LncRNA-KRT18P55上调CDK1促进胃癌细胞增殖侵袭的作用机制研究

Gastric cancer is one of the most common carcinomas in China and it is urgent and important to explore the mechanism of tumorigenesis and progression of gastric cancer. In our previous investigation, we have indicated lncRNA-KRT18P55 is significantly upregulated in gastric cancer, and its expression level is associated with Lauren intestinal gastric cancer. However, the mechanism of KRT18P55 involved in gastric cancer remained unclear. Based on the results of subsequent experiments, we have found that the expression levels of KRT18P55, miR-22-5p and CDK1 presented correlations and might conduct network to regulate the progression of gastric cancer. In addition, our findings also demonstrated that c-Myc had binding site with KRT18P55 and upregulated c-Myc promoted the expression of KRT18P55. Based on aforementioned foundation, we aimed to further explore and verify the upsteam and downsteam regulatory mechanism of KRT18P55 in gastric cancer: KRT18P55 acted as ceRNA to regulate CDK1 expression by sponging miR-22-5p, and c-Myc mediated the transcription of KRT18P55 by binding to the promoter sequences directly. Our findings might provide new targets and evidence for gastric cancer therapy in clinical practice.

胃癌是我国常见的恶性肿瘤之一，阐明胃癌发生发展的分子机制进而指导临床治疗，在我国具有特殊的重要性和迫切性。申请人在前期工作中已证实lncRNA-KRT18P55在胃癌中显著过表达，且其表达水平与患者胃癌Lauren肠型发生相关。然而，KRT18P55参与到胃癌发生发展的分子机制尚不清楚。基于前期工作基础发现：KRT18P55、miR-22-5p及CDK1表达具有相关性，三者可能构成ceRNA网络调控胃癌的发生发展。此外，我们发现c-Myc与KRT18P55启动子序列有潜在的结合位点并具有表达的相关性。在此基础上，本项目拟深入探讨KRT18P55参与到胃癌发生发展中的具体上游及下游机制，验证KRT18P55竞争性结合miR-22-5p调节CDK1的表达进而影响胃癌增殖侵袭，同时证明c-Myc与KRT18P55的启动子序列直接结合促进其转录。本项目将为胃癌的诊治提供新的靶点及理论依据。

胃癌是我国常见的恶性肿瘤之一，阐明胃癌发生发展的分子机制进而指导临床治疗，在我国具有特殊的重要性和迫切性。申请人研究发现lncRNA-KRT18P55在胃癌中显著过表达，且其表达水平与患者胃癌Lauren肠型发生相关。同时，敲低KRT18P55的表达，显著抑制胃癌细胞的侵袭转移、增殖。体内动物实验发现，敲低KRT18P55抑制小鼠内体成瘤的速度和体积。在进一步探索KRT18P55参与胃癌发生发展的具体分子机制，我们发现：KRT18P55、miR-22-5p及CDK1表达具有相关性，三者构成ceRNA网络调控胃癌的发生发展。此外，我们发现c-Myc与KRT18P55启动子序列有潜在的结合位点并具有表达的相关性。基于多角度的实验设计，最终证实KRT18P55通过竞争性结合miR-22-5p调节CDK1的表达进而影响胃癌增殖侵袭。同时，c-Myc与KRT18P55的启动子序列直接结合促进其转录。厘清了c-Myc/KRT18P55/CDK1调控胃癌细胞发挥恶性肿瘤生物行为的机制轴，为胃癌的诊治提供新的靶点及理论依据。研究期间，发表相关SCI论文9篇，申请发明专利2项，协助培养硕士研究生2人。