长非编码RNA RP11-138J23.1竞争性吸附miR-16促进胃癌增殖转移的机制研究

Gastric cancer is one of the common malignant tumor of human. The crucial reason for high mortality is sustained proliferation and the tumor’s metastatic potential. Increasing evidence has suggested that lncRNAs contribute to cancer development and progression, which is a hot research topic areas. In our previous study, we analyzed the lncRNAs profiling in gastric cancer through TCGA and CEO database and found that the lncRNA RP11-138J23.1 is significantly upregulated in gastric cancer. Furthermore, we evaluated the correlation of RP11-138J23.1 expression with clinicopathological parameters (i.e. lymphatic metastasis, infiltration depth) to assess its clinical significance. Our results showed that larger tumors, with lymph node metastasis, had higher RP11-138J23.1 expression levels. Loss of function analysis was demonstrated that RP11-138J23.1 knockdown could have effect on proliferation, apoptosis, cell cycle and metastasis. Bioinformatics analysis and luciferase identified that RP11-138J23.1 could directly bind with miR-16. Earlier experiments have demonstrated that COX-2 is the potential underlying target gene of miR-16, and knockdown of RP11-138J23.1 suppress the expression of COX-2. Therefore, we suppose that RP11-138J23.1 up-regulation could derepression COX-2 expression via sponge of miR-16, thereby promoting gastric carcinoma proliferation and metastasis. We will identify the aboved hypothesis through rescue study, luciferase study, and other techniques. This study will clarify the crucial role of RP11-138J23.1/miR-16/COX-2 regulation network in gastric carcinoma and enrich the molecular mechanism of gastric carcinoma proliferation and metastasis.

胃癌是人类常见的恶性肿瘤之一，其局部增殖及远处转移是预后差的重要因素。LncRNA与众多肿瘤发生发展密切相关，是目前研究的热点。我们前期分析TCGA和GEO中胃癌表达差异的lncRNA，发现RP11-138J23.1在胃癌组织中上调，临床标本验证表明其表达与浸润深度、淋巴结转移相关。干扰其表达后可影响胃癌细胞增殖、凋亡、周期、转移及裸鼠皮下瘤大小。生物信息学及荧光素酶实验表明RP11-138J23.1与miR-16直接结合。干扰RP11-138J23.1后miR-16靶基因COX-2表达下调。故推测：在胃癌中RP11-138J23.1表达增加，可能通过竞争性吸附miR-16发挥ceRNA活性拮抗COX-2的抑制，促进胃癌细胞增殖转移。本课题拟采用拯救实验、荧光素酶等方法验证上述假设，阐明RP11-138J23.1/miR-16/COX-2在胃癌增殖转移中的作用，为胃癌转移提供新的理论依据。

胃癌（GC）是我国及世界上威胁人类健康的恶性肿瘤之一，GC细胞的局部增殖和远处转移是导致 GC患者预后差和治疗失败的重要因素。研究发现长非编码RNA可影响GC细胞增殖侵袭转移能力，但其调控分子机制研究尚少。课题组通过生物信息学分析及qRT-PCR技术检测发现在GC组织中RP11-138J23.1表达升高，且表达水平与患者肿瘤大小、淋巴结转移及TNM分期密切相关。同时，在GC细胞中改变RP11-138J23.1表达水平后发现，敲低RP11-138J23.1表达可抑制GC细胞增殖，降低迁移侵袭能力。机制研究表明，RP11-138J23.1通过结合HuR蛋白转录后水平调控靶基因VAV3的表达，从而促进胃癌细胞增殖、迁移侵袭能力。动物实验证实，敲低RP11-138J23.1表达后抑制GC肿瘤形成。本研究丰富了长非编码RNA与GC分子调控机制，揭示了长非编码RNA在GC增殖转移中的作用，为GC发生发展提供了新理论基础，为临床诊治提供了新思路。