缺氧诱导的HIF-1α/lncRNA NONHSAT077116正反馈信号通路ceRNA竞争性结合方式促进胃癌细胞增殖转移的机制研究

Hypoxia is the important microenvironment for cancer development. But the underlying mechanism is not clear. Our study will investigate the role and mechanism of hypoxia-inducible lncRNA in gastric cancer. Our previous results showed that the expression of NONHSAT0771162 is up-regulated under hypoxia in gastric cancer cells with lncRNA CHIP analysis. Moreover, it could promote the cell growth, invasion and migration of gastric cancer cells. Meanwhile, we found high level of NONHSAT077116 might inhibit HIF-1α degradation by increasing its stability, and there may exist a positive feedback regulation between them. Moreover, there’re two binding sites of miR-149 in the NONHSAT077116 sequence, and miR-149 is as an important tumor suppressor. Thus we suspect hypoxia-induced NONHSAT077116 may act as a competitive ceRNA of miR-149, promoting gastric cancer cell proliferation and metastasis via upregulating miR-149 target gene FOXM1. Clarifying this hypothesis will be helpful in our understanding the molecular mechanism of hypoxia-induced gastric cancer development, and provide novel clues for the diagnosis and treatment of gastric cancer.

缺氧是肿瘤发生发展的重要微环境，但其加剧肿瘤发生发展的具体机制还不清楚。本项目从长链非编码RNA（lncRNA）角度探寻缺氧诱导胃癌发生发展的作用及分子机制。我们在前期研究工作中通过lncRNA芯片方法筛选到NONHSAT077116在缺氧诱导的胃癌细胞中呈高表达，功能研究发现其明显促进胃癌细胞的生长，迁移和侵袭。同时我们还发现，高表达的NONHSAT077116可能通过增加HIF-1α蛋白稳定性的方式抑制其降解，二者之间可能形成一种正反馈调节。另外，NONHSAT077116序列上包含了两个miR-149的结合位点，而miR-149在胃癌中发挥着重要的抑癌基因作用。因此我们推测，缺氧诱导的NONHSAT077116可能作为ceRNA竞争性结合miR-149，通过上调miR-149靶基因FOXM1表达从而发挥促进胃癌增殖和转移的作用，阐明这一假说将有助于深入理解缺氧加剧胃癌发生发展的分子。

缺氧是肿瘤发生发展的重要微环境，但其加剧肿瘤发生发展的具体机制还不清楚。我们在前期研究工作中通过基因芯片方法筛选到lncRNA NONHSAT077116在缺氧诱导的胃癌细胞中高表达，并明显促进胃癌细胞的生长，迁移和侵袭，同时我们猜测NONHSAT077116可能与HIF-1α形成正反馈调节。本项目主要研究NONHSAT077116与HIF-1α之间是否存在正反馈调节作用，以及NONHSAT077116是否通过竞争性结合miR-149从而上调其靶基因FOXM1表达，最终促进胃癌增殖和转移。我们发现，NONHSAT077116并不能直接抑制HIF-1α的泛素化，其可能通过间接作用提高HIF-1α蛋白的稳定性。同时，我们发现低氧相关的miR-148/152家族能够通过负向调节ITGA5抑制胃癌干细胞的成球能力、侵袭能力和干性基因表达。上述结果将有助于深入理解缺氧加剧胃癌发生发展的分子机制，为胃癌的诊断和治疗提供新的线索。