ULK1调控Exo70亚型转换抑制乳腺癌EMT发生机制研究

Breast cancer is the leading cause of cancer-related death in women, with significant local invasion and distant metastasis. ULK1, an autophagy-related gene, has the potential value of tumor diagnosis and targeted therapy. ULK1 and breast cancer invasion and metastasis were negatively correlated, but the mechanism is unclear. Exo70，as an important subunit of exocyst, promote tumor invasion and metastasis and has important clinical significance. ESRP1 is the factor controlling the E/M subtypes transformation of Exo70. Our previous study found that ULK1 inhibits breast cancer EMT and invasion. ULK1 regulates Exo70 isoform switching and the expression of its cleaved sub-ESRP1. Therefore, based on these results, we will provide a comprehensive and systematic mechanism by which ULK1 inhibits breast cancer EMT through the regulation of ESRP1 / Exo70 subtypes, including how ULK1 regulates ESRP1 expression and how Exo70 subtypes regulate breast cancer cell EMT. The in vivo mechanism of ULK1 inhibiting the EMT of breast cancer through the ESRP1-Exo70 axis was studied using a nude mouse model of lung metastasis of breast cancer. Clinical diagnosis and prognostic value of Ulk1, Esrp1 And Exo70 will be studied in different subtypes of breast cancer (including luminal a, luminal b, basal-like and erbb2 +) by testing breast cancer specimens. The research will help to reveal a new mechanism of invasion and metastasis of breast cancer and provide a new target and approach for the reversal treatment of breast cancer signal transduction, which can help solve the problem of breast cancer heterogeneity and promote individualized treatment.

乳腺癌是女性癌症相关死亡的首要原因，有明显的局部侵袭和远处转移的能力。自噬相关基因ULK1与乳腺癌的转移和生存呈负相关，但机制不清。剪切子ESRP1介导的胞外分泌体亚基Exo70亚型转换在乳腺癌EMT及转移过程中发挥重要调节作用。我们前期发现ULK1抑制乳腺癌EMT和侵袭，且ULK1调控了ESRP1的表达和Exo70的亚型转换。因此，本课题将从分子、细胞和动物水平全面系统地探讨ULK1通过调控ESRP1/Exo70亚型转换抑制乳腺癌EMT的体内外作用及机制，探索ULK1对ESRP1的调控机制，明确Exo70亚型转换调控EMT的机制；临床研究ULK1、ESRP1和Exo70在不同亚型乳腺癌临床标本的表达相关性以及诊断和预后价值。研究成果有助于揭示乳腺癌侵袭转移的新机制，为乳腺癌信号传导逆转治疗提供新的靶点和途径，有助于解决乳腺癌异质性的问题而促进个体化治疗。

自噬相关基因ULK1与乳腺癌侵袭转移和生存呈负相关，但机制不清。Exo70促进肿瘤的侵袭转移且具有重要的临床意义。本项目首次发现乳腺癌组织的ULK1、ESRP1和Exo70细胞核内表达显著低于正常组织的细胞核内表达，癌组织的Exo70细胞质表达显著高于正常组织的Exo70细胞质内表达。Exo70乳腺癌组织的细胞核内表达水平与OS及DFS呈统计学意义的负相关。ULK1抑制乳腺癌细胞的侵袭能力并抑制乳腺癌细胞EMT的发生，Exo70-M型和Exo70-E型在乳腺癌细胞的侵袭发挥了不同的作用，是Exo70-M, 而不是 Exo70-E促进了乳腺癌细胞的侵袭转移。ESRP1介导Exo70在乳腺癌EMT过程中的亚型转换，ULK1调控乳腺癌细胞ESRP1的表达和Exo70亚型的转换。课题证明了ULK1通过调控ESRP1表达介导Exo70亚型转换，从而抑制乳腺癌EMT的作用和分子机制。ULK1/ESRP1/Exo70作为乳腺癌侵袭转移的新机制新通路，对于乳腺癌的分子诊断评估和治疗提供新的理论依据，从而达到治疗及预防乳腺癌复发的目的。