Skip to main content

Advertisement

SpringerLink
Log in

TKTL1 expression and its downregulation is implicated in cell proliferation inhibition and cell cycle arrest in esophageal squamous cell carcinoma

  • Research Article
  • Published:
Tumor Biology

Abstract

It is well known that tumor cells mainly depend on the nonoxidative pathway of the pentose phosphate pathway (PPP), and transketolase-like 1 (TKTL1), a kind of crucial metabolism enzyme, participates in the regulation of PPP; notably, overwhelming evidence has demonstrated that TKTL1 plays pivotal roles in the development and progression of multiple tumors. However, there were no reports about the role of TKTL1 in esophageal squamous cell carcinoma (ESCC). Here, we investigated TKTL1 expression and preliminarily elucidated its underlying biological functions in ESCC. We found that TKTL1 exhibited the high expression in ESCC tissues and cells, and the survival rate of patients with negative TKTL1 expression was significantly higher than that of patients with positive TKTL1 staining (P < 0.05). Additionally, significant correlations of TKTL1 expression with histologic grade, clinical stage, and lymph node metastasis were found (P < 0.05). Subsequently, TKTL1 small interfering RNA (siRNA) significantly reduced TKTL1 messenger RNA (mRNA), and protein levels companied with the marked reduce of total transketolase activity but did not affect TKT and TKTL1 mRNA level. More importantly, TKTL1 siRNA obviously induced cell cycle arrest in G0/G1 phase and suppressed cell proliferation in vitro and in vivo coupled with the reduced cyclin D1 and cdk4 levels as well as decrease of Ki-67 proliferation index in EC1 cells. Taken altogether, our results suggest that TKTL1 as a key prognostic factor may be a novel target for therapy of the patients with ESCC.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):10–29.

    Article  PubMed  Google Scholar 

  2. Pennathur A, Gibson MK, Jobe BA, Luketich JD. Oesophageal carcinoma. Lancet. 2013;381(9864):400–12.

    Article  PubMed  Google Scholar 

  3. Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 2006;24(14):2137–50.

    Article  PubMed  Google Scholar 

  4. Lam KY, Ma LT, Wong J. Measurement of extent of spread of oesophageal squamous carcinoma by serial sectioning. J Clin Pathol. 1996;49(2):124–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Vizcaino AP, Moreno V, Lambert R, Parkin DM. Time trends incidence of both major histologic types of esophageal carcinomas in selected countries, 1973–1995. Int J Cancer. 2002;99(6):860–8.

    Article  CAS  PubMed  Google Scholar 

  6. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917.

    Article  CAS  PubMed  Google Scholar 

  7. Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med. 2003;349(23):2241–52.

    Article  CAS  PubMed  Google Scholar 

  8. Javle M, Ailawadhi S, Yang GY, Nwogu CE, Schiff MD, Nava HR. Palliation of malignant dysphagia in esophageal cancer: a literature-based review. J Support Oncol. 2006;4(8):365–73. 379.

    PubMed  Google Scholar 

  9. Furuta E, Okuda H, Kobayashi A, Watabe K. Metabolic genes in cancer: their roles in tumor progression and clinical implications. Biochim Biophys Acta. 2010;1805(2):141–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Hu LH, Yang JH, Zhang DT, Zhang S, Wang L, Cai PC, et al. The TKTL1 gene influences total transketolase activity and cell proliferation in human colon cancer LoVo cells. Anti–Cancer Drugs. 2007;18(4):427–33.

    Article  CAS  PubMed  Google Scholar 

  11. Wamelink MM, Struys EA, Jakobs C. The biochemistry, metabolism and inherited defects of the pentose phosphate pathway: a review. J Inherit Metab Dis. 2008;31(6):703–17.

    Article  CAS  PubMed  Google Scholar 

  12. Coy JF, Dressler D, Wilde J, Schubert P. Mutations in the transketolase-like gene TKTL1: clinical implications for neurodegenerative diseases, diabetes and cancer. Clin Lab. 2005;51(5–6):257–73.

    CAS  PubMed  Google Scholar 

  13. Langbein S, Zerilli M, Zur Hausen A, Staiger W, Rensch-Boschert K, Lukan N, et al. Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted. Br J Cancer. 2006;94(4):578–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Semilia M, Hennenlotter J, Pavone C, Bischoff T, Kuhs U, Gakis G, Bedke J, Stenzl A, Schwentner C, Todenhofer T: Expression patterns and prognostic role of transketolase-like 1 in muscle-invasive bladder cancer. World J Urol 2015. In press

  15. Fritz P, Coy JF, Murdter TE, Ott G, Alscher MD, Friedel G. TKTL-1 expression in lung cancer. Pathol Res Pract. 2012;208(4):203–9.

    Article  CAS  PubMed  Google Scholar 

  16. Kayser G, Sienel W, Kubitz B, Mattern D, Stickeler E, Passlick B, et al. Poor outcome in primary non-small cell lung cancers is predicted by transketolase TKTL1 expression. Pathology. 2011;43(7):719–24.

    Article  PubMed  Google Scholar 

  17. Krockenberger M, Engel JB, Schmidt M, Kohrenhagen N, Hausler SF, Dombrowski Y, et al. Expression of transketolase-like 1 protein (TKTL1) in human endometrial cancer. Anticancer Res. 2010;30(5):1653–9.

    CAS  PubMed  Google Scholar 

  18. Chen H, Yue JX, Yang SH, Ding H, Zhao RW, Zhang S. Overexpression of transketolase-like gene 1 is associated with cell proliferation in uterine cervix cancer. J Exp Clin Cancer Res. 2009;28:43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Raman JD, Mongan NP, Tickoo SK, Boorjian SA, Scherr DS, Gudas LJ. Increased expression of the polycomb group gene, EZH2, in transitional cell carcinoma of the bladder. Clin Cancer Res. 2005;11(24 Pt 1):8570–6.

    Article  CAS  PubMed  Google Scholar 

  20. Liu Y, Li K, Ren Z, Li S, Zhang H, Fan Q. Clinical implication of elevated human cervical cancer oncogene-1 expression in esophageal squamous cell carcinoma. J Histochem Cytochem. 2012;60(7):512–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ji Z, Yang G, Shahzidi S, Tkacz-Stachowska K, Suo Z, Nesland JM, et al. Induction of hypoxia-inducible factor-1alpha overexpression by cobalt chloride enhances cellular resistance to photodynamic therapy. Cancer Lett. 2006;244(2):182–9.

    Article  CAS  PubMed  Google Scholar 

  22. Zhang S, Yue JX, Yang JH, Cai PC, Kong WJ. Overexpression of transketolase protein TKTL1 is associated with occurrence and progression in nasopharyngeal carcinoma: a potential therapeutic target in nasopharyngeal carcinoma. Cancer Biol Ther. 2008;7(4):517–22.

    Article  CAS  PubMed  Google Scholar 

  23. Yan L, Li S, Xu C, Zhao X, Hao B, Li H, et al. Target protein for Xklp2 (TPX2), a microtubule-related protein, contributes to malignant phenotype in bladder carcinoma. Tumour Biol. 2013;34(6):4089–100.

    Article  CAS  PubMed  Google Scholar 

  24. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 2001;25(4):402–8.

    Article  CAS  PubMed  Google Scholar 

  25. Lu Z, Liu H, Xue L, Xu P, Gong T, Hou G. An activated Notch1 signaling pathway inhibits cell proliferation and induces apoptosis in human esophageal squamous cell carcinoma cell line EC9706. Int J Oncol. 2008;32(3):643–51.

    CAS  PubMed  Google Scholar 

  26. Smeets EH, Muller H, de Wael J. A NADH-dependent transketolase assay in erythrocyte hemolysates. Clin Chim Acta. 1971;33(2):379–86.

    Article  CAS  PubMed  Google Scholar 

  27. Phan LM, Yeung SC, Lee MH. Cancer metabolic reprogramming: importance, main features, and potentials for precise targeted anti-cancer therapies. Cancer Biol Med. 2014;11(1):1–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Wittig R, Coy JF. The role of glucose metabolism and glucose-associated signalling in cancer. Perspect Med Chem. 2008;1:64–82.

    Google Scholar 

  29. Zhao J, Zhong CJ. A review on research progress of transketolase. Neurosci Bull. 2009;25(2):94–9.

    Article  PubMed  Google Scholar 

  30. Boros LG, Puigjaner J, Cascante M, Lee WN, Brandes JL, Bassilian S, et al. Oxythiamine and dehydroepiandrosterone inhibit the nonoxidative synthesis of ribose and tumor cell proliferation. Cancer Res. 1997;57(19):4242–8.

    CAS  PubMed  Google Scholar 

  31. Patra KC, Hay N. The pentose phosphate pathway and cancer. Trends Biochem Sci. 2014;39(8):347–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jiang P, Du W, Wu M. Regulation of the pentose phosphate pathway in cancer. Protein Cell. 2014;5(8):592–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lange CA, Tisch-Rottensteiner J, Bohringer D, Martin G, Schwartzkopff J, Auw-Haedrich C. Enhanced TKTL1 expression in malignant tumors of the ocular adnexa predicts clinical outcome. Ophthalmology. 2012;119(9):1924–9.

    Article  PubMed  Google Scholar 

  34. Diaz-Moralli S, Tarrado-Castellarnau M, Alenda C, Castells A, Cascante M. Transketolase-like 1 expression is modulated during colorectal cancer progression and metastasis formation. PLoS One. 2011;6(9), e25323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Langbein S, Frederiks WM, zur Hausen A, Popa J, Lehmann J, Weiss C, et al. Metastasis is promoted by a bioenergetic switch: new targets for progressive renal cell cancer. Int J Cancer. 2008;122(11):2422–8.

    Article  CAS  PubMed  Google Scholar 

  36. Schwaab J, Horisberger K, Strobel P, Bohn B, Gencer D, Kahler G, et al. Expression of Transketolase like gene 1 (TKTL1) predicts disease-free survival in patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy. BMC Cancer. 2011;11:363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Philipp M, Schwaab J, Dietz CT, Hanfstein B, Kalmanti L, Munjal U, et al. Expression of transketolase-like gene 1 (TKTL1) depends on disease phase in patients with chronic myeloid leukaemia (CML). J Cancer Res Clin Oncol. 2014;140(3):411–7.

    Article  CAS  PubMed  Google Scholar 

  38. Zhang S, Yang JH, Guo CK, Cai PC. Gene silencing of TKTL1 by RNAi inhibits cell proliferation in human hepatoma cells. Cancer Lett. 2007;253(1):108–14.

    Article  CAS  PubMed  Google Scholar 

  39. Gottlieb RA, Giesing HA, Zhu JY, Engler RL, Babior BM. Cell acidification in apoptosis: granulocyte colony-stimulating factor delays programmed cell death in neutrophils by up-regulating the vacuolar H(+)-ATPase. Proc Natl Acad Sci U S A. 1995;92(13):5965–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yuan W, Wu S, Guo J, Chen Z, Ge J, Yang P, et al. Silencing of TKTL1 by siRNA inhibits proliferation of human gastric cancer cells in vitro and in vivo. Cancer Biol Ther. 2010;9(9):710–6.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Oncology, The First Affiliated Hospital of Zhengzhou University, 40 Daxue Road, Zhengzhou, 450052, Henan, China

    Zuxuan Shi & Qingxia Fan

  2. Department of Oncology, Henan Provincial People’s Hospital, Zhengzhou, 450003, Henan, China

    Zuxuan Shi

  3. Department of Critical Care Medicine, Henan Provincial People’s Hospital, Zhengzhou, 450003, Henan, China

    Yu Tang

  4. Department of Oncology, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, 450008, Henan, China

    Ke Li

Authors
  1. Zuxuan Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ke Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qingxia Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Qingxia Fan.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shi, Z., Tang, Y., Li, K. et al. TKTL1 expression and its downregulation is implicated in cell proliferation inhibition and cell cycle arrest in esophageal squamous cell carcinoma. Tumor Biol. 36, 8519–8529 (2015). https://doi.org/10.1007/s13277-015-3608-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-3608-7

Keywords

Search

Navigation