长非编码RNA LINC00675稳定p53蛋白的分子机制及其在胃癌增殖中的作用研究

LncRNA plays a crucial role in the proliferation of tumor cells. Our previous study showed that LINC00675 expression was decreased in gastric cancer (GC) tissues and associated with the poor prognosis of patients with GC. Ectopic expression of LINC00675 markedly suppressed the proliferation of gastric cancer cells, but the molecular mechanism remains unclear. Our results via mRNA microarray and qRT-PCR assay revealed that LINC00675 significantly activated p53 pathway signaling and increased the expression of p53’s downstream genes (p21, PAI-1, MDM2 etc.). Rescue experiments showed that LINC00675 exerted its bio-function through regulating p53 protein rather than p53 mRNA. Numerous evidences indicated that MDM2’s main role is that induces p53 negative feedback regulation, but our results showed that MDM2 can’t induce p53 degradation in gastric cancer cells when the LINC00675 expression was overexpressed. Base on the literatures and our previous evidences, we presume that “LINC00675 can interact with p53, MDM2 or their complex, and further inhibits MDM2-induced p53 degradation, followed by increases the expressions of p53’ downstream genes, and finally suppresses the proliferation of GC cells”. Our study will focus on the mechanism by which LINC00675 inhibits MDM2-induced p53 negative feedback regulation, and further expound the molecular mechanism how LINC00675 stabilizes p53 protein. Well understanding of the mechanism will be benefit for searching novel biomarkers and exploring novel therapeutic drugs for GCs.

长链非编码RNA (lncRNA)在肿瘤的增殖中发挥重要作用，课题组前期发现LINC00675在胃癌组织中低表达且与胃癌大小呈负相关，过表达LINC00675显著抑制了胃癌细胞的增殖，但机制不清。mRNA芯片及qRT-PCR结果显示过表达LINC00675显著活化了p53信号通路及p53下游靶基因的表达(p21, PAI-1, MDM2等)；回复实验明确LINC00675主要通过调节p53蛋白(非mRNA)水平发挥其生物学功能。文献证实，MDM2主要介导p53负反馈调节机制，而课题组前期的研究发现LINC00675可能阻断了该机制。基于文献及预实验结果，课题组推测“LINC00675可能与p53蛋白、MDM2或其复合物等发生相互作用，阻断MDM2介导 p53蛋白的泛素化，进而抑制胃癌细胞的增殖”。本课题拟阐明LINC00675稳定p53蛋白的分子机制，为胃癌生物标志及治疗靶点提供新的依据。

长链非编码RNA (lncRNA)在肿瘤的增殖中发挥重要作用，在课题组前期发现INC00675在胃癌组织中低表达且与胃癌大小呈负相关，过表达LINC00675显著抑制了胃癌细胞增殖的基础上。通过mRNA芯片、qRT-PCR等技术手段，发现到LINC00675与p53蛋白、MDM2或其复合物等发生相互作用，阻断MDM2介导 p53蛋白的泛素化，进而抑制胃癌细胞的增殖。初步阐明了LINC00675抑制胃癌的分子机制，为胃癌生物标志及治疗靶点提供新的依据。