DIRAS3通过下调RAC1调控非小细胞肺癌转移的分子机制

DIRAS3, a member of the RAS subfamily of small G proteins, is a candidate tumor suppressor protein in this family. It plays a vital role in cell proliferation, migration, apoptosis and autophagy. However, the molecular mechanism underlying its expression and functions in non-small cell lung cancer remains unclear. Our preliminary results indicated that the overexpression of DIRAS3 inhibited migration and lamellipodia formation of non-small cell lung cancer cells. Besides, DIRAS3 could interact with RAC1 which is a key protein in the lamellipodia formation of cells, and promote its degradation by ubiquitin-proteasome pathway. Furthermore, we discovered RNF19B, which was a potential E3 ubiquitin ligase of RAC1. Based on this, we propose the following hypothesis: DIRAS3 can promote the binding of RAC1 and E3 ligase RNF19B, thus enhancing the degradation of RAC1 by ubiquitin-proteasome pathway and downregulating its expression. Eventually, the ability of cell migration, invasion and metastasis is affected by this axis. Accordingly, the present project is going to use cell and animal models to elucidate the molecular mechanism that DIRAS3 modulates migration of non-small cell lung cancer by inhibiting RAC1. Hopefully, the study can help us understand the metastatic network in non-small cell lung cancer cells. In addition, it will have great biological and clinical significances for developing the novel anti-metastasis drugs for cancer therapy in the future.

小G蛋白RAS亚家族成员DIRAS3是一个潜在的肿瘤抑制蛋白，在调控细胞的增殖、迁移、凋亡和自噬等生物学过程中发挥重要作用，但其在非小细胞肺癌细胞中的表达及调控转移的机制并不清楚。前期数据表明，过表达DIRAS3抑制非小细胞肺癌细胞的迁移和伪足形成；DIRAS3能够与细胞片状伪足形成关键蛋白RAC1结合，并促进其泛素-蛋白酶体途径的降解；并且筛选出RAC1潜在的E3泛素连接酶RNF19B。基于此，我们提出如下假说：在非小细胞肺癌细胞中，DIRAS3可能通过加强RAC1与其E3连接酶RNF19B的结合，促进RAC1泛素-蛋白酶体途径的降解，下调其蛋白水平，最终影响细胞的迁移能力。本研究拟利用细胞和动物模型，深入探讨DIRAS3通过下调RAC1调控非小细胞肺癌转移的分子机制。将有助于加深对非小细胞肺癌转移调控网络的了解，对于将来抗转移药物的研发具有重要的生物学和临床指导意义。

非小细胞肺癌是最常见的肺癌类型，它的高死亡率主要与远端转移相关。小G蛋白DIRAS3是RAS亚家族的肿瘤抑制蛋白，在多种肿瘤组织中表达下调。然而，DIRAS3对非小细胞肺癌转移的调控机制仍不清楚。本项目中我们发现DIRAS3能够抑制非小细胞肺癌细胞迁移,并且其表达水平与肺癌病人恶性进展具有临床相关性。进一步研究发现DIRAS3促进RAC1的泛素化修饰从而下调RAC1蛋白水平。接下来，RBR E3泛素连接酶家族成员RNF19B被发现作为E3连接酶参与DIRAS3对RAC1的泛素化调控。DIRAS3增强RNF19B与其底物RAC1的结合，诱导RAC1泛素-蛋白酶体途径的降解。最后，我们证明DIRAS3-RNF19B-RAC1轴与非小细胞肺癌病人的恶性进展相关。综上，DIRAS3通过促进RNF19B对RAC1的泛素化修饰，下调RAC1蛋白表达，从而抑制非小细胞肺癌细胞迁移。本项目的研究发现可能有助于开发潜在的非小细胞肺癌预后标志物，并提供有效的治疗策略。