Molecular Basis of Familial Paraganglioma

描述（由申请人提供）：癌细胞被比作超速行驶的汽车。突变的致癌基因抑制油门踏板;突变的肿瘤抑制基因破坏刹车。虽然这种类比经常很有用，但在家族性副神经节瘤（PGL）这个迷人的病例中完全失败了。令人惊讶的是，PGL是一种神经内分泌癌，由中枢代谢的三羧酸（TCA）循环中琥珀酸脱氢酶的丢失引起。这等于是让一辆汽车的引擎严重失灵！代谢酶的功能丧失突变怎么可能致癌，为什么只发生在神经内分泌细胞？这些不可抗拒的生物化学问题推动了这一提议，而答案对癌症治疗的意义将远远超过PGL。中心假设是由于SDH的损失引起的琥珀酸积累通过表观遗传效应触发神经内分泌细胞转化，表观遗传效应由至少三种不同的产生琥珀酸作为副产物的2-酮戊二酸依赖性双加氧酶的抑制引起。这就好像癌症的超速汽车失去了控制，因为司机是从一个有故障的发动机的烟雾陶醉！我们假设双加氧酶抑制通过新的表观遗传效应改变基因表达，包括（i）缺氧诱导因子（HIF）的不适当激活，（ii）甲基化组蛋白的积累，和（iii）基因组5-羟甲基胞嘧啶的消耗。该策略是表征PGL肿瘤和缺乏SDH功能的哺乳动物细胞，并在秀丽隐杆线虫中开发用于药物筛选的PGL线虫模型。目的1将寻找在原发性人PGL肿瘤样品中双加氧酶抑制的证据。目的2探讨SDH缺失对培养的人和小鼠细胞中双加氧酶的抑制作用。目的3监测PGL在条件性SDH破坏小鼠中的成瘤性。最后，Aim 4将开发一个C。elegans PGL模型来发现新的治疗方法。

DESCRIPTION (provided by applicant): Cancer cells have been likened to speeding cars. Mutated oncogenes hold down accelerator pedals; mutated tumor suppressor genes ruin brakes. Though often helpful, this analogy completely fails in the fascinating case of familial paraganglioma (PGL). Amazingly, PGL is a neuroendocrine cancer caused by loss of succinate dehydrogenase in the tricarboxylic acid (TCA) cycle of central metabolism. This is equivalent to severely disabling the engine of a car! How can loss-of-function mutations in a metabolic enzyme possibly be oncogenic, and why only in neuroendocrine cells? These irresistible biochemical questions drive this proposal, and answers will have significance for cancer therapy far beyond PGL. The central hypothesis is that succinate accumulation due to loss of SDH triggers neuroendocrine cell transformation by epigenetic effects resulting from inhibition of at least three different 2-ketoglutarate- dependent dioxygenase enzymes that produce succinate as a byproduct. It is as if the speeding car of cancer loses control because the driver is intoxicated by fumes from a faulty engine! We hypothesize that dioxygenase inhibition alters gene expression by novel epigenetic effects including (i) inappropriate activation of Hypoxia Inducible Factor (HIF), (ii) accumulation of methylated histones, and (iii) depletion of genomic 5-hydroxymethylcytosine. The strategy is to characterize PGL tumors and mammalian cells lacking SDH function, and to develop a nematode model of PGL for drug screening in Caenorhabditis elegans. Aim 1 will seek evidence for dioxygenase inhibition in primary human PGL tumor samples. Aim 2 will explore dioxygenase inhibition in cultured human and mouse cells lacking SDH. Aim 3 will monitor PGL tumorigenesis in mice with conditional SDH disruption. Finally, Aim 4 will develop a C. elegans model of PGL to uncover new therapeutics.