环状RNA circTNK2as通过靶向调节TNK2而活化雄激素受体及促进前列腺癌发展

CircularRNA (circRNA) plays an important role in development of disease by interacting with miRNA. Previously, we have observed that the expression of circRNA circTNK2as and its parent gene TNK2 in prostate cancer tissues was significantly higher than adjacent tissues and benign prostatic hyperplasia.TNK2 is a direct target of miR-138 gene by bioinformatics analysis and experiments in vitro. Besides, we have found that circTNK2as has multiple binding sites with miR-138 by bioinformatics analysis. Based on these findings, we hypothesized that circTNK2as works as antisense RNA，by directly combining with TNK2，playing the role of stabling mRNA. On the other hand, circTNK2as works as miRNA sponges, by combined with miR-138，relieving the repression of TNK2 expression. Up-regulated-TNK2 stimulates the phosphorylation of AR, then contributes to the development of prostate cancer. In this research, We will study the mechanism of circTNK2as activating AR signaling pathways by targeting TNK2, and explore the prevention and treatment of prostate cancer.

环状RNA(circRNA)通过与miRNA相互作用在疾病发生发展中起着重要的调控作用。我们前期实验发现，环状RNA circTNK2as及其亲本基因TNK2在前列腺癌组织中的表达显著高于癌旁组织和前列腺增生组织。生物信息学分析显示，circTNK2as存在多个与miR-138种子序列结合的位点。体外实验证实TNK2是miR-138直接靶基因。我们推测，作为反义RNA的circTNK2as可能直接与TNK2的mRNA结合，发挥稳定mRNA的作用；另一方面，circTNK2as起到miRNA海绵作用，吸附miR-138使其不能与TNK2结合，从而解除对TNK2表达的阻抑。上调的TNK2活化AR信号途径，进而促进前列腺癌的发生发展。本项目对circTNK2as靶向调节TNK2进而活化AR信号途径的作用及机制进行研究，为揭示circRNA在前列腺癌发生发展中的作用机制及前列腺癌防治提供实验依据。

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circAMOTL1LmiR-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。