摘要
研究背景与目的:结直肠癌是世界上第三大常见的恶性肿瘤,全球每年新发病例约120万例,死亡人数达60万。在我国,结直肠癌位居恶性肿瘤死亡率第四位。近年来,我国结直肠癌的发病和死亡呈明显上升趋势。结直肠癌的发生、发展是一个涉及多基因、多步骤、多阶段的复杂过程。80%以上的结直肠癌是从腺瘤癌变而来,而从腺瘤的发生至癌变的发生、发展,主要涉及癌基因、抑癌基因、错配修复基因等三类基因的变化。其中抑癌基因的异常在结直肠癌的发生发展中起关键作用,其失活或缺失可导致细胞去调节性生长,克隆性扩张。因此,在结直肠癌病因学研究中,有必要寻找与其发生、发展相关的抑癌基因,探讨其在疾病发生发展中的作用,进一步从分子水平阐明结直肠癌的发病机制,为疾病的早发现、早诊断和早治疗提供重要的理论基础。
本课题组前期研究采用荧光差异双向电泳技术构建了不同临床分期结直肠癌蛋白质差异表达谱,发现琥珀酸脱氢酶(succinate dehydrogenase, SDH)是结直肠癌发病过程中一个差异表达蛋白质分子,可能具有潜在的抑癌功能。SDH也称为线粒体复合物Ⅱ,定位于线粒体内膜,是由A、B、C、D四个亚基组成的异源四聚体,分别由相应的核基因编码。SDH是三羧酸循环和线粒体呼吸链的组成部分,其在细胞能量代谢中起到重要的作用。SDH作为一个抑癌基因,其基因缺陷或表达异常与多种疾病的发生有关,如副神经节瘤、嗜铬细胞瘤、肾癌、胃肠道间质瘤、Leigh综合征等。前期研究中我们利用免疫组化技术检测了包含103例病例的结直肠组织芯片中SDH的表达情况,发现SDHB蛋白在结直肠癌组织的表达较正常结直肠粘膜明显下调,且SDHB在低分化结直肠癌组织中表达较中、高分化癌组织明显减弱。
目前对SDH基因在结直肠癌发生发展中的作用及机制国内外尚未见报道。本课题在前期工作的基础上,扩大样本量检测SDHB在低分化结肠癌组织中的表达以进一步证实SDHB的表达与结肠癌分化程度的关系。为了进一步深入研究SDHB基因在结直肠癌发生发展中的作用,我们构建了SDHB过表达稳定转染细胞系以明确SDHB基因对结肠癌细胞SW620生物学行为的影响。同时研究了SDHB基因对SW620细胞基因表达谱的影响。此外,我们从SDHB基因突变和启动子甲基化两个方面对SDHB在结直肠癌中表达下调的机制进行了探讨。
方法:本研究在包含32个点阵的低分化结肠癌组织芯片中应用免疫组化技术检测了SDHB蛋白的表达。而后采用真核表达载体pIRESneo3构建了SDHB基因稳定表达载体pIRES-SDHB,利用脂质体转染的方法将其导入SW620细胞,建立了SDHB稳定转染结肠癌细胞系。通过细胞生长曲线、平板集落形成、裸鼠移植瘤形成试验等明确SDHB对结肠癌细胞生长与增殖的作用。通过流式细胞仪检测SDHB对SW620细胞周期的影响,同时采用Western blot及免疫细胞化学法分别检测细胞周期相关分子cyclin D1和PCNA的表达。通过构建人全基因组表达谱芯片探究了SDHB基因过表达对SW620细胞基因表达谱的影响。此外,提取了40对结直肠癌及配对的癌旁正常结直肠粘膜组织gDNA,一方面采用PCR扩增了SDHB基因各外显子片段,产物纯化后进行双向测序检测各外显子突变情况;另一方面将gDNA经亚硫酸氢盐修饰后,采用甲基化特异性PCR检测SDHB基因启动子甲基化状态。
结果:(1) SDHB在结直肠癌组织中的表达
①免疫组织化学检测SDHB蛋白在结直肠癌组织芯片中的表达,发现SDHB在结直肠癌组织的表达较正常结直肠粘膜明显下调,且其在低分化结直肠癌组织中表达较中、高分化明显减弱。
②Western blot检测SDHB蛋白在结直肠癌组织中的表达,发现SDHB在结直肠癌组织中表达正常粘膜组织明显减弱。
(2) SDHB基因转染对结肠癌SW620细胞生物学功能的影响
①细胞生长曲线显示转染SDHB基因显著抑制了SW620细胞的生长。
②平板集落形成试验显示转染SDHB基因显著抑制SW620细胞的集落形成能力。
③裸鼠移植瘤形成实验表明SDHB抑制结肠癌SW620细胞致瘤性。
④流式细胞仪检测发现稳定转染SDHB基因导致SW620细胞周期发生G1-S期阻滞。
⑤Western blot及免疫细胞化学法检测发现SDHB下调SW620细胞中cyclin D1及PCNA的表达。
(3) SDHB对结肠癌细胞基因表达谱的影响
①采用Illumina公司的人全基因组表达谱芯片(Human HT-12v4)共筛选出受SDHB基因调控结肠癌SW620细胞中差异表达的基因共1653个,其中上调基因1382个,下调基因271个。
②采用real-time PCR验证了部分差异表达基因,结果与芯片检测结果一致,说明芯片数据可靠。
③GO分析发现差异表达基因主要参与细胞周期及其调控、细胞增殖调控、转录调控、细胞信号传导等过程。
④KEGG数据库分析发现差异表达基因主要参与p53、MAPK、 Toll样受体、ErbB、Jak-STAT、T细胞受体、Notch、Wnt、TGF-β、 VEGF、细胞因子相互作用等信号传导途径。
(4) SDHB在结直肠癌组织中表达下调的机制
①PCR扩增SDHB基因各外显子片段,测序后发现在40例结直肠癌和与配对的正常结直肠粘膜组织标本中SDHB基因第一外显子第18个碱基处存在一个SNP位点,碱基由C颠换成A,致第6位密码子由GCC变为GCA,两个密码子均编码丙氨酸,为一同义突变;未发现致病性突变。结果提示SDHB基因外显子突变可能不是单纯性结直肠癌的致病原因。
②MSP法未能在上述40对组织中检测出SDHB基因启动子区CpG岛甲基化,推测SDHB在结肠癌组织中表达下调可能不是由启动子区甲基化引起的。
结论:(1) SDHB在结直肠癌组织中表达下调,且表达水平与结直肠癌组织分化程度相关,在低分化癌组织中表达较中、高分化癌组织明显减弱。
(2)SDHB可抑制体外SW620细胞的生长与增殖,诱导细胞G1-S期阻滞;抑制SW620细胞裸鼠皮下移植瘤的形成。
(3) SDHB基因外显子点突变和启动子区甲基化可能不是SDHB在结直肠癌组织中表达下调的机制。
Background and objective:Colorectal cancer (CRC) is the third most prevalent cancer in the world, accounting for approximately1.2million new cases and more than600,000cancer-related deaths each year worldwide. In China, CRC ranks fourth in cancer mortality, and in recent years, the morbidity and mortality of CRC in China shows an obvious upward trend. The occurrence and development of CRC is a complex process involving multi-gene, multi-step, and multi-stage. More than80%of CRC begins with adenomatous polyp, further advances to adenoma with high grade dysplasia and finally progresses to an invasive cancer. This process mainly involves three types of genetic changes in oncogenes, tumor suppressor genes, and mismatch repair genes. The defect of tumor suppressor genes plays a key role in the development of CRC, which could cause cells to grow out of control and tumor progression. Therefore, it is necessary to find the tumor suppressor genes involved in the development of CRC, to explore their roles in tumor development, and to further clarify the pathogenesis at the molecular level in the etiology study, which could provide an important theoretical basis for early detection, diagnosis, and treatment of CRC.
In previous study, protein dynamic expression patterns in different stages of CRC were established using two-dimensional gel electrophoresis. The results showed that SDH exhibited potential tumor suppressor function in the pathogenesis of CRC. SDH (also known as mitochondrial complex Ⅱ) is a heterotetrameric protein consists of A, B, C and D subunits encoded by corresponding nuclear genes, localized on the inner mitochondrial membrane which catalyse the oxidative dehydrogenation of succinate and, as part of complex Ⅱ of the electron transport chain, couple this to the reduction of ubiquinone (succinate-ubiquinone oxidoreductase). As a tumor suppressor gene, genetic defects or abnormal expression in SDH are associated with a diverse collection of diseases, including paragangliomas (PGL), pheochromocytoma, renal cancer, gastrointestinal stromal cell tumor, and Leigh syndrome. Initially, the SDH expression was detected by immunohistochemistry using tissue microarray (TMA) sections which containing103cases of CRC tissue specimens. Expression of SDHB protein was found to be significantly lower in CRC tissues compared to the normal mucosa. And the expression of SDHB was negatively correlated with the differentiation status of CRC tissues.
The role of SDH in CRC development has not been reported previously. Based on preliminary work, we detect SDHB expression in poorly differentiated CRC tissues with expanded sample to further confirm the correlation between SDHB expression and differentiation status of CRC in the present study. In order to further investigate the potential SDH tumor suppressor functions in CRC, we stably expressed SDHB protein in human colon cancer cells to determine the effects of SDHB expression on tumor cell growth and tumorigenesis. And differential expression of genes induced by ectopic SDHB expression in cancer cells was screened by microarray analysis. Moreover, we investigated the mechanism for downregulated expression of SDHB in CRC in genetic and epigenetic aspects, such as gene mutations and DNA methylation.
Methods:In this study, we examined SDHB protein expression in a TMA containing32cases of poorly differentiated colon cancer tissues by immunohistochemistry. Then SDHB was transfected into colon cancer cell line (SW620) by lipofectin and a stable cell line of pIRES-SDHB overexpressing SDHB gene was established. The effect of SDHB on malignant behavior of SW620was assessed by growth curves of cells, colony formation, and tumor formation in nude mice. The effect of SDHB on cell cycle progression in SW620was investigated by flow cytometry.The expression of cell cycle related proteins cyclin D1and PCNA was detected by western blot and immunocytochemistry. In order to identify genes modulated by SDHB in CRC, the expression profile of SDHB expressing colon cancer cells and controls were investigated. Moreover, genomic DNA was extracted in forty CRC and paired normal mucosa tissues. On the one hand, SDHB gene exons were amplified by PCR and all products were purified and sequenced from both directions to detect gene mutations. On the other hand, genomic DNA was treated by sodium bisulfite modification and then amplified by methylation-specific PCR to assess the SDHB promoter methylation status.
Results:(1) Protein expression of SDHB in CRC
①Immunohistochemical results showed that expression of SDHB protein was found to be significantly lower in CRC tissues compared to the normal mucosa. And the expression of SDHB in poorly differentiated CRC was significantly lower compared to that in moderately and well differentiated CRC.
②Western blot showed the same results which were consistent with that of immunohistochemistry.
(2) Effects of SDHB expression on tumor cell growth and tumorigenesis
①Cell growth curves showed the restoration of SDHB significantly inhibited the growth of SW620cells.
②Colony formation showed the ectopic expression of SDHB substantially inhibited tumor cell colony formation.
③Xenograft tumor formation assay showed that SDHB inhibited tumorigenicity in SW620cells.
④Flow cytometry results of the cell cycle distribution showed that SDHB induced cell cycle arrest at the G1phase.
⑤Western blot and immunocytochemistry showed that SDHB downregulated expression of cyclin D1and PCNA.
(3) Effects of SDHB expression on the gene expression profile of colon cancer cells
①cDNA microarray analysis showed total of1,653differentially expressed genes with more than a twofold change (p<0.01), of which1,382gene expressions were upregulated and271gene expressions were downregulated in SW620-SDHB cells compared with vector control cells.
②The differentially expressed genes were validated by real-time RT-PCR.
③Most of the differentially expressed genes were grouped in GO with regard to "cell cycle","cellular process","transcriptional regulation" or "cell signaling".
④The KEGG database analysis showed that the differentially expressed genes were mainly involved in the p53, MAPK, Toll-like receptors, ErbB, Jak-STAT, T cell receptor, Notch, Wnt, TGF-β, VEGF, cytokines interaction signal transduction pathway.
(4) Mechanism for downregulated expression of SDHB in CRC
①Forty cases of CRC and paired normal mucosa tissues contained a single nueleotide polymorphism in SDHB exonl which located in the18th base pair, C substituted by A, making the6th codon changed from GCC to GCA. However, both GCC and GCA are encode for alamine. And no pathogenic mutation was found. The results suggested that the exon mutation in SDHB gene may not be the cause of CRC.
②Methylation-specific PCR failed to detect SDHB promoter methylation in all these CRC and paired normal mucosa tissues, which suggested that the mechanism for downregulated expression of SDHB in CRC may not be caused by promoter methylation.
Conclusion:(1) Expression of SDHB protein was significantly lower in CRC tissues compared to the normal mucosa, and its expression was negatively correlated with the differentiation status of CRC tissues.
(2) Restoration of SDHB could inhibit tumor cell growth, colony formation, tumorigenicity, and induce cell cycle arrest at the G1phase.
(3) The mechanism for downregulated expression of SDHB in CRC may not be due to exon mutation or promoter methylation.
引文
[1]Jemal A, Center MM, DeSantis C, et al. Global patterns of cancer incidence and mortality rates and trends[J]. Cancer Epidemiol Biomarkers Prev,2010,19(8): 1893-1907.
[2]李连弟,饶克勤,张思维,等.中国12市县1993年~1997年肿瘤发病和死亡登记资料统计分析[J].中国肿瘤,2002,11(9):497-507.
[3]You WC, Jin F, Devesa S, et al. Rapid increase in colorectal cancer rates in urban Shanghai,1972-97, in relation to dietary changes[J]. J Cancer Epidemiol Prev, 2002,7(3):143-146.
[4]董志伟,乔友林,李连弟,等.中国癌症控制策略研究报告[J].中国肿瘤,2002,11(5):250-260.
[5]代珍,郑荣寿,邹小农,等.中国结直肠癌发病趋势分析和预测[J].中华预防医学杂志,2012,46(7):598-603.
[6]Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development[J]. N Engl J Med,1988,319(9):525-532.
[7]来茂德.大肠癌发生的分子机理[J].实用肿瘤杂志,2000,15(2):73-78.
[8]Gitai Z, Yu TW, Lundquist EA, et al. The netrin receptor UNC-40/DCC stimulates axon attraction and outgrowth through enabled and, in parallel, Rac and UNC-115/AbLIM[J]. Neuron,2003,37(1):53-65.
[9]Peng Y, Li X, Wu M, et al. New prognosis biomarkers identified by dynamic proteomic analysis of colorectal cancer[J]. Mol Biosyst,2012,8(11):3077-3088.
[10]Scheffler IE. Molecular genetics of succinate:Quinone oxidoreductase in eukaryotes[J]. Prog Nucleic Acid Res Mol Biol,1998,60:267-315.
[11]Saraste M. Oxidative phosphorylation at the fin de siecle[J]. Science,1999, 283(5407):1488-1493.
[12]Rustin P, Munnich A, Rotig A. Succinate dehydrogenase and human diseases:New insights into a well-known enzyme[J]. Eur J Hum Genet,2002,10(5): 289-291.
[13]Bourgeron T, Rustin P, Chretien D, et al. Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency [J]. Nat Genet,1995,11(2):144-149.
[14]Parfait B, Chretien D, Rotig A, et al. Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with leigh syndrome[J]. Hum Genet,2000,106(2):236-243.
[15]Van Coster R, Seneca S, Smet J, et al. Homozygous Gly555Glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex Ⅱ [J]. Am J Med Genet A,2003,120(1):13-18.
[16]Pagnamenta AT, Hargreaves IP, Duncan AJ, et al. Phenotypic variability of mitochondrial disease caused by a nuclear mutation in complex Ⅱ[J]. Mol Genet Metab,2006,89(3):214-221.
[17]Burnichon N, Briere J J, Libe R, et al. SDHA is a tumor suppressor gene causing paraganglioma[J]. Hum Mol Genet,2010,19(15):3011-3020.
[18]Korpershoek E, Favier J, Gaal J, et al. SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas[J]. J Clin Endocrinol Metab,2011,96(9):1472-1476.
[19]Pantaleo MA, Nannini M, Astolfi A, et al. A distinct pediatric-type gastrointestinal stromal tumor in adults:potential role of succinate dehydrogenase subunit Amutations[J]. Am J Surg Pathol,2011,35(11):1750-1752.
[20]Kantorovich V, King KS, Pacak K. SDH-related pheochromocytoma and paraganglioma[J]. Best Pract Res Clin Endocrinol Metab,2010,24(3):415-424.
[21]Pasini B, Stratakis CA. SDH mutations in tumorigenesis and inherited endocrine tumours:lesson from the phaeochromocytoma-paraganglioma syndromes[J]. J Intern Med,2009,266(1):19-42.
[22]Rutter J, Winge DR, Schifman JD. Succinate dehydrogenase-Assembly, regulation and role in human disease [J]. Mitochondrion,2010,10(4):393-401.
[23]Vanharanta S, Buchta M, McWhinney SR, et al. Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma[J]. Am J Hum Genet,2004,74(1):153-159.
[24]Bolland M, Benn D, Croxson M, et al. Gastrointestinal stromal tumour in succinate dehydrogenase subunit B mutation-associated familial phaeochromocytoma/paraganglioma[J]. ANZ J Surg,2006,76(8):763-764.
[25]Neumann HP, Pawlu C, Pezkowska M, et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations[J]. JAMA,2004,292(8):943-951.
[26]Amar L, Bertherat J, Baudin E, et al. Genetic testing in pheochromocytoma or functional paraganglioma[J]. J Clin Oncol,2005,23(34):8812-8818.
[27]Braun S, Riemann K, Pusch CM, et al. Paraganglioma in the area of the head and neck. A review of molecular genetic research[J]. HNO,2004,52(1):11-17.
[28]Adachi H, Fujiwara Y, Ishii N. Effects of oxygen on protein carbonyl and aging in Caenorhabditis elegans mutants with long (age-1) and short (mev-1) life spans[J]. J Gerontol A Biol Sci Med Sci,1998,53(4):B240-244.
[29]Ishii T, Yasuda K, Akatsuka A, et al. A mutation in the SDHC gene of complex II increases oxidative stress, resulting in apoptosis and tumorigenesis[J]. Cancer Res,2005,65(1):203-209.
[30]Slane BG, Aykin-Burns N, Smith BJ, et al. Mutation of succinate dehydrogenase subunit c results in increased O2·-, oxidative stress, and genomic instability [J]. Cancer Res,2006,66(15):7615-7620.
[31]Smith EH, Janknecht R, Maher LJ, et al. Succinate inhibition of a-ketoglutarate-dependent enzymes in a yeast model of paraganglioma[J]. Hum Mol Genet,2007,16(24):3136-3148.
[32]Goffrini P, Ercolino T, Panizza E, et al. Functional study in a yeast model of a novel succinate dehydrogenase subunit B gene germline missense mutation (C191Y) diagnosed in a patient affected by a glomus tumor[J]. Hum Mol Genet,2009,18(10): 1860-1868.
[33]Szeto SS, Reinke SN, Sykes BD, et al. Ubiquinone-binding site mutations in the Saccharomyces cerevisiae succinate dehydrogenase generate superoxide and lead to the accumulation of succinate[J]. J Biol Chem,2007,282(37):27518-27526.
[34]Gimenez-Roqueplo AP, Favier J, Rustin P, et al. The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway [J]. Am J Hum Genet,2001,69(6):1186-1197.
[35]Selak MA, Armour SM, MacKenzie ED, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-a prolyl hydroxylase[J]. Cancer Cell, 2005,7(1):77-85.
[36]张德才.线粒体琥珀酸脱氢酶复合物在结直肠癌中的表达及临床意义[D].长沙:中南大学,2000.
[37]Leibovitz A, Stinson JC, McCombs WB, et al. Classification of human colorectal adenocarcinoma cell lines[J]. Cancer Res,1976,36(12):4562-4569.
[38]Huang da W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources[J]. Nat Protoc, 2009,4(1):44-57.
[39]Astuti D, Morris M, Krona C, et al. Investigation of the role of SDHB inactivation in sporadic phaeochromocytoma and neuroblastoma[J]. Br J Cancer,2004, 91(10):1835-1841.
[40]Wettergren Y, Odin E, Nilsson S, et al. p16INK4a gene promoter hypermethylation in mucosa as a prognostic factor for patients with colorectal cancer[J]. Mol Med,2008,14(7-8):412-421.
[41]Nakayama G, Hibi K, Nakayama H, et al. A highly sensitive method for the detection of p16 methylation in the serum of colorectal cancer patients [J]. Anticancer Res,2007,27(3B):1459-1463.
[42]Goto T, Mizukami H, Shirahata A, et al. Aberrant methylation of the p16 gene is frequently detected in advanced colorectal cancer [J]. Anticancer Res,2009, 29(1):275-277.
[43]Printz C. American cancer society reports progress in reducing cancer deaths:however, some groups still lag behind this trend[J]. Cancer,2011,117(20): 4573-4574.
[44]Tomitsuka E, Hirawake H, Goto Y, et al. Direct evidence for two distinct forms of the flavoprotein subunit of human mitochondrial complex II (succinate-ubiquinone reductase) [J]. J Biochem,2003,134(2):191-195.
[45]Favier J, Briere JJ, Strompf L, et al. Hereditary paraganglioma/pheochromocytoma and inherited succinate dehydrogenase deficiency[J]. HormRes,2005,63(4):171-179.
[46]van Nederveen FH, Gaal J, Favier J, et al. An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations:a retrospective and prospective analysis[J]. Lancet Oncol,2009,10(8):764-771.
[47]Gill AJ, Benn DE, Chou A, et al. Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, or SDHD in paraganglioma-pheochromocytoma syndromes[J]. Hum Pathol,2010,41(6):805-814.
[48]司徒镇强.细胞培养[M].北京:世界图书出版公司,2007.
[49]Scala G, Quinto I, Ruocco MR, et al. Expression of an exogenous interleukin 6 gene in human Epstein Barr virus B cells confers growth advantage and in vivo tumorigenicity[J]. J Exp Med,1990,172(1):61-68.
[50]Colombo MP, Ferrari G, Stoppacciaro A, et al. Granulocyte colony-stimulating factor gene transfer suppresses tumorigenicity of a murine adenocarcinoma in vivo[J]. J Exp Med,1991,173(4):889-897.
[51]Siprashvili Z, Sozzi G, Barnes LD, et al. Replacement of Fhit in cancer cells suppresses tumorigenicity[J]. Proc Natl Acad Sci U S A,1997,94(25):13771-13776.
[52]Tu SP, Jiang XH, Lin MC, et al. Suppression of survivin expression inhibits in vivo tumorigenicity and angiogenesis in gastric cancer[J]. Cancer Res,2003, 63(22):7724-7732.
[53]Wunderlich V, Rajewsky MF. "Tumour suppressor gene" concept of carcinogenesis[J]. Lancet,1995,345(8964):1570-1571.
[54]Skuse GR, Ludlow JW. Tumour suppressor genes in disease and therapy[J]. Lancet,1995,345(8954):902-906.
[55]覃吉超,陶德定,舒丹,等.对MOLT-4细胞用cyclin E+A/DNA流式细胞术分析——细胞周期六分法的建立[J].中华医学杂志(英文版),2001,114(9):967-971.
[56]宋鑫,曹亚.癌变多阶段形成过程中的细胞稳态反馈机制及其通路[J].国外医学(肿瘤学分册),2001,28(6):407-409.
[57]Musgrove EA, Caldon CE, Barraclough J, et al. Cyclin D as a therapeutic target in cancer[J]. Nat Rev Cancer,2011,11(8):558-572.
[58]Miyachi K, Fritzler MJ, Tan EM. Autoantibody to a nuclear antigen in proliferating cells[J]. J Immunol,1978,121(6):2228-2234.
[59]Jussila L, Alitalo K. Vascular growth factors and lymphangiogenesis[J]. Physiol Rev,2002,82(3):673-700.
[60]Mostovich LA, Prudnikova TY, Kondratov AG, et al. The TCF4/β-catenin pathway and chromatin structure cooperate to regulate D-glucuronyl C5-epimerase expression in breast cancer[J]. Epigenetics,2012,7(8):930-939.
[61]Brown PO, Botstein D. Exploring the new world of the genome with DNA microarrays[J]. Nat Genet,1999,21:33-37.
[62]Schena M, Shalon D, Davis RW, et al. Quantitative monitoring of gene expression patterns with a complementary DNA microarray[J]. Science,1995, 270(5235):467-470.
[63]Ashburner M, Ball CA, Blake JA, et al. Gene ontology:tool for the unification of biology[J]. The gene ontology consortium. Nat Genet,2000,25(1): 25-29.
[64]Wixon J, Kell D. The Kyoto encyclopedia of genes and genomes--KEGG[J]. Yeast,2000,17(1):48-55.
[65]Kanehisa M, Goto S. KEGG:kyoto encyclopedia of genes and genomes[J]. Nucleic Acids Res,2000,28(1):27-30.
[66]Glenney JR, Jr., Zokas L. Novel tyrosine kinase substrates from Rous sarcoma virus-transformed cells are present in the membrane skeleton[J]. J Cell Biol, 1989,108(6):2401-2408.
[67]Rothberg KG, Heuser JE, Donzell WC, et al. Caveolin, a protein component of caveolae membrane coats[J]. Cell,1992,68(4):673-682.
[68]Li S, Couet J, Lisanti MP. Src tyrosine kinases, Galpha subunits, and H-Ras share a common membrane-anchored scaffolding protein, caveolin. Caveolin binding negatively regulates the auto-activation of Src tyrosine kinases [J]. J Biol Chem,1996, 271(46):29182-29190.
[69]Engelman JA, Chu C, Lin A, et al. Caveolin-mediated regulation of signaling along the p42/44 MAP kinase cascade in vivo. A role for the caveolin-scaffolding domain[J]. FEBS Lett,1998,428(3):205-211.
[70]Hulit J, Bash T, Fu M, et al. The cyclin D1 gene is transcriptionally repressed by caveolin-1[J]. J Biol Chem,2000,275(28):21203-21209.
[71]Bender FC, Reymond MA, Bron C, et al. Caveolin-1 levels are down-regulated in human colon tumors, and ectopic expression of caveolin-1 in colon carcinoma cell lines reduces cell tumorigenicity[J]. Cancer Res,2000,60(20): 5870-5878.
[72]Byrd PJ, Stankovic T, McConville CM, et al. Identification and analysis of expression of human VACM-1, a cullin gene family member located on chromosome 11q22-23[J]. Genome Res,1997,7(1):71-75.
[73]Singhal S, Amin KM, Kruklitis R, et al. Alterations in cell cycle genes in early stage lung adenocarcinoma identified by expression profiling[J]. Cancer Biol Ther,2003,2(3):291-298.
[74]Burnatowska-Hledin MA, Kossoris JB, Van Dort CJ, et al. T47D breast cancer cell growth is inhibited by expression of VACM-1, a cul-5 gene[J], Biochem Biophys Res Commun,2004,319(3):817-825.
[75]Baxter SS, Carlson LA, Mayer AM, et al. Granulocytic differentiation of HL-60 promyelocytic leukemia cells is associated with increased expression of Cul5[J]. In Vitro Cell Dev Biol Anim,2009,45(5-6):264-274.
[76]Luo K, Ehrlich E, Xiao Z, et al. Adenovirus E4orf6 assembles with Cullin5-ElonginB-Elonginc E3 ubiquitin ligase through an HIV/SIV Vif-like BC-box to regulate p53[J]. FASEB J,2007,21(8):1742-1750.
[77]Yao XL, Liu J, Lee E, et al. Cullin 5 gene expression in the rat cerebral cortex and hippocampus following traumatic brain injury (TBI) [J]. Neurosci Lett, 2006,409(1):65-69.
[78]Ayyub C, Sen A, Gonsalves F, et al. Cullin-5 plays multiple roles in cell fate specification and synapse formation during Drosophila development[J]. Dev Dyn, 2005,232(3):865-875.
[79]Barry M, Fruh K. Viral modulators of cullin RING ubiquitin ligases:culling the host defense[J]. Sci STKE,2006,2006(335):pe21.
[80]Buchwalter A, Van Dort C, Schultz S, et al. Expression of VACM-1/cul5 mutant in endothelial cells induces MAPK phosphorylation and maspin degradation and converts cells to the angiogenic phenotype[J]. Microvasc Res,2008,75(2): 155-168.
[81]Xu XM, Wang XB, Chen MM, et al. Microrna-19a and-19b regulate cervical carcinoma cell proliferation and invasion by targeting CUL5[J]. Cancer Lett, 2012,322(2):148-158.
[82]Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer[J]. Science,1997,275(5308): 1943-1947.
[83]Stambolic V, Suzuki A, de la Pompa JL, et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN[J]. Cell,1998,95(1): 29-39.
[84]Weng LP, Brown JL, Baker KM, et al. PTEN blocks insulin-mediated ETS-2 phosphorylation through map kinase, independently of the phosphoinositide 3-kinase pathway[J]. Hum Mol Genet,2002,11(15):1687-1696.
[85]Song MS, Salmena L, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor [J]. Nat Rev Mol Cell Biol,2012,13:283-296.
[86]Ni Y, Zbuk KM, Sadler T, et al. Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes [J]. Am J Hum Genet,2008,83(2):261-268.
[87]Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma[J]. Am J Hum Genet,2001,69(1):49-54.
[88]Baysal BE, Willett-Brozick JE, Filho PA, et al. An Alu-mediated partial SDHC deletion causes familial and sporadic paraganglioma[J]. J Med Genet,2004, 41(9):703-709.
[89]Boedeker CC, Neumann HP, Maier W, et al. Malignant head and neck paragangliomas in SDHB mutation carriers[J]. Otolaryngol Head Neck Surg,2007, 137(1):126-129.
[90]Klein RD, Jin L, Rumilla K, et al. Germline SDHB mutations are common in patients with apparently sporadic sympathetic paragangliomas[J]. Diagn Mol Pathol,2008,17(2):94-100.
[91]Gimenez-Roqueplo AP, Favier J, Rustin P, et al. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas[J]. Cancer Res,2003,63(17):5615-5621.
[92]Pasini B, McWhinney SR, Bei T, et al. Clinical and molecular genetics of patients with the Carney-stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDCH, and SDHD[J]. Eur J Hum Genet,2008,16(1):79-88.
[93]Collins F S, Lander E S, Rogers J, et al. Finishing the euchromatic sequence of the human genome[J]. Nature,2004,431(7011):931-945.
[94]冯影.副神经节瘤SDHD、SDHB基因突变分析[D].天津:天津医科大学,2008.
[95]McWhinney SR, Pilarski RT, Forrester SR, et al. Large germline deletions of mitochondrial complex Ⅱ subunits SDHB and SDHD in hereditary paraganglioma[J]. J Clin Endocrinol Metab,2004,89(11):5694-5699.
[96]Cascon A, Montero-Conde C, Ruiz-Llorente S, et al. Gross SDHB deletions in patients with paraganglioma detected by multiplex PCR:a possible hot spot? [J] Genes Chromosomes Cancer,2006,45(3):213-219.
[97]Knudson AG, Jr. Genetics of human cancer[J]. Annu Rev Genet,1986,20: 231-251.
[98]Gimenez-Roqueplo AP, Favier J, Rustin P, et al. Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma[J]. J Clin Endocrinol Metab,2002,87(10):4771-4774.
[99]Benn DE, Dwight T, Richardson AL, et al. Sporadic and familial pheochromocytomas are associated with loss of at least two discrete intervals on chromosome 1p[J]. Cancer Res,2000,60(24):7048-7051.
[100]Tate PH, Bird AP. Effects of DNA methylation on DNA-binding proteins and gene expression[J]. Curr Opin Genet Dev,1993,3(2):226-231.
[101]Comb M, Goodman HM. CpG methylation inhibits proenkephalin gene expression and binding of the transcription factor AP-2[J]. Nucleic Acids Res,1990, 18(13):3975-3982.
[102]Meehan RR, Lewis JD, Bird AP. Characterization of MeCP2, a vertebrate DNA binding protein with affinity for methylated DNA[J]. Nucleic Acids Res,1992, 20(19):5085-5092.
[103]Jost JP, Hofsteenge J. The repressor MDBP-2 is a member of the histone H1 family that binds preferentially in vitro and in vivo to methylated nonspecific DNA sequences[J]. Proc Natl Acad Sci U S A,1992,89(20):9499-9503.
[104]Courtier B, Heard E, Avner P. Xce haplotypes show modified methylation in a region of the active X chromosome lying 3'to xist[J]. Proc Natl Acad Sci U S A, 1995,92(8):3531-3535.
[105]Jones PL, Veenstra GJ, Wade PA, et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription[J]. Nat Genet,1998,19(2): 187-191.
[106]Nan X, Ng HH, Johnson CA, et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex[J]. Nature,1998,393(6683):386-389.
[107]Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation[J]. N Engl J Med,2003,349(21):2042-2054.
[108]Feinberg AP, Tycko B. The history of cancer epigenetics[J]. Nat Rev Cancer,2004,4(2):143-153.
[109]Huang KT, Dobrovic A, Fox SB. No evidence for promoter region methylation of the succinate dehydrogenase and fumarate hydratase tumour suppressor genes in breast cancer[J]. BMC Res Notes,2009,2(1):194.
[110]Cao Z, Song JH, Kang YW, et al. Analysis of succinate dehydrogenase subunit B gene alterations in gastric cancers[J]. Pathol Int,2010,60(8):559-565.
[1]Warburg O. On respiratory impairment in cancer cells[J]. Science,1956, 124(3215):269-270.
[2]Rustin P, Munnich A, Rotig A. Succinate dehydrogenase and human diseases: New insights into a well-known enzyme[J]. Eur J Hum Genet,2002,10(5):289-291.
[3]Scheffler IE. Molecular genetics of succinate:Quinone oxidoreductase in eukaryotes[J]. Prog Nucleic Acid Res Mol Biol,1998,60:267-315.
[4]孙飞,饶子和.膜蛋白三维结构研究的新突破—线粒体呼吸链膜蛋白复合物Ⅱ结构解析[J].中国科学院院刊,2005,20(5):381-384.
[5]Saraste M. Oxidative phosphorylation at the fin de siecle[J]. Science,1999, 283(5407):1488-1493.
[6]王喜忠,丁明孝,张穿茂(译),Gerald Karp(原著).分子细胞生物学(中文版)[M].北京:高等教育出版社,2005:177-210.
[7]Thompson L. World health organization classification of tumours:Pathology and genetics of head and neck tumours[J]. Ear Nose Throat J,2006,85(2):74.
[8]Gimenez-Roqueplo AP, Favier J, Rustin P, et al. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas[J]. Cancer Res,2003,63(17):5615-5621.
[9]Bayley JP, van Minderhout I, Weiss MM, et al. Mutation analysis of SDHB and SDHC:novel germline mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma[J]. BMC Med Genet,2006,7(1): 1.
[10]Jansen JC, van den Berg R, Kuiper A, et al. Estimation of growth rate in patients with head and neck paragangliomas influences the treatment proposal [J]. Cancer,2000,88(12):2811-2816.
[11]Pacak K, Eisenhofer G, Ahlman H, et al. Pheochromocytoma: recommendations for clinical practice from the First International Symposium[J]. October 2005. Nat Clin Pract Endocrinol Metab,2007,3(2):92-102.
[12]Knudson AG, Jr. Genetics of human cancer[J]. Annu Rev Genet,1986,20: 231-251.
[13]Baysal BE, Ferrell RE, Willett-Brozick JE, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma[J]. Science,2000, 287(5454):848-851.
[14]Taschner PE, Jansen JC, Baysal BE, et al. Nearly all hereditary paragangliomas in the netherlands are caused by two founder mutations in the SDHD gene[J]. Genes Chromosomes Cancer,2001,31(3):274-281.
[15]Dannenberg H, Dinjens WN, Abbou M, et al. Frequent germ-line succinate dehydrogenase subunit D gene mutations in patients with apparently sporadic parasympathetic paraganglioma[J]. Clin Cancer Res,2002,8(7):2061-2066.
[16]Fakhry N, Niccoli-Sire P, Barlier-Seti A, et al. Cervical paragangliomas:is SDH genetic analysis systematically required? [J] Eur Arch Otorhinolaryngol,2008, 265(5):557-563.
[17]Cremers CW, De Monnink JP, Arts N, et al. Clinical report on the L95P mutation in a Dutch family with paraganglioma[J]. Otol Neurotol,2002,23(5): 755-759.
[18]Ogawa K, Shiga K, Saijo S, et al. A novel G106D alteration of the SDHD gene in a pedigree with familial paraganglioma[J]. Am J Med Genet A,2006,140(22): 2441-2446.
[19]Neumann HP, Pawlu C, Peczkowska M, et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations[J]. JAMA,2004,292(8):943-951.
[20]Boedeker CC, Neumann HP, Ridder GJ, et al. Paragangliomas in patients with mutations of the SDHD gene[J]. Otolaryngol Head Neck Surg,2005,132(3): 467-470.
[21]Hensen EF, Bay ley JP. Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma[J]. Fam Cancer,2011,10(2):355-363.
[22]Burnichon N, Rohmer V, Amar L, et al. The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas[J]. J Clin Endocrinol Metab,2009,94(8):2817-2827.
[23]Hirawake H, Taniwaki M, Tamura A, et al. Cytochrome b in human complex II (succinate-ubiquinone oxidoreductase):cDNA cloning of the components in liver mitochondria and chromosome assignment of the genes for the large (SDHC) and small (SDHD) subunits to 1q21 and 11q23[J]. Cytogenet Cell Genet,1997, 79(1-2):132-138.
[24]Heutink P, van der Mey AG, Sandkuijl LA, et al. A gene subject to genomic imprinting and responsible for hereditary paragangliomas maps to chromosome 11q23-qter[J]. Hum Mol Genet,1992,1(1):7-10.
[25]Baysal BE, McKay SE, Kim YJ, et al. Genomic imprinting at a boundary element flanking the SDHD locus[J]. Hum Mol Genet,2011,20(22):4452-4461.
[26]Muller U. Pathological mechanisms and parent-of-origin effects in hereditary paraganglioma/pheochromocytoma (PGL/PCC) [J]. Neurogenetics,2011, 12(3):175-181.
[27]Hensen EF, Jordanova ES, van Minderhout IJ, et al. Somatic loss of maternal chromosome 11 causes parent-of-origin-dependent inheritance in SDHD-linked paraganglioma and phaeochromocytoma families[J]. Oncogene,2004, 23(23):4076-4083.
[28]Pigny P, Vincent A, Cardot Bauters C, et al. Paraganglioma after maternal transmission of a succinate dehydrogenase gene mutation[J]. J Clin Endocrinol Metab, 2008,93(5):1609-1615.
[29]Neumann HP, Erlic Z. Maternal transmission of symptomatic disease with SDHD mutation:fact or fiction? [J] J Clin Endocrinol Metab,2008,93(5): 1573-1575.
[30]Baysal BE, Willett-Brozick JE, Lawrence EC, et al. Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas[J]. J Med Genet,2002,39(3):178-183.
[31]Mhatre AN, Li Y, Feng L, et al. SDHB, SDHC, and SDHD mutation screen in sporadic and familial head and neck paragangliomas[J]. Clin Genet,2004,66(5): 461-466.
[32]Lima J, Feijao T, Ferreira da Silva A, et al. High frequency of germline succinate dehydrogenase mutations in sporadic cervical paragangliomas in northern spain:mitochondrial succinate dehydrogenase structure-function relationships and clinical-pathological correlations [J]. J Clin Endocrinol Metab,2007,92(12): 4853-4864.
[33]Astuti D, Hart-Holden N, Latif F, et al. Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility[J]. Clin Endocrinol (Oxf),2003,59(6):728-733.
[34]Amar L, Bertherat J, Baudin E, et al. Genetic testing in pheochromocytoma or functional paraganglioma[J]. J Clin Oncol,2005,23(34):8812-8818.
[35]Naito M, Usui T, Tamanaha T, et al. R27X nonsense mutation of the SDHB gene in a patient with sporadic malignant paraganglioma[J]. Endocrine,2009,36(1): 10-15.
[36]Brouwers FM, Eisenhofer G, Tao JJ, et al. High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas:implications for genetic testing[J]. J Clin Endocrinol Metab,2006, 91(11):4505-4509.
[37]Amar L, Baudin E, Burnichon N, et al. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas[J]. J Clin Endocrinol Metab,2007,92(10):3822-3828.
[38]Timmers HJ, Gimenez-Roqueplo AP, Mannelli M, et al. Clinical aspects of SDHx-related pheochromocytoma and paraganglioma[J]. Endocr Relat Cancer,2009, 16(2):391-400.
[39]Jimenez C, Cote G, Arnold A, et al. Review:Should patients with apparently sporadic pheochromocytomas or paragangliomas be screened for hereditary syndromes? [J] J Clin Endocrinol Metab,2006,91(8):2851-2858.
[40]Niemann S, Muller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3[J]. Nat Genet,2000,26(3):268-270.
[41]Niemann S, Muller U, Engelhardt D, et al. Autosomal dominant malignant and catecholamine-producing paraganglioma caused by a splice donor site mutation in SDHC[J]. Hum Genet,2003,113(1):92-94.
[42]Schiavi F, Boedeker CC, Bausch B, et al. Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene[J]. JAMA, 2005,294(16):2057-2063.
[43]Burnichon N, Briere JJ, Libe R, et al. SDHA is a tumor suppressor gene causing paraganglioma[J]. Hum Mol Genet,2010,19(15):3011-3020.
[44]Korpershoek E, Favier J, Gaal J, et al. SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas[J]. J Clin Endocrinol Metab,2011,96(9):E1472-1476.
[45]Hao HX, Khalimonchuk O, Schraders M, et al. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma[J]. Science, 2009,325(5944):1139-1142.
[46]Bayley JP, Kunst HP, Cascon A, et al. SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma[J]. Lancet Oncol,2010,11(4): 366-372.
[47]Bauters C, Vantyghem MC, Leteurtre E, et al. Hereditary phaeochromocytomas and paragangliomas:A study of five susceptibility genes[J]. J Med Genet,2003,40(6):e75.
[48]Gimm O, Armanios M, Dziema H, et al. Somatic and occult germ-line mutations in SDHD, a mitochondrial complex Ⅱ gene, in nonfamilial pheochromocytoma[J]. Cancer Res,2000,60(24):6822-6825.
[49]Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma[J]. Am J Hum Genet,2001,69(1):49-54.
[50]Neumann HP, Erlic Z, Boedeker CC, et al. Clinical predictors for germline mutations in head and neck paraganglioma patients:cost reduction strategy in genetic diagnostic process as fall-out[J]. Cancer Res,2009,69(8):3650-3656.
[51]Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the stomach:a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up [J]. Am J Surg Pathol,2005,29(1):52-68.
[52]Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors[J]. Science,2003,299(5607):708-710.
[53]Rubin BP, Singer S, Tsao C, et al. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors[J]. Cancer Res,2001,61(22):8118-8121.
[54]Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors[J]. Science,1998,279(5350):577-580.
[55]Kinoshita K, Hirota S, Isozaki K, et al. Absence of c-kit gene mutations in gastrointestinal stromal tumours from neurofibromatosis type 1 patients [J]. J Pathol, 2004,202(1):80-85.
[56]Gill AJ, Chou A, Vilain R, et al. Immunohistochemistry for SDHB divides gastrointestinal stromal tumors (GISTs) into 2 distinct types[J]. Am J Surg Pathol, 2010,34(5):636-644.
[57]Prakash S, Sarran L, Socci N, et al. Gastrointestinal stromal tumors in children and young adults:a clinicopathologic, molecular, and genomic study of 15 cases and review of the literature[J]. J Pediatr Hematol Oncol,2005,27(4):179-187.
[58]Miettinen M, Lasota J, Sobin LH. Gastrointestinal stromal tumors of the stomach in children and young adults:a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases with long-term follow-up and review of the literature[J]. Am J Surg Pathol,2005,29(10):1373-1381.
[59]Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors:A consensus approach[J]. Hum Pathol,2002,33(5):459-465.
[60]Carney JA, Stratakis CA. Familial paraganglioma and gastric stromal sarcoma:a new syndrome distinct from the Carney triad[J]. Am J Med Genet,2002, 108(2):132-139.
[61]Pasini B, Mc Whinney SR, Bei T, et al. Clinical and molecular genetics of patients with the carney-stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD[J]. Eur J Hum Genet,2008,16(1):79-88.
[62]Pantaleo MA, Nannini M, Astolfi A, et al. A distinct pediatric-type gastrointestinal stromal tumor in adults:potential role of succinate dehydrogenase subunit Amutations[J]. Am J Surg Pathol,2011,35(11):1750-1752.
[63]Pantaleo MA, Astolfi A, Indio V, et al. SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing[J]. J Natl Cancer Inst,2011,103(12):983-987.
[64]Janeway KA, Kim SY, Lodish M, et al. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations [J]. Proc Natl Acad Sci U S A,2011,108(1):314-318.
[65]Miettinen M, Wang ZF, Sarlomo-Rikala M, et al. Succinate dehydrogenase-deficient GISTs:A clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age[J]. Am J Surg Pathol,2011,35(11):1712-1721.
[66]Gaal J, Stratakis CA, Carney JA, et al. SDHB immunohistochemistry:a useful tool in the diagnosis of Carney-Stratakis and Carney triad gastrointestinal stromal tumors[J]. Mod Pathol,2011,24(1):147-151.
[67]Gill AJ. Succinate dehydrogenase (SDH) and mitochondrial driven neoplasia[J]. Pathology,2012,44(4):285-292.
[68]Thoenes W, Storkel S, Rumpelt HJ. Histopathology and classification of renal cell tumors (adenomas, oncocytomas and carcinomas). The basic cytological and histopathological elements and their use for diagnostics [J]. Pathol Res Pract,1986, 181(2):125-143.
[69]Schaefer A, Stephan C, Busch J, et al. Diagnostic, prognostic and therapeutic implications of microRNAs in urologic tumors[J]. Nat Rev Urol,2010, 7(5):286-297.
[70]Cohen HT, McGovern FJ. Renal-cell carcinoma[J]. N Engl J Med,2005, 353(23):2477-2490.
[71]Kim NW, Piatyszek MA, Prowse KR, et al. Specific association of human telomerase activity with immortal cells and cancer[J]. Science,1994,266(5193): 2011-2015.
[72]Takakura M, Kyo S, Kanaya T, et al. Expression of human telomerase subunits and correlation with telomerase activity in cervical cancer[J]. Cancer Res, 1998,58(7):1558-1561.
[73]Pavlovich CP, Schmidt LS. Searching for the hereditary causes of renal-cell carcinoma[J]. Nat Rev Cancer,2004,4(5):381-393.
[74]Tomlinson IP, Alam NA, Rowan AJ, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer[J]. Nat Genet,2002,30(4):406-410.
[75]Gill AJ, Pachter NS, Chou A, et al. Renal tumors associated with germline SDHB mutation show distinctive morphology [J]. Am J Surg Pathol,2011,35(10): 1578-1585.
[76]Ricketts C, Woodward ER, Killick P, et al. Germline SDHB mutations and familial renal cell carcinoma[J]. J Natl Cancer Inst,2008,100(17):1260-1262.
[77]Vanharanta S, Buchta M, McWhinney SR, et al. Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma[J]. Am J Hum Genet,2004,74(1):153-159.
[78]Tuthill M, Barod R, Pyle L, et al. A report of succinate dehydrogenase B deficiency associated with metastatic papillary renal cell carcinoma:successful treatment with the multi-targeted tyrosine kinase inhibitor sunitinib[J]. BMJ Case Rep, 2009,2009
[79]Henderson A, Douglas F, Perros P, et al. SDHB-associated renal oncocytoma suggests a broadening of the renal phenotype in hereditary paragangliomatosis[J]. Fam Cancer,2009,8(3):257-260.
[80]Housley SL, Lindsay RS, Young B, et al. Renal carcinoma with giant mitochondria associated with germ-line mutation and somatic loss of the succinate dehydrogenase B gene[J]. Histopathology,2010,56(3):405-408.
[81]Douwes Dekker PB, Hogendoorn PC, Kuipers-Dijkshoorn N, et al. SDHD mutations in head and neck paragangliomas result in destabilization of complex II in the mitochondrial respiratory chain with loss of enzymatic activity and abnormal mitochondrial morphology[J]. J Pathol,2003,201(3):480-486.
[82]Malinoc A, Sullivan M, Wiech T, et al. Biallelic inactivation of the SDHC gene in renal carcinoma associated with paraganglioma syndrome type 3[J]. Endocr Relat Cancer,2012,19(3):283-290.
[83]Leigh D. Subacute necrotizing encephalomyelopathy in an infant[J]. J Neurol Neurosurg Psychiatry,1951,14(3):216-221.
[84]Benit P, Slama A, Cartault F, et al. Mutant NDUFS3 subunit of mitochondrial complex I causes leigh syndrome[J]. J Med Genet,2004,41(1):14-17.
[85]Tatuch Y, Christodoulou J, Feigenbaum A, et al. Heteroplasmic mtDNA mutation (T----G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high[J]. Am J Hum Genet,1992,50(4):852-858.
[86]Komaki H, Akanuma J, Iwata H, et al. A novel mtDNA C11777A mutation in Leigh syndrome[J]. Mitochondrion,2003,2(4):293-304.
[87]DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases[J]. N Engl J Med,2003,348(26):2656-2668.
[88]Rahman S, Blok RB, Dahl HH, et al. Leigh syndrome:clinical features and biochemical and DNA abnormalities[J]. Ann Neurol,1996,39(3):343-351.
[89]Pequignot MO, Dey R, Zeviani M, et al. Mutations in the SURF1 gene associated with Leigh syndrome and cytochrome C oxidase deficiency [J]. Hum Mutat, 2001,17(5):374-381.
[90]Lissens W, De Meirleir L, Seneca S, et al. Mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency[J]. Hum Mutat,2000,15(3):209-219.
[91]Bourgeron T, Rustin P, Chretien D, et al. Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency [J]. Nat Genet,1995,11(2):144-149.
[92]Parfait B, Chretien D, Rotig A, et al. Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex Ⅱ in a patient with Leigh syndrome[J]. Hum Genet,2000,106(2):236-243.
[93]Van Coster R, Seneca S, Smet J, et al. Homozygous Gly555Glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex Ⅱ [J]. Am J Med Genet A,2003,120A(1):13-18.
[94]Pagnamenta AT, Hargreaves IP, Duncan AJ, et al. Phenotypic variability of mitochondrial disease caused by a nuclear mutation in complex Ⅱ[J]. Mol Genet Metab,2006,89(3):214-221.
[95]Gonzalez C, Almaraz L, Obeso A, et al. Carotid body chemoreceptors:from natural stimuli to sensory discharges [J]. Physiol Rev,1994,74(4):829-898.
[96]Gimenez-Roqueplo AP, Favier J, Rustin P, et al. The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway [J]. Am J Hum Genet,2001,69(6):1186-1197.
[97]Dahia PL, Ross KN, Wright ME, et al. A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas[J]. PLoS Genet,2005,1(1): 72-80.
[98]Li L, Madu CO, Lu A, et al. HIF-1α promotes a hypoxia-independent cell migration[J]. Open Biol J,2010,3:8-14.
[99]Poon E, Harris AL, Ashcroft M. Targeting the hypoxia-inducible factor (HIF) pathway in cancer[J]. Expert Rev Mol Med,2009,11(1):e26.
[100]Fedele AO, Whitelaw ML, Peet DJ:Regulation of gene expression by the hypoxia-inducible factors[J]. Mol Interv,2002,2(4):229-243.
[101]Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics[J]. Oncogene,2010,29(5):625-634.
[102]Kantorovich V, King KS, Pacak K. SDH-related pheochromocytoma and paraganglioma[J]. Best Pract Res Clin Endocrinol Metab,2010,24(3):415-424.
[103]Luna-Ortiz K, Rascon-Ortiz M, Villavicencio-Valencia V, et al. Carotid body tumors:review of a 20-year experience[J]. Oral Oncol,2005,41(1):56-61.
[104]Davidovic L, Ilic N, Dimitrijevic M, et al. Surgical management of cervical paragangliomas[J]. Am Surg,2008,74(12):1171-1176.
[105]Douwes Dekker PB, Kuipers-Dijkshoorn NJ, Baelde HJ, et al. Basic fibroblast growth factor and fibroblastic growth factor receptor-1 may contribute to head and neck paraganglioma development by an autocrine or paracrine mechanism[J]. Hum Pathol,2007,38(1):79-85.
[106]Ishii N, Fujii M, Hartman PS, et al. A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes[J]. Nature,1998, 394(6694):694-697.
[107]Selak MA, Armour SM, MacKenzie ED, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase[J]. Cancer Cell,2005,7(1):77-85.
[108]Pollard PJ, Briere JJ, Alam NA, et al. Accumulation of Krebs cycle intermediates and over-expression of HIF1 alpha in tumours which result from germline FH and SDH mutations[J]. Hum Mol Genet,2005,14(15):2231-2239.
[109]van Gurp M, Festjens N, van Loo G, et al. Mitochondrial intermembrane proteins in cell death[J]. Biochem Biophys Res Commun,2003,304(3):487-497.
[110]Senoo-Matsuda N, Hartman PS, Akatsuka A, et al. A complex II defect affects mitochondrial structure, leading to ced-3-and ced-4-dependent apoptosis and aging[J]. J Biol Chem,2003,278(24):22031-22036.