p53家族蛋白调控的细胞代谢在肿瘤发生发展中的作用及机制研究

The uncontrolled cell proliferation represents the essence of neoplastic diseases. In order to meet the demands of rapid tumor growth, cancer cells must reprogram their metabolism. Increasing evidence suggests that the distinct metabolic alterations allow cancer cells to facilitate the uptake and incorporation of nutrients into cellular building blocks, such as nucleotides, amino acids and lipids, that are needed for tumorigenesis. However, the detailed signaling pathways and molecular mechanisms of cancer cell metabolic reprogramming, and especially how this desregulated cell metabolism contributes to tumor progression remain largely unknown. Our recent studies have revealed the important roles of p53 family proteins in the regulation of glucose and lipid metabolism. In this study, we will further study the molecular mechanisms underlying the regulation of glucose metabolism, lipid metabolism and autophagy by the tumor suppressor p53 and its family protein p63. We will specifically investigate how p53 regulates lipid metabolism through aromatase in mouse, whether p63 regulates pentose phosphate pathway (PPP) through 6-phosphogluconate dehydrogenase (6PGD), and how lincRNA-H6, a p53-responsive long non coding RNA, affects autophagic process. More importantly, we aim to address how the above mentioned metabolic alterations mediated by p53 family proteins regulate tumorgenesis at the molecular, cellular and physiological levels. We believe this study will generate novel insights into the anti-tumor effects of p53 family proteins and will also provide a novel foundation to improve cancer therapeutics by targeting cancer cell metabolism.

肿瘤细胞最重要的特征表现为它无限制的增殖；为了满足其快速增殖的需要，肿瘤细胞显示出与正常组织不同的代谢方式。随着对肿瘤研究的逐步深入，人们对肿瘤细胞所特有的代谢途径及作用机制已具有了一些初步的认识，但肿瘤细胞代谢内在的生物学基础、它的调控网络以及与肿瘤发生发展相关的生理学意义仍然处在起步阶段。本项目将通过肿瘤抑制因子p53家族及其成员(p63等)对糖代谢、脂代谢以及自噬代谢的分子机制的研究去探究(1)p53通过芳香化酶(aromatase)调控小鼠体内脂肪代谢的机制;(2)p63通过6-磷酸葡萄糖酸脱氢酶(6PGD)对磷酸戊糖途径的调控机制;(3)p53调控的长片段RNA lincRNA-H6对自噬代谢的影响;在分子、细胞及生理水平上阐明这些代谢的改变如何影响肿瘤的发生发展，是本项目最重要的目标。相信以上这些研究的顺利实施，将会对人们所预期的用干预代谢的方法预防和治疗肿瘤提供新的理论基础。

肿瘤细胞最重要的特征表现为它无限制的增殖；为了满足其快速增殖的需要，肿瘤细胞显示出与正常组织不同的代谢方式。随着对肿瘤研究的逐步深入，人们对肿瘤细胞所特有的代谢途径及作用机制已具有了一些初步的认识，但我们对肿瘤细胞代谢内在的生物学基础、调控网络以及与肿瘤发生发展相关的生理学意义的了解仍然处在起步阶段。我们通过研究肿瘤抑制因子p53家族及其成员、受p53调控的蛋白及非编码RNA影响肿瘤细胞代谢的分子机制，在分子、细胞及生理水平上阐明这些代谢的改变如何影响肿瘤的发生发展。我们取得的代表性成果包括：（1）阐明了受p53调控的lncRNA GUARDIN参与细胞细胞衰老代谢及DNA修复，并表明GUARDIN可能成为癌症临床药物治疗的潜在靶标；（2）环形RNA CircACC1调控细胞代谢，研究发现了从营养缺乏下的一条JNK-c-JUN-circACC1-AMPK 细胞存活通路。通过这一信号通路，丰富了我们对环形RNA参与细胞代谢调控的认识。相信我们的研究成果将会对人们所预期的用干预代谢的方法预防和治疗肿瘤提供新的理论基础。