环状RNA circAMOTL1as与KLF4形成反馈环路共同参与血管重塑过程

Interacting with miRNAs or proteins, circularRNA(circRNA) plays an important role in many diseases. We found that the expression of circAMOTL1as in vessels significantly higher than in other tissues. However, its expression was significantly down-regulated after femoral artery injury. Bioinformatics analysis revealed that circAMOTL1as has multiple binding sites with miR-103/107 seed sequence. Expression of miR-103/107 were significantly increased in injured vessels. But the expression of KLF4, the target of miR-103/107, was significantly down-regulated. Furthermore, bioinformatics analysis shown that there are a plurality of KLF4 binding sites in AMOTL1 promoter. Together, we hypothesized that the expression of circAMOTL1as will be down-regulated after intimal injury, then release the adsorbed miR-103/107, thereby inhibit the expression of KLF4 and promote the proliferation and migration of VSMC. Meanwhile, the down-regulated KLF4 reduces transcription of circAMOTL1as, which forms a feedback loop. In this research, we will study the mechanism of circAMOTL1as in vascular remodeling and explore the prevention and treatment of vascular remodeling diseases.

环状RNA(circRNA)通过与miRNA或蛋白质相互作用在疾病中发挥着重要调控作用。我们前期实验发现，环状RNA circAMOTL1as在血管中的表达显著高于其它组织，而在股动脉内膜损伤后的表达显著下降。生物信息学分析显示，circAMOTL1as存在多个与miR-103/107种子序列结合的位点。miR-103/107在损伤的血管组织中均上调，而其靶基因KLF4的表达显著下降。分析发现，AMOTL1基因启动子上存在多个KLF4结合的位点。我们猜测，在血管内膜损伤后，作为海绵体的circAMOTL1as表达下调，释放出所吸附的miR-103/107，进而抑制KLF4表达，促进VSMC的增殖迁移；下调的KLF4同时降低circAMOTL1as基因的转录水平，它们之间形成反馈调节。本项目将对circAMOTL1as在血管重塑过程中的作用及机制进行研究，为防治血管重塑性疾病提供实验依据。

p53，circRNA和miRNA是激活癌症转移及上皮-间质转化程序调控网络的重要组成部分。然而，在疾病如前列腺癌（PCa）中，circRNA和miRNA如何通过p53调节EMT尚不清楚。本研究我们发现，人类PCa中Amotl1衍生的circRNA，即circAMOTL1L，被下调，而减少的circAMOTL1L通过下调E-钙黏着蛋白和上调波形蛋白促进PCa细胞迁移和侵袭，从而导致EMT和PCa进展。机制上，我们证明PCa细胞中circAMOTL1L充当miR-193a-5p的海绵，减轻了miR-193a-5p靶向抑制Pcdha基因簇。因此，由circAMOTL1L下调介导的circAMOTL1L-miR-193a-5p-Pcdha8调节途径的失调有促进体内PCa的进展。此外，我们表明RBM25直接结合到circAMOTL1L并诱导其生物合成，而p53通过RBM25基因的直接激活来调节EMT。这些发现表明p53 / RBM25介导的circAMOTL1L-miR-193a-5p-Pcdha调节轴与PCa转移进展中的EMT相关联。针对这个调节轴可能为PCa提供了潜在的治疗策略。