circ-DONSON/miR-129-5p/MCM8轴通过DNMT3B介导的DNA甲基化调控胃癌细胞增殖及凋亡的机制研究

胃癌恶性程度高、进展快，细胞增殖及凋亡失控是主要原因之一。环状RNA在其中发挥重要作用并可能成为潜在靶点。我们已报道circ-DONSON在胃癌中表达明显升高并具有显著的促增殖、抑凋亡功能，但机制尚未阐明。本项目前期发现：circ-DONSON可通过竞争性结合miR-129-5p调控靶基因MCM8，发挥促癌作用；并且MCM8可与DNA甲基转移酶DNMT3B结合来调节多个抑癌基因表达。据此我们提出假说：circ-DONSON可竞争性结合miR-129-5p调控靶基因MCM8，而MCM8可通过调节DNMT3B，介导多个抑癌基因DNA甲基化，促进胃癌细胞增殖、抑制细胞凋亡，导致胃癌进展。本项目拟从分子、细胞、动物和临床角度证明circ-DONSON/miR-129-5p/MCM8信号轴通过调节DNMT3B介导的DNA甲基化促进胃癌进展的机制及临床意义。本研究将为开发胃癌治疗新靶点提供理论依据。

Gastric cancer (GC) is a high malignancy with rapid progression. Lose control of cell proliferation and apoptosis is one of the main causes of GC fast progression. Circular RNAs (circRNAs) have important functions in this process, and may become potential therapeutic targets. We have reported that circ-DONSON is highly expressed in GC cells as well as in GC tissues, and facilitates GC progression by accelerating cell proliferation and inhibiting cell apoptosis. However, the underlying molecular mechanisms are still not clear. Our pilot experiments found that circ-DONSON, acting as competing endogenous RNAs (ceRNAs), could sponge miR-129-5p to regulate its target gene MCM8 in facilitating GC progression. Moreover, the preliminary data showed that MCM8 could interact with DNMT3B, which is a key DNA methyltransferase in GC. DNMT3B could induce DNA methylation of several tumor-suppressor genes (TSGs) to regulate the expression of these genes. Therefore, we hypothesize that circ-DONSON could regulate MCM8 through competive sponging miR-129-5p. Furthermore, MCM8 could promote GC progression by accelerating cell proliferation and inhibiting cell apoptosis through regulation of DNMT3B, which could induce DNA methylation of correlated TSGs. This study is intended to test and verify the hypothesis from the perspective of molecule, cell, animal and clinic by multiple advanced techniques. We aim to demonstrate the regulation mechanisms and clinical value of circ-DONSON/miR-129-5p/MCM8 signaling pathway in modulation of DNMT3B, which promotes GC progression through DNA methylation of correlated TSGs. This project will provide new theoretical foundation for developing novel therapeutic targets in the treatment of GC.