Lehtonen Heli J, Mäkinen Markus J, Kiuru Maija, Laiho Päivi, Herva Riitta, van Minderhout Ivonne, Hogendoorn Pancras C W, Cornelisse Cees, Devilee Peter, Launonen Virpi, Aaltonen Lauri A
Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
Int J Cancer. 2007 Sep 15;121(6):1386-9. doi: 10.1002/ijc.22819.
Germline mutations in nuclear genes encoding mitochondrial enzymes fumarate hydratase (FH) and succinate dehydrogenase (subunits SDHB/C/D) have been implicated in the development of tumor syndromes referred to as hereditary leiomyomatosis and renal cell cancer (HLRCC) and hereditary paragangliomatosis (HPGL), respectively. FH and SDH are operating in the tricarboxylic acid cycle (the TCA cycle, the Krebs cycle). In the FH and SDH deficient tumors, accumulation of the substrates, fumarate and succinate, has been shown to cause stabilization of hypoxia inducible factor 1 alpha (HIF1 alpha). According to recent studies, HIF1 alpha could contribute to the hypoxia induced genomic instability seen in many cancers, through repression of mismatch repair (MMR) protein MSH2. In this study, in agreement with previous works, we found HIF1 alpha to be moderately or highly stabilized in 67% (16/24) and 77% (48/62) of HLRCC tumors and SDHB/C/D paragangliomas (PGL) and pheochromocytomas (PHEO), respectively. In addition, a set of 54 other familial and nonfamilial PGLs/PHEOs were studied. Moderately or highly stabilized HIF1 alpha was present in 68% (26/38) of the PGLs but in PHEOs (n = 16) no such pattern was observed. We then analyzed the suggested link between HIF1 alpha stabilization and MSH2 repression, in HLRCC and HPGL tumor material. No microsatellite instability (MSI) or lack of MSH2 expression was, however, observed. Thus we failed to provide in vivo evidence for the proposed link between HIF1 alpha stabilization and functional MMR deficiency, in TCAC deficient tumors.
编码线粒体酶延胡索酸水合酶（FH）和琥珀酸脱氢酶（亚基SDHB/C/D）的核基因中的种系突变，分别与被称为遗传性平滑肌瘤病和肾细胞癌（HLRCC）以及遗传性副神经节瘤病（HPGL）的肿瘤综合征的发生有关。FH和SDH在三羧酸循环（TCA循环，即克雷布斯循环）中发挥作用。在FH和SDH缺陷型肿瘤中，已表明底物富马酸和琥珀酸的积累会导致缺氧诱导因子1α（HIF1α）的稳定。根据最近的研究，HIF1α可能通过抑制错配修复（MMR）蛋白MSH2，导致在许多癌症中出现的缺氧诱导的基因组不稳定。在本研究中，与之前的研究一致，我们发现HLRCC肿瘤和SDHB/C/D副神经节瘤（PGL）及嗜铬细胞瘤（PHEO）中，分别有67%（16/24）和77%（48/62）的肿瘤中HIF1α呈中度或高度稳定。此外，还研究了另外一组54个家族性和非家族性PGL/PHEO。68%（26/38）的PGL中存在中度或高度稳定的HIF1α，但在PHEO（n = 16）中未观察到这种模式。然后，我们在HLRCC和HPGL肿瘤材料中分析了HIF1α稳定与MSH2抑制之间的假定联系。然而，未观察到微卫星不稳定性（MSI）或MSH2表达缺失。因此，我们未能在体内为TCA循环缺陷型肿瘤中HIF1α稳定与功能性MMR缺陷之间的假定联系提供证据。
