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01-08-2013 | Research Article

Reduced succinate dehydrogenase B expression is associated with growth and de-differentiation of colorectal cancer cells

Authors: Decai Zhang, Wei Wang, Bo Xiang, Nan Li, Shuo Huang, Weiwei Zhou, Yingnan Sun, Xiaoyan Wang, Jian Ma, Guiyuan Li, Xiayu Li, Shourong Shen

Published in: Tumor Biology | Issue 4/2013

Abstract

Succinate dehydrogenases (SDH), including SDHA, SDHB, SDHC, and SDHD, form the respiratory complex II in the mitochondria and play an important role in cell growth and homeostasis. In order to evaluate the expression and functional significance of SDH in colorectal cancer, the expression of four SDH subunits was analyzed, and SDHB protein was found to be significantly lower in colorectal cancer tissues. In vitro experiments including cell growth assay, colony formation assay, cell cycle analysis, and nude mouse xenograft of SDHB-transfected colorectal cancer cell line SW620 were performed. Notably, reduced SDHB expression in tumor tissues was associated with tumor de-differentiation, and restoration of SDHB could inhibit the growth of cancer cells both in vitro and in vivo. Furthermore, cDNA microarray of SDHB-transfected cell line showed that most of the differentially expressed genes are related to cell cycle control and cell proliferation. Thus, we conclude that SDHB expression is significantly decreased in human colorectal cancer tissues, and reconstitution of SDHB in colorectal cancer may be a potential therapeutic approach to inhibit aggressiveness of colorectal cancer.

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Jemal A, Center MM, DeSantis C, Ward EM. Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev. 2010;19:1893–907.PubMedCrossRef

Markowitz SD, Bertagnolli MM. Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med. 2009;361:2449–60.PubMedCrossRef

Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–67.PubMedCrossRef

Macleod K. Tumor suppressor genes. Curr Opin Genet Dev. 2000;10:81–93.PubMedCrossRef

Peng Y, Li X, Wu M, Yang J, Liu M, Zhang W, et al. New prognosis biomarkers identified by dynamic proteomic analysis of colorectal cancer. Mol Biosyst. 2012;8:3077–88.PubMedCrossRef

Bardella C, Pollard PJ, Tomlinson I. SDH mutations in cancer. Biochim Biophys Acta. 1807;2011:1432–43.

Rustin P, Munnich A, Rötig A. Succinate dehydrogenase and human diseases: new insights into a well-known enzyme. Eur J Hum Genet. 2002;10:289–91.PubMedCrossRef

Saraste M. Oxidative phosphorylation at the fin de siècle. Science. 1999;283:1488–93.PubMedCrossRef

Scheffler IE. Molecular genetics of succinate:quinone oxidoreductase in eukaryotes. Prog Nucleic Acid Res Mol Biol. 1998;60:267–315.PubMedCrossRef

10.

Bolland M, Benn D, Croxson M, McCall J, Shaw JF, Baillie T, et al. Gastrointestinal stromal tumour in succinate dehydrogenase subunit B mutation-associated familial phaeochromocytoma/paraganglioma. ANZ J Surg. 2006;76:763–4.PubMedCrossRef

11.

Kantorovich V, King KS, Pacak K. SDH-related pheochromocytoma and paraganglioma. Best Pract Res Clin Endocrinol Metab. 2010;24:415–24.PubMedCrossRef

12.

Pasini B, Stratakis CA. SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma-paraganglioma syndromes. J Intern Med. 2009;266:19–42.PubMedCrossRef

13.

Rutter J, Winge DR, Schiffman JD. Succinate dehydrogenase—assembly, regulation and role in human disease. Mitochondrion. 2010;10:393–401.PubMedCrossRef

14.

Vanharanta S, Buchta M, McWhinney SR, Virta SK, Peczkowska M, Morrison CD, et al. Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. Am J Hum Genet. 2004;74:153–9.PubMedCrossRef

15.

Dahia PL, Ross KN, Wright ME, Hayashida CY, Santagata S, Barontini M, et al. A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet. 2005;1:72–80.PubMedCrossRef

16.

Gimenez-Roqueplo AP, Favier J, Rustin P, Mourad JJ, Plouin PF, Corvol 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. Am J Hum Genet. 2001;69:1186–97.PubMedCrossRef

17.

Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Kerlan V, Plouin PF, et al. Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma. J Clin Endocrinol Metab. 2002;87:4771–4.PubMedCrossRef

18.

Pollard PJ, Briere JJ, Alam NA, Barwell J, Barclay E, Wortham NC, et al. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet. 2005;14:2231–9.PubMedCrossRef

19.

Peng Y, Li H, Wu M, Wang X, Fan S, Liu F, et al. NGX6 inhibits AP-1 and Ets-1 expression and down-regulates cyclin D1 in human colorectal cancer. Acta Biochim Biophys Sin (Shanghai). 2009;41:504–14.CrossRef

20.

Li W, Li X, Wang W, Tan Y, Yi M, Yang J, et al. NOR1 is an HSF1- and NRF1-regulated putative tumor suppressor inactivated by promoter hypermethylation in nasopharyngeal carcinoma. Carcinogenesis. 2011;32:1305–14.PubMedCrossRef

21.

da Huang W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4:44–57.CrossRef

22.

Burnichon N, Brière JJ, Libé R, Vescovo L, Rivière J, Tissier F, et al. SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet. 2010;19:3011–20.PubMedCrossRef

23.

Celestino R, Lima J, Faustino A, Máximo V, Gouveia A, Vinagre J, et al. A novel germline SDHB mutation in a gastrointestinal stromal tumor patient without bona fide features of the Carney-Stratakis dyad. Fam Cancer. 2012;11:189–94.PubMedCrossRef

24.

Zantour B, Guilhaume B, Tissier F, Louvel A, Jeunemaitre X, Gimenez-Roqueplo AP, et al. A thyroid nodule revealing a paraganglioma in a patient with a new germline mutation in the succinate dehydrogenase B gene. Eur J Endocrinol. 2004;151:433–8.PubMedCrossRef

25.

Armstrong R, Greenhalgh KL, Rattenberry E, Judd B, Shukla R, Losty PD, et al. Succinate dehydrogenase subunit B (SDHB) gene deletion associated with a composite paraganglioma/neuroblastoma. J Med Genet. 2009;46:215–6.PubMedCrossRef

26.

Housley SL, Lindsay RS, Young B, McConachie M, Mechan D, Baty D, et al. Renal carcinoma with giant mitochondria associated with germ-line mutation and somatic loss of the succinate dehydrogenase B gene. Histopathology. 2010;56:405–8.PubMedCrossRef

27.

Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell. 2005;7:77–85.PubMedCrossRef

28.

Yankovskaya V, Horsefield R, Törnroth S, Luna-Chavez C, Miyoshi H, Léger C, et al. Architecture of succinate dehydrogenase and reactive oxygen species generation. Science. 2003;299:700–4.PubMedCrossRef

29.

Gottlieb E, Tomlinson IP. Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer. 2005;5:857–66.PubMedCrossRef

30.

Kaelin Jr WG, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008;30:393–402.PubMedCrossRef

31.

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 Gerontol A Biol Sci Med Sci. 1998;53:B240–4.PubMedCrossRef

32.

Ishii T, Yasuda K, Akatsuka A, Hino O, Hartman PS, Ishii N. A mutation in the SDHC gene of complex II increases oxidative stress, resulting in apoptosis and tumorigenesis. Cancer Res. 2005;65:203–9.PubMed

33.

Slane BG, Aykin-Burns N, Smith BJ, Kalen AL, Goswami PC, Domann FE, et al. Mutation of succinate dehydrogenase subunit C results in increased O2.-, oxidative stress, and genomic instability. Cancer Res. 2006;66:7615–20.PubMedCrossRef

34.

Smith EH, Janknecht R, Maher 3rd LJ. Succinate inhibition of alpha-ketoglutarate-dependent enzymes in a yeast model of paraganglioma. Hum Mol Genet. 2007;16:3136–48.PubMedCrossRef

35.

Goffrini P, Ercolino T, Panizza E, Giachè V, Cavone L, Chiarugi A, 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. Hum Mol Genet. 2009;18:1860–8.PubMedCrossRef

36.

Szeto SS, Reinke SN, Sykes BD, Lemire BD. Ubiquinone-binding site mutations in the Saccharomyces cerevisiae succinate dehydrogenase generate superoxide and lead to the accumulation of succinate. J Biol Chem. 2007;282:27518–26.PubMedCrossRef

37.

Leibovitz A, Stinson JC, McCombs 3rd WB, McCoy CE, Mazur KC, Mabry ND. Classification of human colorectal adenocarcinoma cell lines. Cancer Res. 1976;36:4562–9.PubMed

38.

Lewis SP, Willis AN, Johnson AE, Resau J, Burnatowska-Hledin MA. Mutational analysis of VACM-1/cul5 exons in cancer cell lines. APMIS. 2011;119:421–30.PubMedCrossRef

39.

Xu XM, Wang XB, Chen MM, Liu T, Li YX, Jia WH, et al. Microrna-19a and -19b regulate cervical carcinoma cell proliferation and invasion by targeting CUL5. Cancer Lett. 2012;322:148–58.PubMedCrossRef

40.

Bender FC, Reymond MA, Bron C, Quest AF. Caveolin-1 levels are down-regulated in human colon tumors, and ectopic expression of caveolin-1 in colon carcinoma cell lines reduces cell tumorigenicity. Cancer Res. 2000;60:5870–8.PubMed

41.

Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 1998;95:29–39.PubMedCrossRef

42.

Weng LP, Brown JL, Baker KM, Ostrowski MC, Eng C. PTEN blocks insulin-mediated ETS-2 phosphorylation through MAP kinase, independently of the phosphoinositide 3-kinase pathway. Hum Mol Genet. 2002;11:1687–96.PubMedCrossRef

43.

Ni Y, Zbuk KM, Sadler T, Patocs A, Lobo G, Edelman E, et al. Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes. Am J Hum Genet. 2008;83:261–8.PubMedCrossRef

Title: Reduced succinate dehydrogenase B expression is associated with growth and de-differentiation of colorectal cancer cells
Authors: Decai Zhang
Wei Wang
Bo Xiang
Nan Li
Shuo Huang
Weiwei Zhou
Yingnan Sun
Xiaoyan Wang
Jian Ma
Guiyuan Li
Xiayu Li
Shourong Shen
Publication date: 01-08-2013
Publisher: Springer Netherlands
Published in: Tumor Biology / Issue 4/2013
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI: https://doi.org/10.1007/s13277-013-0781-4

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