UPK1A-AS1编码的多肽LUP调控脂质代谢促进肝癌进展的机制研究

Metabolic reprogramming is an important cause of Hepatocellular Carcinoma (HCC) progression. Our recent preliminary experiments demonstrated that hypoxia-induced long non-coding RNA (lncRNA) UPK1A-AS1 encoded LUP, which promoted the fatty acid synthesis in HCC cells through regulating the expression of SERBP1; meanwhile, LUP inhibited fatty acid oxidation (FAO) by stabilizing HIF-1α and thus decreased the reactive oxygen species of HCC cell under hypoxia. The study aims to explore the molecular mechanism by which LUP-SREBP1- fatty acid synthesis and LUP-HIF-1α-FAO axis help the progression of HCC. Firstly, the study will determine the biological functions of LUP in HCC and its impacts on fatty acid synthesis. Secondly, we will investigate the molecular mechanism of LUP in inducing the fatty acid synthesis and further suppressing fatty acid oxidation within HCC cells. Thirdly, we will figure out the potential of LUP as a therapeutic target of tumor treatment. Lastly, the expression of LUP, SREBP1 and HIF-1α will be detected through maximus sample clinical survey to elucidate their relationship with the development, progression and prognosis of HCC. In all, thorough investigations into the biological functions and mechanisms of poly-peptide LUP in HCC will enlighten researchers with novel insights for understanding the developing and progressing machinery as well as prognosis of HCC, which further provides new targets for HCC therapy.

代谢重编程是肝癌进展的重要原因。我们的预实验结果表明：乏氧诱导的长链非编码RNA（lncRNA）UPK1A-AS1编码多肽LUP，LUP通过调控SREBP1的表达促进脂肪酸合成；同时，LUP通过稳定HIF-1α的表达抑制脂肪酸β氧化（FAO），抑制细胞内活性氧累积。基于前期研究结果，本项目拟探讨LUP－SREBP1－脂肪酸合成、LUP－HIF-1α－FAO轴调控脂质代谢促进肝癌进展的分子机制。首先，通过体内外实验探讨LUP在肝癌中的生物学功能及对脂质代谢的影响；其次，探讨LUP促进肝癌细胞脂肪酸合成，抑制FAO的分子机制；再次，探讨以LUP为治疗靶点进行肿瘤治疗的可能性；最后，通过临床大样本检测LUP、SREBP1、HIF-1α在肝癌中的表达，阐明它们与肝癌发生、发展及预后的关系。据此，阐明LUP调控脂质代谢促进肝癌进展的分子机制，为肝癌治疗提供新靶点。

代谢重编程以适应局部微环境是肝癌进展的重要原因。肝癌肿瘤组织内部存在严重乏氧现象，肝癌细胞如何调控代谢重编程以适应乏氧微环境并促进肝癌进展的机制目前尚不清楚。因此，阐明肝癌调控代谢重编程的分子机制，寻找其中的关键基因，对肝癌的早期诊断、预后判断和靶向治疗具有重要的意义。本研究以乏氧诱导的lncRNA UPK1A-AS1通过编码多肽调控肝癌代谢重编程这一机制为切入点，深入探讨lncRNA编码的多肽在肿瘤中的作用及其调控机制。本研究1）通过乏氧芯片联合染色质免疫共沉淀等实验阐明HIF-1α转录调控lncRNA UPK1A-AS1；2）通过体内外实验阐明lncRNA UPK1A-AS1编码的多肽对肝癌进展的影响；3）通过体内外实验阐明lncRNA UPK1A-AS1编码的多肽与HIF-1α形成正反馈环路调控肝癌细胞葡萄糖代谢；4）阐明lncRNA UPK1A-AS1编码的多肽调控HIF-1α的分子机制；5）通过体内外实验揭示lncRNA UPK1A-AS1作为lncRNA 本身对肝癌进展的影响；6）通过体内外实验探讨lncRNA UPK1A-AS1及其编码的多肽作为治疗靶点的可能性；7）采用临床大样本验证lncRNA UPK1A-AS1在肝癌中的表达及其与肝癌患者预后之间的关系。本研究进而得出以下结论：乏氧诱导的lncRNA UPK1A-AS1通过编码多肽与HIF-1α形成正反馈环路调控肝癌糖酵解，从而促进肝癌增殖；此外，lncRNA UPK1A-AS1作为lncRNA促进肝癌增殖； lncRNA UPK1A-AS1在肝癌组织中高表达，其高表达与肝癌患者不良预后相关，特异性靶向lncRNA UPK1A-AS1及其编码的多肽能抑制肝癌进展。因此，lncRNA UPK1A-AS1及其编码的多肽可作为预测肝癌患者预后的分子标志物及潜在治疗靶点。本项目的顺利实施对于理解lncRNA的作用机制增加新的理论依据和视角。同时，本项目紧密结合临床，探讨UPK1A-AS1及其编码的多肽在肝癌中的意义，为肝癌的预后判断和新的治疗靶点奠定新的理论基础。

内容获取失败，请点击重试