非经典前折叠蛋白URI对原发性肝癌自噬与代谢功能的调节及机制

The essential hallmarkers of cancer are intertwined with an altered cancer cell-intrinsic metabolism,either as a consequence or as a cause. Autophagy is a conserved catabolic process by which cells themselves digest their organelles and correlated with cellular metabolic status. Autophagy has emerged as a homeostatic mechanism buffering metabolic stress induced under starvation conditions by recycling intracellular constituents. The amino acids and fatty acids generated by autophagic degradation are used by the tricarboxylic acid cycle to produce ATP. An interesting finding is that autophagy is suppressed in the primary liver cancer, which brings the question that what causes the loss of authophgy. The relationship between autophagy and cell metabolism also is an urgent issue needed to be explored. Recently, we found that unconventional prefoldin RPB5 interactor (URI)could regulate autophay and cellular metabolism of liver cancer. Further, we found URI positively modulated p70S6K activity in liver cancer cells with starvation culture, which indicated that URI may effect mTOR signaling. In addition, knockdown URI in hepatic carcinoma cells increased phosphorelation of AMPK both in normal or starvation culture medium, suggesting URI involved in cell energy metabolic prosess. Our research will further defined the biological function of URI in cell autophagy and cell metabolism during the progress of liver cell malignant transformation and progression. Meanwhile, the project plans to use URI knockout mice to perform the study in vivo, which will improve our knowledge in understanding the reprogramed metabolism of cells in carcinogenesis and progression of liver cancer. Thereby, the study is also expected to provide the new target for prevention and clinical therapy in liver cancer.

细胞代谢方式转变是肿瘤细胞为适应环境而生存的重要特征。自噬是保守的生命现象，与细胞能量代谢状况密切相关。当营养缺乏时，细胞自噬活性增高，通过自噬降解细胞质和受损细胞器以提供细胞生存所需的能量。但是在肝癌发生过程中自噬却是缺失的，那么哪些因素调节了细胞自噬成为亟待回答的问题。在肝癌细胞内能量代谢与自噬的相互关系如何也是非常重要的问题。我们在前期研究中发现非经典前折叠蛋白URI（Unconventional prefoldin RPB5 Interactor）对肝细胞肝癌和肝内胆管细胞癌的自噬和能量代谢均具有显著的调节作用。随后发现URI正性调节mTOR及负性调节AMPK的活性，这一结果也提示我们其对于癌细胞能量代谢可能具有调节作用。因此，本课题拟应用代谢组学技术系统研究URI对于肝癌细胞代谢的影响，并在体内外深入研究URI对自噬的调节机制。希望该研究能为阐述肝癌中自噬与代谢相互关系提供线索。

细胞代谢方式转变是肿瘤细胞为适应环境而生存的重要特征。自噬是保守的生命现象，与细胞能量代谢状况密切相关。当营养缺乏时，细胞自噬活性增高，通过自噬降解细胞质和受损细胞器以提供细胞生存所需的能量。但是在肝癌发生过程中自噬却是缺失的，那么哪些因素调节了细胞自噬成为亟待回答的问题。在肝癌细胞内能量代谢与自噬的相互关系如何也是非常重要的问题。我们在前期研究中发现非经典前折叠蛋白URI（Unconventional prefoldin RPB5 Interactor）对肝细胞肝癌和肝内胆管细胞癌的自噬和能量代谢均具有显著的调节作用。随后发现URI正性调节mTOR及负性调节AMPK的活性，这一结果也提示我们其对于癌细胞能量代谢可能具有调节作用。因此，本课题应用代谢组学技术系统研究URI对于肝癌细胞代谢的影响，并在体内外深入研究URI对自噬的调节机制。研究中我们分析了URI在肝癌和胆管癌中表达及与临床资料相关性，发现URI表达预示着病人不良生存期。我们着重研究阐释了URI对肝癌细胞自噬和能量代谢有重要调节作用，特别对自噬的调节作用与不同细胞背景有很大关联；我们发现URI对自噬的调节在不同P53状态细胞中出现相反的调节作用；在肝细胞癌和胆管细胞癌中，URI的表达赋予了肿瘤细胞对抗氧化应激的能力，主要通过稳定Nrf2蛋白上调抗氧化基因表达，促进了肿瘤细胞的恶性进展。