环状RNA circ-0000231通过miR-140-3p/Bcl-2信号通路调节自噬介导结肠癌细胞增殖的分子机制研究

Circular RNA recently was reported to play an important role in colon cancer. Our preliminary study identified that circRNA0000231 was a key circular RNA in proliferation of colon cancer cells using circRNA microarray chip and bioinformatics analysis. We also put forward that circRNA0000231 might regulate malignant biological behavior of colon cancer through affecting autophagy by miR-140-3p/Bcl-2 signaling pathway. This present study is planned to evaluate the expression level of circRNA0000231, miR-140-3p and Bcl-2 in primary colon cancer tissues and according adjacent normal colon tissues, exploring the correlation with clinicopathological characteristics and prognosis. In addition, we are also going to investigate the mechanism by which circRNA0000231 inhibits miR-140-3p/Ago2 complex in Bcl-2 down-regulation, to clarify the molecular mechanism by which Bcl-2 expression level and phosphorylation impact colon cancer cell autophagy through Atg12 regulation, and finally to verify the hypothesis above in animal models. The research of circRNA0000231 associated pathways might throw a new light for treatment of colon cancer.

环状RNA在结肠癌分子调控中发挥重要作用。我们前期通过circRNA微阵列芯片、生物信息学等筛选出circRNA0000231为调控结肠癌细胞增殖的关键环状RNA，并可能通过miR-140-3p/Bcl-2通路调控细胞自噬影响结肠癌细胞的恶性表型。本课题拟在人结肠癌组织和血浆中检测circRNA0000231、miR-140-3p、和Bcl-2的表达及与临床病理预后的关系；探索circRNA0000231通过“分子海绵”作用阻遏miR-140-3p/Ago2对Bcl-2 mRNA降解的机制；探讨Bcl-2的表达水平及其磷酸化修饰调控自噬相关蛋白Atg12影响结肠癌细胞自噬进而参与细胞增殖的分子机制；在裸鼠体内验证circRNA0000231调控Bcl-2表达影响自噬的具体机制。旨在阐明circRNA0000231调控结肠癌细胞增殖的作用机制，为结肠癌诊治提供新靶点。

环状RNA在结肠癌分子调控中发挥重要作用。我们前期通过circRNA微阵列芯片、生物信息学等筛选出circRNA0000231为调控结肠癌细胞增殖的关键环状RNA，并可能通过miR-140-3p/Bcl-2通路调控细胞自噬影响结肠癌细胞的恶性表型。本课题进一步研究发现circ_0000231在结直肠癌肿瘤组织中显著高表达，与肿瘤脉管癌栓、T分期、N 分期及AJCC分期相关，肿瘤组织中circ_0000231高表达患者的预后较差；高表达水平的circ_0000231可促进结直肠癌细胞的分裂，提高直肠癌细胞的增殖、侵袭、迁移能力及成瘤能力；circ_0000231通过miR-140-3p/Bcl2通路，与Atg12蛋白相互作用，调节自噬水平，影响结直肠癌细胞的生物学行为；circ_0000231可能成为结直肠早期诊断和分子治疗的潜在标志物与治疗靶点。