lncRNA-uc341在缺氧诱导胃癌转移中的机制研究

It is now becoming clear that the tumour microenvironment (e.g: hypoxia) is an indispensable participant in the cancer metastasis.We initially confirm that hypoxia is a key factor to promote the migration and invasion of gastric cancer cells. However, the mechanism still remains unclear.Long non-coding RNAs (lncRNAs) are a novel class of non-coding transcripts, which are more than 200 nucleotides in length and involved in the regulation of gene expression in various ways.It has been a popular topic in tumor study.Differentially expressed lncRNAs between gastric cancer cells exposed to hypoxia and normoxia; normal human gastric epithelia,primary gastric carcinomas, and distant metastatic tissues and cell lines were identified by microarray . LncRNA-uc341 expression was markedly upregulated in gastric cancer cell lines exposed to hypoxia compared with normoxia and also overexpressed in distant metastatic tissues and cell lines compared with normal's and non- metastatic's by RT-PCR.Here, we demonstrated the role of lncRNA-uc341 in hypoxic metastasis and invasion in gastric cancer.Further bioinformatics analysis and systematic literature review, we identify its location in the chromosomes coincides with the metastases-associated target gene- HOXC10,may play its regulation mechanism by DNA methylation.This project will further explore the mechanism of how lncRNA-uc341 mediate HOXC10 in hypoxia condition by RT-PCR, CHIP, EMSA, DNA methylation techniques.To reveal the mechanisms of lncRNA-uc341-HOXC10 contributes to hypoxia-induced invasion in gastric cancer, and provide a new thinking of reversing tumor metastasis in clinical.

肿瘤特殊微环境在肿瘤转移中发挥重要作用，我们前期证实缺氧是促进胃癌转移的关键因素，但机制尚不清楚。LncRNA是一类长度大于200nt的非编码RNA，可从多个角度调节蛋白编码基因活性，是当前肿瘤研究热点。我们首次用高通量lncRNA芯片进行了缺氧诱导的胃癌细胞以及高转移胃癌组织、细胞中的lncRNA的差异筛选，发现lncRNA-uc341在缺氧诱导以及胃癌高转移的组织和细胞中均上调。功能学实验证实了其在缺氧诱导胃癌细胞转移中发挥重要作用。进一步的生物信息学分析以及文献回顾发现其定位于转移相关靶基因HOXC10附近，可能通过甲基化作用发挥其调控机制的。本项目拟借助RT-PCR,CHIP，EMSA、启动子甲基化等技术进一步探讨缺氧条件下其对HOXC10的转录调控机制，以揭示lncRNA-uc341-HOXC10在缺氧诱导胃癌转移中的作用机制，为临床阻断转移提供新思路。

缺氧在胃癌转移过程中发挥着重要作用，但是其中的机制尚未完全阐明。而lncRNAs是否参与了缺氧对胃癌转移的作用过程也不得而知。在本项研究中，我们发现缺氧可以诱导胃癌细胞中lncRNA-uc341的表达，并且证实lncRNA-uc341介导了缺氧诱导的胃癌细胞转移。此外，lncRNA-uc341在胃癌组织中常常表达上调，上调的lncRNA-uc341与患者的肿瘤淋巴结转移相关。高表达lncRNA-uc341的胃癌患者相比低表达lncRNA-uc341的胃癌患者具有更差的预后。我们发现，转移相关基因HOXC10受到lncRNA-uc341的调控，在检测的临床样本中HOXC10的表达与lncRNA-uc341的表达正相关。有趣的是，缺氧条件下HOXC10表达也出现上升，而lncRNA-uc341上调HOXC10表达导致缺氧诱导的胃癌细胞转移。这些结果进一步深化了对lncRNA-uc341在调节缺氧信号途径中的作用，并有可能为开发针对肿瘤转移的治疗策略提供新的途径。