DOI QR코드

DOI QR Code

Prognostic Significance of Sirtuins Expression in Papillary Thyroid Carcinoma

  • Kang, Yea Eun (Department of Endocrinology and Metabolism, College of Medicine, Chungnam National University) ;
  • Shong, Minho (Department of Endocrinology and Metabolism, College of Medicine, Chungnam National University) ;
  • Kim, Jin Man (Department of Pathology, College of Medicine, Chungnam National University) ;
  • Koo, Bon Seok (Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University)
  • Received : 2018.08.14
  • Accepted : 2018.09.13
  • Published : 2018.11.30

Abstract

Background and Objectives: Sirtuins (SIRTs) play important roles in cellular and organismal homeostasis. They have distinct gene expression patterns in various cancers; however, the relationship between SIRT expression and the progression of thyroid cancer is unclear. We investigated the expression of SIRTs in patients with papillary thyroid carcinoma (PTC) and their role as biomarkers for predicting the aggressiveness of this disease. Materials and Methods: We used immunohistochemical staining to evaluate the expression of SIRT1 and SIRT3 in tumor specimens from 270 patients with PTC. We also evaluated the potential association between SIRT expression and diverse clinicopathological features. Results: High SIRT1 expression was negatively correlated with lymphovascular invasion, central lymph node metastasis, and lateral lymph node metastasis. Multivariate analyses revealed that high SIRT1 expression was a negative independent risk factor for lateral lymph node metastasis. By contrast, high SIRT3 expression was positively correlated with locoregional recurrence. Interestingly, when patients were grouped by tumor SIRT expression patterns, the group with low SIRT1 expression and high SIRT3 expression was correlated with more aggressive cancer phenotypes including central lymph node metastasis and lateral lymph node metastasis. Conclusion: Our results suggest that SIRTs play dual roles in tumor progression, and the combination of decreased SIRT1 expression and increased SIRT3 expression is significantly associated with a poor prognosis in patients with PTC.

Keywords

Acknowledgement

Supported by : National Research Foundation of Korea (NRF)

References

  1. Guarente L. Franklin H. Epstein lecture: sirtuins, aging, and medicine. N Engl J Med 2011;364(23):2235-44. https://doi.org/10.1056/NEJMra1100831
  2. Frye RA. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun 2000;273(2):793-8. https://doi.org/10.1006/bbrc.2000.3000
  3. Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell 2012;21(3):297-308. https://doi.org/10.1016/j.ccr.2012.02.014
  4. Chalkiadaki A, Guarente L. The multifaceted functions of sirtuins in cancer. Nat Rev Cancer 2015;15(10):608-24. https://doi.org/10.1038/nrc3985
  5. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144(5):646-74. https://doi.org/10.1016/j.cell.2011.02.013
  6. Mirebeau-Prunier D, Le Pennec S, Jacques C, Fontaine JF, Gueguen N, Boutet-Bouzamondo N, et al. Estrogen-related receptor alpha modulates lactate dehydrogenase activity in thyroid tumors. PLoS One 2013;8(3):e58683. https://doi.org/10.1371/journal.pone.0058683
  7. Lee MH, Lee SE, Kim DW, Ryu MJ, Kim SJ, Kim SJ, et al. Mitochondrial localization and regulation of BRAFV600E in thyroid cancer: a clinically used RAF inhibitor is unable to block the mitochondrial activities of BRAFV600E. J Clin Endocrinol Metab 2011;96(1):E19-30. https://doi.org/10.1210/jc.2010-1071
  8. Herranz D, Maraver A, Canamero M, Gomez-Lopez G, Inglada-Perez L, Robledo M, et al. SIRT1 promotes thyroid carcinogenesis driven by PTEN deficiency. Oncogene 2013;32(34):4052-6. https://doi.org/10.1038/onc.2012.407
  9. Kweon KH, Lee CR, Jung SJ, Ban EJ, Kang SW, Jeong JJ, et al. Sirt1 induction confers resistance to etoposide-induced genotoxic apoptosis in thyroid cancers. Int J Oncol 2014;45(5):2065-75. https://doi.org/10.3892/ijo.2014.2585
  10. Finkel T, Deng CX, Mostoslavsky R. Recent progress in the biology and physiology of sirtuins. Nature 2009;460(7255):587-91. https://doi.org/10.1038/nature08197
  11. Pfluger PT, Herranz D, Velasco-Miguel S, Serrano M, Tschop MH. Sirt1 protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci U S A 2008;105(28):9793-8. https://doi.org/10.1073/pnas.0802917105
  12. Herranz D, Munoz-Martin M, Canamero M, Mulero F, Martinez-Pastor B, Fernandez-Capetillo O, et al. Sirt1 improves healthy ageing and protects from metabolic syndromeassociated cancer. Nat Commun 2010;1:3. https://doi.org/10.1038/ncomms1001
  13. Fang Y, Nicholl MB. Sirtuin 1 in malignant transformation: friend or foe? Cancer Lett 2011;306(1):10-4. https://doi.org/10.1016/j.canlet.2011.02.019
  14. Deng CX. SIRT1, is it a tumor promoter or tumor suppressor? Int J Biol Sci 2009;5(2):147-52.
  15. Huffman DM, Grizzle WE, Bamman MM, Kim JS, Eltoum IA, Elgavish A, et al. SIRT1 is significantly elevated in mouse and human prostate cancer. Cancer Res 2007;67(14):6612-8. https://doi.org/10.1158/0008-5472.CAN-07-0085
  16. Bradbury CA, Khanim FL, Hayden R, Bunce CM, White DA, Drayson MT, et al. Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors. Leukemia 2005;19(10):1751-9. https://doi.org/10.1038/sj.leu.2403910
  17. Lim CS. SIRT1: tumor promoter or tumor suppressor? Med Hypotheses 2006;67(2):341-4. https://doi.org/10.1016/j.mehy.2006.01.050
  18. Banks AS, Kon N, Knight C, Matsumoto M, Gutierrez-Juarez R, Rossetti L, et al. SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab 2008;8(4):333-41. https://doi.org/10.1016/j.cmet.2008.08.014
  19. Firestein R, Blander G, Michan S, Oberdoerffer P, Ogino S, Campbell J, et al. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS One 2008;3(4):e2020. https://doi.org/10.1371/journal.pone.0002020
  20. Kabra N, Li Z, Chen L, Li B, Zhang X, Wang C, et al. SirT1 is an inhibitor of proliferation and tumor formation in colon cancer. J Biol Chem 2009;284(27):18210-7. https://doi.org/10.1074/jbc.M109.000034
  21. Wang RH, Zheng Y, Kim HS, Xu X, Cao L, Luhasen T, et al. Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis. Mol Cell 2008;32(1):11-20. https://doi.org/10.1016/j.molcel.2008.09.011
  22. Lombard DB, Alt FW, Cheng HL, Bunkenborg J, Streeper RS, Mostoslavsky R, et al. Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol Cell Biol 2007;27(24):8807-14. https://doi.org/10.1128/MCB.01636-07
  23. Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 2010;464(7285):121-5. https://doi.org/10.1038/nature08778
  24. Sundaresan NR, Gupta M, Kim G, Rajamohan SB, Isbatan A, Gupta MP. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J Clin Invest 2009;119(9):2758-71. https://doi.org/10.1172/jci39162
  25. Li S, Banck M, Mujtaba S, Zhou MM, Sugrue MM, Walsh MJ. p53-induced growth arrest is regulated by the mitochondrial SirT3 deacetylase. PLoS One 2010;5(5):e10486. https://doi.org/10.1371/journal.pone.0010486
  26. Ashraf N, Zino S, Macintyre A, Kingsmore D, Payne AP, George WD, et al. Altered sirtuin expression is associated with node-positive breast cancer. Br J Cancer 2006;95(8):1056-61. https://doi.org/10.1038/sj.bjc.6603384
  27. Allison SJ, Milner J. SIRT3 is pro-apoptotic and participates in distinct basal apoptotic pathways. Cell Cycle 2007;6(21):2669-77. https://doi.org/10.4161/cc.6.21.4866
  28. Ford J, Jiang M, Milner J. Cancer-specific functions of SIRT1 enable human epithelial cancer cell growth and survival. Cancer Res 2005;65(22):10457-63. https://doi.org/10.1158/0008-5472.CAN-05-1923
  29. Bell EL, Guarente L. The SirT3 divining rod points to oxidative stress. Mol Cell 2011;42(5):561-8. https://doi.org/10.1016/j.molcel.2011.05.008
  30. Hallows WC, Yu W, Smith BC, Devries MK, Ellinger JJ, Someya S, et al. Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction. Mol Cell 2011;41(2):139-49. https://doi.org/10.1016/j.molcel.2011.01.002
  31. Wang RH, Sengupta K, Li C, Kim HS, Cao L, Xiao C, et al. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell 2008;14(4):312-23. https://doi.org/10.1016/j.ccr.2008.09.001
  32. Jang KY, Noh SJ, Lehwald N, Tao GZ, Bellovin DI, Park HS, et al. SIRT1 and c-Myc promote liver tumor cell survival and predict poor survival of human hepatocellular carcinomas. PLoS One 2012;7(9):e45119. https://doi.org/10.1371/journal.pone.0045119