Skip to main content
SpringerLink
Log in

miR-34 is associated with poor prognosis of patients with gallbladder cancer through regulating telomere length in tumor stem cells

  • Research Article
  • Published:
Tumor Biology

Abstract

miR-34a has been identified as a tumor suppressor in several tumors, but its involvement in gallbladder cancer (GBC) has not been reported. In this study, the miR-34a level and telomere length were measured in 77 gallbladder adenocarcinomas and 36 peritumoral tissues by real-time PCR. Forced miR-34a expression was established by an adenovirus carrying a miR-34a expression cassette. The colony-forming ability of isolated CD44+CD133+ GBC tumor stem-like cells was measured by matrigel colony assay. The xenograft tumor models were established by inoculating nude mice with CD44+CD133+cells. Results showed that significantly lower miR-34a expression and longer telomere length were observed in gallbladder adenocarcinoma tissues, which correlated with poor prognosis of GBC patients. Forced overexpression of miR-34a inhibited the colony-forming ability of CD44+CD133+ GBC tumor stem-like cells in vitro and xenograft tumor growth in vivo. Injection of Ad-miR-34a downregulated PNUTS expression and reduced telomere length in xenograft GBC tumor cells. In conclusion, miR-34a is a tumor suppressor in gallbladder cancer. Both low miR-34a expression and long telomere length are markers for poor prognosis of patients with gallbladder adenocarcinoma. Our study also suggests that the miR-34a gene could be a target for targeting therapy of GBC.

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

Similar content being viewed by others

References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics 2008. CA Cancer J Clin. 2008;58:71–96.

    Article  PubMed  Google Scholar 

  2. Jayaraman S, Jarnagin WR. Management of gallbladder cancer. Gastroenterol Clin North Am. 2010;39:331–42.

    Article  PubMed  Google Scholar 

  3. Hawkins WG, DeMatteo RP, Jarnagin WR, Ben-Porat L, Blumgart LH, Fong Y. Jaundice predicts advanced disease and early mortality in patients with gallbladder cancer. Ann Surg Oncol. 2004;11:310–5.

    Article  PubMed  Google Scholar 

  4. Ootani T, Shirai Y, Tsukada K, Muto T. Relationship between gallbladder carcinoma and the segmental type of adenomyomatosis of the gallbladder. Cancer. 1992;69:2647–52.

    Article  CAS  PubMed  Google Scholar 

  5. Roa JC, Tapia O, Cakir A, Basturk O, Dursun N, Akdemir D, et al. Squamous cell and adenosquamous carcinomas of the gallbladder: clinicopathological analysis of 34 cases identified in 606 carcinomas. Mod Pathol. 2011;24:1069–78.

    Article  PubMed  Google Scholar 

  6. Park SB, Kim YH, Rho HL, Chae GB, Hong SK. Primary carcinosarcoma of the gallbladder. J Korean Surg Soc. 2012;82:54–8.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Valencia-Sanchez MA, Liu J, Hannon GJ, Parker R. Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 2006;20:515–24.

    Article  CAS  PubMed  Google Scholar 

  8. Bagga S, Pasquinelli AE. Identification and analysis of microRNAs. Genet Eng (N Y). 2006;27:1–20.

    Article  CAS  Google Scholar 

  9. Xiong J, Du Q, Liang Z. Tumor-suppressive microRNA-22 inhibits the transcription of E-box-containing c-Myc target genes by silencing c-Myc binding protein. Oncogene. 2010;29:4980–8.

    Article  CAS  PubMed  Google Scholar 

  10. Raver-Shapira N, Marciano E, Meiri E, Spector Y, Rosenfeld N, Moskovits N, et al. Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol Cell. 2007;26:731–43.

    Article  CAS  PubMed  Google Scholar 

  11. Tarasov V, Jung P, Verdoodt B, Lodygin D, Epanchintsev A, Menssen A, et al. Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR-34a is a p53 target that induces apoptosis and G1-arrest. Cell Cycle. 2007;6:1586–93.

    Article  CAS  PubMed  Google Scholar 

  12. Corney DC, Flesken-Nikitin A, Godwin AK, Wang W, Nikitin AY. MicroRNA-34b and microRNA-34c are targets of p53 and cooperate in control of cell proliferation and adhesion-independent growth. Cancer Res. 2007;67:8433–8.

    Article  CAS  PubMed  Google Scholar 

  13. Bommer GT, Gerin I, Feng Y, Kaczorowski AJ, Kuick R, Love RE, et al. p53-mediated activation of miRNA34 candidate tumor-suppressor genes. Curr Biol. 2007;17:1298–307.

    Article  CAS  PubMed  Google Scholar 

  14. Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, Lee KH, et al. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell. 2007;26:745–52.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Lodygin D, Tarasov V, Epanchintsev A, Berking C, Knyazeva T, Korner H, et al. Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer. Cell Cycle. 2008;7:2591–600.

    Article  CAS  PubMed  Google Scholar 

  16. Boon RA, Iekushi K, Lechner S, Seeger T, Fischer A, Heydt S, et al. MicroRNA-34a regulates cardiac ageing and function. Nature. 2013;495:107–10.

    Article  CAS  PubMed  Google Scholar 

  17. Sahin E, DePinho RA. Axis of ageing: telomeres, p53 and mitochondria. Nat Rev Mol Cell Biol. 2012;13:397–404.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Res. 2002;30:e47.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Hu Y, Ou Y, Wu K, Chen Y, Sun W. miR-143 inhibits the metastasis of pancreatic cancer and an associated signaling pathway. Tumour Biol. 2012;33:1863–70.

    Article  CAS  PubMed  Google Scholar 

  20. Zhang X, Kon T, Wang H, Li F, Huang Q, Rabbani ZN, et al. Enhancement of hypoxia-induced tumor cell death in vitro and radiation therapy in vivo by use of small interfering RNA targeted to hypoxia-inducible factor-1alpha. Cancer Res. 2004;64:8139–42.

    Article  CAS  PubMed  Google Scholar 

  21. Ogawa T, Saiki Y, Shiga K, Chen N, Fukushige S, Sunamura M, et al. miR-34a is downregulated in cis-diamminedichloroplatinum treated sinonasal squamous cell carcinoma patients with poor prognosis. Cancer Sci. 2012;103:1737–43.

    Article  CAS  PubMed  Google Scholar 

  22. Gallardo E, Navarro A, Viñolas N, Marrades RM, Diaz T, Gel B, et al. miR-34a as a prognostic marker of relapse in surgically resected non-small-cell lung cancer. Carcinogenesis. 2009;30:1903–9.

    Article  CAS  PubMed  Google Scholar 

  23. Hermeking H. The miR-34 family in cancer and apoptosis. Cell Death Differ. 2010;17:193–9.

    Article  CAS  PubMed  Google Scholar 

  24. Eisenberg DTA. An evolutionaty review of human telomere biology: The thirty telomere hypothesis and notes on potential adaptive paternal effects. Am J Hum Biol. 2011;23:149–67.

    Article  PubMed  Google Scholar 

  25. Svenson U, Roos G. Telomere length as a biological marker in malignancy. Biochim Biophys Acta. 2009;1792:317–23.

    Article  CAS  PubMed  Google Scholar 

  26. Bisofti M, Heaphy CM, Griffith JK. Telomeres: Prognostic markers for solid tumors. Int J Cancer. 2006;119:2255–60.

    Article  Google Scholar 

  27. Avigad S, Naumov I, Ohali A, Jeison M, Berco GH, Mardoukh J, et al. Short telomeres: a novel potential predictor of relapse in Ewing sarcoma. Clin Cancer Res. 2007;13:5777–83.

    Article  CAS  PubMed  Google Scholar 

  28. Shirotani Y, Hiyama K, Ishioka S, Inyaku K, Awaya Y, Yonehara S, et al. Alteration in length of telomeric repeats in lung cancer. Lung Cancer. 1994;11:29–41.

    Article  CAS  PubMed  Google Scholar 

  29. Hirashima T, Komiya T, Nitta T, Takada Y, Kobayashi M, Masuda N, et al. Prognostic significance of telomeric repeat length alterations in pathological stage I–IIIA non-small cell lung cancer. Anticancer Res. 2000;20:2181–7.

    CAS  PubMed  Google Scholar 

  30. Frías C, García-Aranda C, De Juan C, Morán A, Ortega P, Gómez A, et al. Telomere shortening is associated with poor prognosis and telomerase activity correlates withDNArepair impairment in non-small cell lung cancer. Lung Cancer. 2008;60:416–25.

    Article  PubMed  Google Scholar 

  31. Shi C, Tian R, Wang M, Wang X, Jiang J, Zhang Z, et al. CD44 + CD133+ population exhibits cancer stem cell-like characteristics in human gallbladder carcinoma. Cancer Biol Ther. 2010;11:1182–90.

    Article  Google Scholar 

  32. Kim H, Lee OH, Xin H, Chen LY, Qin J, Chae HK, et al. TRF2 functions as a protein hub and regulates telomere maintenance by recognizing specific peptide motifs. Nat Struct Mol Biol. 2009;16:372–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Hi-tech Program (863 Project) of China (No. 2007AA021804, 2007AA021809).

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Department of Radiology, Hunan Children’s Hospital, Changsha, Hunan, 410007, China

    Ke Jin, Yonghua Xiang, Jing Tang, Guangchun Wu, Junwei Li, Huaichun Xiao & Chunwang Li

  2. Hepatobiliary & Enteric Surgery Research Center, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, Hunan, 410008, China

    Yuxiang Chen & Jingfeng Zhao

Authors
  1. Ke Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yonghua Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jing Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guangchun Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Junwei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Huaichun Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chunwang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yuxiang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jingfeng Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jingfeng Zhao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jin, K., Xiang, Y., Tang, J. et al. miR-34 is associated with poor prognosis of patients with gallbladder cancer through regulating telomere length in tumor stem cells. Tumor Biol. 35, 1503–1510 (2014). https://doi.org/10.1007/s13277-013-1207-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-013-1207-z

Keywords

Search

Navigation