剪接因子SF3B1突变影响FIR可变剪接促进胰腺癌有氧糖酵解的机制研究

Pre-mRNA的可变剪接在肿瘤发生发展中发挥着重要的作用，探索其分子机制将为肿瘤的防治提供新的思路。剪接因子SF3B1与血液系统肿瘤发生发展密切相关，但在实体肿瘤中的研究极少。我们前期研究发现SF3B1不仅是胰腺癌中突变率最高的剪接因子且与较差的预后相关，还可显著增强胰腺癌细胞增殖、迁移及有氧糖酵解能力；转录组测序发现SF3B1突变后导致FIRΔexon2可变剪接的产生；而FIRΔexon2可变剪接可作为转录因子促进c-myc的转录表达。因此本研究拟验证剪接因子SF3B1突变导致的FIRΔexon2可变剪接是否通过激活了c-myc的转录活性增加了有氧糖酵解关键酶的表达，并最终增强了胰腺癌有氧糖酵解。以期为深入理解胰腺癌发病的分子机制提供实验依据，为胰腺癌临床治疗寻找新的靶点。

Pre-mRNA alternative splicing is a crucial step in tumorigenesis and progression, hence exploring the molecular mechanism may reveals new insights for cancer prevention treatment. Splicing factor SF3B1 has close relation with initiation and development in hematologic malignancies, but there is little study in solid tumors. Our previous research indicated that SF3B1 not only ranked the highest in mutation rate among splicing factor in pancreatic cancer and related to poor prognosis, but also significantly enhanced cell proliferation, migration and aerobic glycolysis. RNA sequencing revealed SF3B1 mutation mediated alternative splicing of FIRΔexon2 which served as transcription factor to promote the expression of c-myc. Therefore, our study intends to investigate if FIRΔexon2 causing by SF3B1 mutations activate the c-myc transcription activity and increase the key enzymes expression to enhance the aerobic glycolysis in pancreatic cancer. We aim to provide experimental evidences for understanding the molecular mechanism of pancreatic cancer and looking for novel therapeutic target for clinical treatment.