血管内皮sohlh2/sirt1/NFκB信号通路对三阴性乳腺癌细胞肺转移的调控

Lung metastasis is the major cause of death in patients with triple negative breast cancer (TNBC). The molecular mechanism of TNBC metastasis is very complicated. Blocking the vascular endothelial dysfunction caused by circulating breast cancer cells may be a new way of antimetastatic therapy of TNBC. Sohlh2 is a novel tumor suppressor. The preliminary results of in vitro experiments showed that sohlh2 overexpression in endothelial cells could not only inhibit vascular endothelial senescence and inflammatory response induced by TNBC cells, but also significantly reduce TNBC cells adhesion to the vascular endothelium and trans-endothelial migration. Sohlh2 may play a role by up-regulating Sirt1 expression and inhibiting the activation of NFκB signaling pathway. On the basis of the previous studies, the co-culture system of TNBC cells/vascular endothelial cells , conditional sohlh2 knock-in mice, sohlh2 / Sirt1 - / - mice and TNBC lung metastasis model will be used to detect the roles of sohlh2 / Sirt1 / NFκB signaling pathway in TNBC lung metastasis in vivo and in vitro. This study not only helps to elucidate the molecular mechanism of TNBC lung metastasis, but also provide new ideas and targets for TNBC metastatic therapy.

三阴性乳腺癌（TNBC）肺转移是临床致死的主要因素，其发生机制非常复杂。阻断血循环中乳腺癌细胞所致的血管内皮功能障碍，可能是TNBC转移治疗的新途径。Sohlh2是一个新的抑癌基因。前期体外实验结果显示，血管内皮sohlh2过表达可抑制TNBC细胞诱导的血管内皮衰老和炎症反应，也可明显减弱TNBC细胞粘附于血管内皮和跨内皮迁移。Sohlh2可能通过上调Sirt1表达，抑制NFκB信号通路激活，从而发挥作用。在前期研究基础上，本项目将利用TNBC细胞/血管内皮细胞共培养体系、血管内皮sohlh2条件性敲入小鼠、sohlh2/Sirt1-/-小鼠和TNBC肺转移模型，在体和体外检测血管内皮sohlh2/Sirt1/NFκB信号通路在TNBC肺转移中的调控作用。本研究不仅有助于阐明TNBC肺转移的分子调控机制，而且可为TNBC转移治疗提供新思路和新靶点。

三阴性乳腺癌（TNBC）是恶性程度最高的乳腺癌亚型，易发生远处转移。深入研究血管内皮基因对TNBC肺转移的调控机制，有助于为早期预防和治疗TNBC转移提供新思路和潜在的分子靶标。利用血管内皮特异性Sohlh2基因敲入小鼠、TNBC肺转移模型和TNBC/血管内皮细胞共培养体系，在体和体外研究结果证实了,过表达Sohlh2可通过减弱TNBC细胞粘附和跨内皮迁移、并阻断TNBC细胞诱导的血管内皮细胞衰老、通透性改变和炎症反应，进而抑制TNBC细胞肺转移。Sirt1是Sohlh2直接作用的靶基因，Sirt1介导 Sohlh2抑制血管内皮细胞NFκB信号通路激活和TNBC肺转移的作用。本研究揭示了血管内皮Sohlh2抑制TNBC肺转移的作用机制，提示Sohlh2及其靶基因Sirt1有潜力成为治疗TNBC转移的新靶点。