胰岛素剪接异构体IR-A/IR-B失衡通过COX-1调控花生四烯酸代谢促进乳腺癌发生发展的机制研究

高胰岛素血症、胰岛素抵抗状态等代谢失调是乳腺癌的显著危险因素，但调控机制尚不清楚。胰岛素受体存在IR-A和IR-B两种剪接异构体，课题组前期研究证实，IR-A/IR-B的比值在乳腺肿瘤组织和细胞中明显高于正常组织，并促进肿瘤的增殖、侵袭和转移；进一步构建IR-B敲除、促使IR-A/IR-B显著失衡的细胞系，可显著增强肿瘤细胞的恶性生物学行为。代谢组学和转录组学分析结果显示IR-A/IR-B失衡促进花生四烯酸等多不饱和脂肪酸的生成，并上调花生四烯酸代谢关键酶COX-1的表达。这一发现高度提示IR-A/IR-B失衡可能通过调控COX-1介导的花生四烯酸代谢通路促进乳腺癌的发生发展。本项目拟进一步通过不同分子亚型乳腺癌细胞系、临床组织样本结合乳腺组织特异性的基因敲除小鼠模型，在体外实验和体内水平解析IR-A/IR-B失衡在乳腺癌发生发展的功能和机制，为乳腺癌的早期诊断和治疗提供新的思路。

Hyperinsulinemia and insulin resistance are significant risk factors for breast cancer, but the mechanism is still unclear. The insulin receptor has two splicing isoforms IR-A and IR-B. Our previous research confirmed that the ratio of IR-A / IR-B in breast tumor tissues and cells is significantly higher than that in normal tissues, and promotes tumor proliferation, invasion and metastasis; we further construct IR-B knockout cell lines which has significant imbalance ratio of IR-A / IR-B and found the increasing cancer-promoting effect of cells. Metabolomics and transcriptomics analysis results showed that IR-A / IR-B imbalance promoted the production of polyunsaturated fatty acids such as arachidonic acid and up-regulated the expression of COX-1, a key enzyme in arachidonic acid metabolism. This finding highly suggests that IR-A / IR-B imbalance may promote the development of breast cancer by regulating COX-1 mediated arachidonic acid metabolism pathway. Our study intends to further analyze the function and mechanism of IR-A / IR-B imbalance in vitro experiments and in vivo levels through cancer cells and clinical tissue samples combined with breast tissue-specific gene knockout mouse models, which will provide new ideas for early diagnosis and treatment of breast cancer.