LncRNA调控肝癌细胞衰老的新机制：LINC-PINT翻译多肽封闭FOXM1的DNA结合域抑制其转录调控功能

肝癌细胞衰老逃逸是促进肿瘤进展的重要因素，转录因子FOXM1活性增强是介导细胞衰老逃逸的关键环节。LINC-PINT是项目组前期发现的参与调控肝癌细胞衰老的lncRNA，并可能影响FOXM1功能，但其机制不清楚。项目组最近发现，LINC-PINT具有翻译多肽的新功能，该多肽可能与FOXM1蛋白DNA结合域结合。我们猜测，LINC-PINT翻译的多肽通过抑制FOXM1转录活性进而发挥促进肝癌细胞衰老的作用。基于此，本项目拟：①探讨衰老状态对LINC-PINT翻译多肽（PINT87aa）能力的影响，以及PINT87aa促进肝癌细胞衰老的功能；②基于结构生物学技术验证多肽PINT87aa与FOXM1蛋白DNA结合域的亲和性；③构建含PINT87aa结构的重组穿膜融合多肽，并评估其抗肝癌效果。本项目从功能验证、结构解析、药物开发三个层次展开，其成果将丰富人们对非编码RNA翻译多肽这一新机制的认识。

The escape of cellular senescence is a key characteristic of hepatocellular carcinoma (HCC) cells. The enhanced transcriptional activity of FOXM1 is found to mediate the escape of cellular senescence of HCC cells. We previously found that LINC-PINT was a lncRNA involving in the regulation of HCC cell senescence and might affect FOXM1 transcriptional activity. However, the detailed mechanism is still unclear. We recently discovered that LINC-PINT had a novel function of translating a polypeptide which may bind to the FOXM1 protein DNA binding domain. We hypothesized that LINC-PINT inhibited the transcriptional activity of FOXM1 by translating peptides and enclosing FOXM1 DNA binding domain. Based on above hypothesis, we aim to: 1) explore the impact of cellular senescent status on the ability of LINC-PINT translation peptide (PINT87aa), and the function of PINT87aa on induction of cellular senescence; 2) verify the binding of peptide PINT87aa and FOXM1 protein DNA binding domain by employing structural biology techniques; 3) construct a recombinant transmembrane fusion polypeptide containing PINT87aa structure and evaluate its anti-HCC effect. The project combined three levels, including functional verification, structural analysis, and drug development. Our results will enrich people's understanding of the new mechanism of non-coding RNA translating peptides.