Skip to main content
Log in

Overexpression of Sirtuin-1 is associated with poor clinical outcome in esophageal squamous cell carcinoma

  • Original Article
  • Published:
Tumor Biology

Abstract

Sirtuin-1 (SIRT1), one member of the mammalian sirtuin family, has been suggested to play an essential role in the development and progression of many tumors. However, the relationship between expression of SIRT1 and prognosis of esophageal cancer is still unknown. This study aimed to investigate SIRT1 expression and its possible prognostic value in esophageal squamous cell carcinoma (ESCC). A total of 86 patients with ESCC were enrolled in our study group. Clinical data and matched tissues were collected. Western blotting and real-time quantitative reverse transcription PCR (RT-PCR) were carried out to explore the expression of SIRT1 in four human ESCC cell lines, one human normal epithelial cell line, and clinical ESCC tissues. Expression levels of SIRT1 protein in tissues of specimens were detected by immunohistochemistry (IHC). Survival analysis was carried out using the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were performed to evaluate the correlation of SIRT1 expression with clinical features and prognosis of ESCC patients. Basal expression levels of SIRT1 protein in ESCC tumor tissues and cell lines were higher than those in the control groups. IHC analysis showed that expression levels of SIRT1 protein significantly correlated with TNM stage and lymph node status of ESCC patients. Moreover, upregulated SIRT1 expression was associated with poor clinical prognosis. High SIRT1 expression in ESCC could serve as an independent predictive biomarker for diagnosis and prognosis in ESCC patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

SIRT1:

Sirtuin-1

ESCC:

Esophageal squamous cell carcinoma

EA:

Esophageal adenocarcinoma

RT-PCR:

Reverse transcription-polymerase chain reaction

IHC:

Immunohistochemistry

PBS:

Phosphate-buffered saline

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

References

  1. Stewart BW, Wild C, International Agency for Research on Cancer, World Health Organization. World cancer report 2014

  2. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA: Cancer J Clin. 2015;65(2):87–108. doi:10.3322/caac.21262.

    Google Scholar 

  3. Carafa V, Nebbioso A, Altucci L. Sirtuins and disease: the road ahead. Front Pharmacol. 2012;3:4. doi:10.3389/fphar.2012.00004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 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. doi:10.1158/0008-5472.CAN-07-0085.

    Article  CAS  PubMed  Google Scholar 

  5. Lee H, Kim KR, Noh SJ, Park HS, Kwon KS, Park BH, et al. Expression of DBC1 and SIRT1 is associated with poor prognosis for breast carcinoma. Hum Pathol. 2011;42(2):204–13. doi:10.1016/j.humpath.2010.05.023.

    Article  CAS  PubMed  Google Scholar 

  6. Stunkel W, Peh BK, Tan YC, Nayagam VM, Wang X, Salto-Tellez M, et al. Function of the SIRT1 protein deacetylase in cancer. Biotechnol J. 2007;2(11):1360–8. doi:10.1002/biot.200700087.

    Article  CAS  PubMed  Google Scholar 

  7. Benavente CA, Schnell SA, Jacobson EL. Effects of niacin restriction on sirtuin and PARP responses to photodamage in human skin. PLoS One. 2012;7(7), e42276. doi:10.1371/journal.pone.0042276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Liu T, Liu PY, Marshall GM. The critical role of the class III histone deacetylase SIRT1 in cancer. Cancer Res. 2009;69(5):1702–5. doi:10.1158/0008-5472.CAN-08-3365.

    Article  CAS  PubMed  Google Scholar 

  9. Deng CX. SIRT1, is it a tumor promoter or tumor suppressor? Int J Biol Sci. 2009;5(2):147–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Benayoun BA, Georges AB, L’Hote D, Andersson N, Dipietromaria A, Todeschini AL, et al. Transcription factor FOXL2 protects granulosa cells from stress and delays cell cycle: role of its regulation by the SIRT1 deacetylase. Hum Mol Genet. 2011;20(9):1673–86. doi:10.1093/hmg/ddr042.

    Article  CAS  PubMed  Google Scholar 

  11. Wang H, Liu H, Chen K, Xiao J, He K, Zhang J, et al. SIRT1 promotes tumorigenesis of hepatocellular carcinoma through PI3K/PTEN/AKT signaling. Oncol Rep. 2012;28(1):311–8. doi:10.3892/or.2012.1788.

    PubMed  Google Scholar 

  12. Pruitt K, Zinn RL, Ohm JE, McGarvey KM, Kang SH, Watkins DN, et al. Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS Genet. 2006;2(3), e40. doi:10.1371/journal.pgen.0020040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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. doi:10.1016/j.ccr.2008.09.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 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. doi:10.1371/journal.pone.0002020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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. doi:10.1016/j.molcel.2008.09.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cho IR, Koh SS, Malilas W, Srisuttee R, Moon J, Choi YW, et al. SIRT1 inhibits proliferation of pancreatic cancer cells expressing pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, by suppression of beta-catenin. Biochem Biophys Res Commun. 2012;423(2):270–5. doi:10.1016/j.bbrc.2012.05.107.

    Article  CAS  PubMed  Google Scholar 

  17. Tanno M, Sakamoto J, Miura T, Shimamoto K, Horio Y. Nucleocytoplasmic shuttling of the NAD+-dependent histone deacetylase SIRT1. J Biol Chem. 2007;282(9):6823–32. doi:10.1074/jbc.M609554200.

    Article  CAS  PubMed  Google Scholar 

  18. Byles V, Chmilewski LK, Wang J, Zhu L, Forman LW, Faller DV, et al. Aberrant cytoplasm localization and protein stability of SIRT1 is regulated by PI3K/IGF-1R signaling in human cancer cells. Int J Biol Sci. 2010;6(6):599–612.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Han L, Liang XH, Chen LX, Bao SM, Yan ZQ. SIRT1 is highly expressed in brain metastasis tissues of non-small cell lung cancer (NSCLC) and in positive regulation of NSCLC cell migration. Int J Clin Exp Pathol. 2013;6(11):2357–65.

    PubMed  PubMed Central  Google Scholar 

  20. Pandeya N, Olsen CM, Whiteman DC. Sex differences in the proportion of esophageal squamous cell carcinoma cases attributable to tobacco smoking and alcohol consumption. Cancer Epidemiol. 2013;37(5):579–84. doi:10.1016/j.canep.2013.05.011.

    Article  CAS  PubMed  Google Scholar 

  21. Zhang T, Rong N, Chen J, Zou C, Jing H, Zhu X, et al. SIRT1 expression is associated with the chemotherapy response and prognosis of patients with advanced NSCLC. PLoS One. 2013;8(11), e79162. doi:10.1371/journal.pone.0079162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Li C, Wang L, Zheng L, Zhan X, Xu B, Jiang J, et al. SIRT1 expression is associated with poor prognosis of lung adenocarcinoma. OncoTargets Ther. 2015;8:977–84. doi:10.2147/OTT.S82378.

    Article  CAS  Google Scholar 

  23. Noguchi A, Kikuchi K, Zheng H, Takahashi H, Miyagi Y, Aoki I, et al. SIRT1 expression is associated with a poor prognosis, whereas DBC1 is associated with favorable outcomes in gastric cancer. Cancer Med. 2014;3(6):1553–61. doi:10.1002/cam4.310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lavu S, Boss O, Elliott PJ, Lambert PD. Sirtuins—novel therapeutic targets to treat age-associated diseases. Nat Rev Drug Discov. 2008;7(10):841–53. doi:10.1038/nrd2665.

    Article  CAS  PubMed  Google Scholar 

  25. Alcain FJ, Villalba JM. Sirtuin inhibitors. Expert Opin Ther Patents. 2009;19(3):283–94. doi:10.1517/13543770902755111.

    Article  CAS  Google Scholar 

  26. Lain S, Hollick JJ, Campbell J, Staples OD, Higgins M, Aoubala M, et al. Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell. 2008;13(5):454–63. doi:10.1016/j.ccr.2008.03.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Oh WK, Cho KB, Hien TT, Kim TH, Kim HS, Dao TT, et al. Amurensin G, a potent natural SIRT1 inhibitor, rescues doxorubicin responsiveness via down-regulation of multidrug resistance 1. Mol Pharmacol. 2010;78(5):855–64. doi:10.1124/mol.110.065961.

    Article  CAS  PubMed  Google Scholar 

  28. Heltweg B, Gatbonton T, Schuler AD, Posakony J, Li H, Goehle S, et al. Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res. 2006;66(8):4368–77. doi:10.1158/0008-5472.CAN-05-3617.

    Article  CAS  PubMed  Google Scholar 

  29. Salahshoor MR, Dastjerdi MN, Jalili C, Mardani M, Khazaei M, Darehdor AS, et al. Combination of salermide and cholera toxin B induce apoptosis in MCF-7 but not in MRC-5 cell lines. Int J Prev Med. 2013;4(12):1402–13.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from National Natural Science Foundation of China (No. 81301914) and Natural Science Foundation of Jiangsu province (No. BK. 2012371).

Authors’ contributions

LC and HS conceived and designed the experiments. ZH and JY participated in the experiments and drafted the manuscript. LJ contributed to the sample collection and interpretation of the data. ZH and BP performed the statistical analysis. LC and HS revised the manuscript. All authors read and approved the final manuscript.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Longbang Chen or Haizhu Song.

Ethics declarations

Conflicts of interest

None

Ethics approval and consent to participate

The research protocol was reviewed and approved by the Ethical Committee and Institutional Review Board of Jinling Hospital, and written informed consent was obtained from each patient included in the study.

Additional information

Zhenyue He and Jun Yi are co-first authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

He, Z., Yi, J., Jin, L. et al. Overexpression of Sirtuin-1 is associated with poor clinical outcome in esophageal squamous cell carcinoma. Tumor Biol. 37, 7139–7148 (2016). https://doi.org/10.1007/s13277-015-4459-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-4459-y

Keywords

Navigation