可变剪接体RON∆160的形成在胃癌进展中作用机制的研究

受体酪氨酸激酶RON的可变剪接现象与胃癌发生发展密切相关，阻断RON可变剪接体的形成可作为抗胃癌药物筛选的重要切入点。课题组发表成果证实胃癌中存在的可变剪接体RON△160具有更强的促胃癌细胞生长能力，但其形成机制仍不清楚。我们前期发现：外显子连接复合物组分MAGOH在胃癌中表达异常；MAGOH及受其调控的环状RNA-circSRPK1可促进RON△160生成；circSRPK1可结合并抑制mRNA剪接因子hnRNPH1核转位，可能参与RONmRNA可变剪接。因此，我们拟通过临床和功能学实验证实如下假说：胃癌中高表达的MAGOH激活circSRPK1转录，circSRPK1通过直接结合hnRNPH1调控RONmRNA的可变剪接，诱导RON△160生成，增强胃癌细胞生长能力。本项目将揭示MAGOH调控的RON△160形成机制在胃癌进程中的作用，为临床开发新的胃癌靶向治疗策略提供依据。

The variable splicing of receptor tyrosine kinase RON is closely related to the occurrence and development of gastric cancer. Blocking the formation of RON spliceosome can be an important entry point for the screening of drugs for gastric cancer. Our previous work reported the existence of an alternative splicing form of RON (RON△160), which possesses an increased capacity to promote the growth and metastasis of gastric cancer. But the formation mechanism of RON△160 is not clear. In the present study, we found that MAGOH，a component of exon junction complex, was abnormally expressed in gastric cancer. Both MAGOH and its regulatory circle RNA circSRPK1 affected the generation of RON△160. Mechanistically, circSRPK1 interacted with hnRNPH1 and thus inhibited hnRNPH1 nuclear translocation which induced RON△160 generation via mRNA alternative splicing. Based on these results, we hypothesize that High expression of MAGOH in gastric cancer promotes the transcription of circSRPK1 to regulate the function of hnRNPH1 on RON mRNA alternative splicing, leading to the generation of RON△160 and the accelerated gastric cancer growth. Our project can hopefully reveal the role of RON△160 formation mechanism regulated by MAGOH in the progression of gastric cancer, and provide a basis for the clinical development of new targeted therapeutic strategies for gastric cancer.