LncRNA-uc002kmd.1促进胃癌发生发展的作用及其调控机制

Gastric cancer is a very common cancer with a high mortality and incidence rate. Recently, the role of long non coding (lnc) RNAs in human cancers has drawn much attention. LncRNAs have been reported being involved with the development of several cancers, such as breast cancer and hepatocellular carcinoma, however, there are few studies of gastrointestinal cancer related lncRNAs. In our previous research, we found that lncRNA-uc002kmd.1 was overexpressed in human gastric cancer. Downregulation of uc002kmd.1 significantly increased the expression of p53 and its downstream target genes, and inhibited cell proliferation, induced cell apoptosis and cell-cycle arrest. Overexpression of p53 enhence the level of uc002kmd.1. Based on our preliminary datas, we will reveal the mechanism of uc002kmd.1 regulates the development of gastric cancer through p53-Bax/p21 pathways, and demonstrate the mechanism by which uc002kmd.1 interacts with p53, discuss the significance of uc002kmd.1 in clinical diagnosis. In a word, we will explore the mechanism by which uc002kmd.1 interacts with p53 and promotes the development of gastric cancer through p53-Bax/p21 pathways via in vitro, in vivo experiments and patient samples.

胃癌的发生率和死亡率居高不下。近年来，长链非编码（long non coding，lnc）RNA在人类肿瘤中的作用逐渐被关注，其与乳腺癌和肝癌等多种肿瘤发生有关，但在胃癌发生发展中的作用及其机制未明。我们的前期研究发现 lncRNA-uc002kmd.1在胃癌组织中高表达。敲低uc002kmd.1可上调p53及其下游靶基因，显著抑制胃癌细胞增殖及诱导凋亡和周期阻滞；而过表达p53则可上调uc002kmd.1。在此基础上，本研究拟探讨uc002kmd.1通过调控p53-Bax/p21通路影响胃癌发生发展的确切方式；进一步阐明p53与uc002kmd.1相互作用形成反馈环路对胃癌发生发展的影响；分析uc002kmd.1作为临床诊断新靶点的意义。从细胞实验、临床标本和动物学实验等方面探讨uc002kmd.1与p53相互作用影响p53-Bax/p21通路从而促进胃癌发生发展的作用及其机制。

近年来，长链非编码（long non coding，lnc）RNA在人类肿瘤中的作用逐渐被关注，其与乳腺癌和肝癌等多种肿瘤发生有关，但在胃癌发生发展中的作用及其机制未明。在此项研究中，我们通过高通量的芯片检测及原位杂交技术，首次筛选出在胃癌组织中显著高表达的长度为924bp的lncRNA-uc002kmd.1，并证明其可作为区分胃癌的标志物，将其命名为GAPLINC。GAPLINC促进胃癌细胞侵袭和增殖。GAPLINC促进CD44表达，且GAPLINC促进细胞侵袭的能力可以被CD44 siRNA削弱。进一步研究其中机制，我们发现GAPLINC可通过miR-211-3p影响CD44的表达。miR-211-3p可同时与GAPLINC和CD44结合。运用原位杂交技术，在90对胃癌病人的癌组织及对应癌旁组织中检测GAPLINC表达，结果显示GAPLINC高表达的胃癌病人生存期明显缩短。此研究首次证明了原癌基因CD44的一条非编码调控通路，为胃癌细胞侵袭机制的研究提供了新的思路和方向。