Advertisement

Investigational New Drugs

, Volume 37, Issue 6, pp 1177–1186 | Cite as

Increased DKC1 expression in glioma and its significance in tumor cell proliferation, migration and invasion

  • Fa-an Miao
  • Kun Chu
  • Hai-rong Chen
  • Meng Zhang
  • Pei-cong Shi
  • Jin BaiEmail author
  • Yong-ping YouEmail author
PRECLINICAL STUDIES

Summary

The dyskeratosis congenita 1 (DKC1) gene is located on the X chromosome at Xq28. Dyskerin encoded by the DKC1 gene is associated with the formation of certain small RNAs and the telomerase activity. Inherited mutations in DKC1 inactivate the dyskerin and causes dyskeratosis congenital, which is characterized by skin defects, hematopoiesis failure, and increased susceptibility to cancer. DKC1 reportedly up-regulates in several human cancers, including renal cell carcinoma and prostate cancer. Dyskerin is deregulated in B-chronic lymphocytic leukemia and breast carcinomas, but its expression and function in glioma have hardly been investigated. Hence, we were prompted to collect tissue samples and implement cell experiments. Our study reveals that DKC1 expression is significantly increased in the pathological tissues of glioma compared with that in normal tissues. The increased staining of DKC1 is related to the World Health Organization stages of tumors. DKC1 knockdown also significantly inhibits glioma cell growth by altering the expression of cell cycle-relative molecules to arrest at the G1 phase. In the transwell chamber, DKC1 knockdown glioma cells exhibit low motility. Consistent with classic oncogenic pathways, N-cadherin, HIF-1α, and MMP2 expression levels are lower compared with those of the control group. Therefore, DKC1 up-regulation in gliomas is common and necessary for extensive tumor growth. The phenotype of glioma cell lines after DKC1 down-regulation suggests its use as a valuable clinical treatment strategy.

Keywords

DKC1 Glioma Proliferation Migration Invasion 

Notes

Funding

This study was funded by grants from the National Natural Science Foundation of China (No. 81672845, 81872304), the Project of Invigorating Health Care through Science, Technology and Education from Jiangsu Province (ZDRCC2016009), the Priority Academic Program for the Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine).

Compliance with ethical standards

Conflict of interest

The authors have declared that no competing interests exist.

Ethical approval

This study was performed under a protocol approved by the Institutional Review Boards of the Affiliated Hospital of Xuzhou Medical University.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He JJCCJC (2016) Cancer statistics in China, 2015. CA Cancer J Clin 66(2):115–132CrossRefGoogle Scholar
  2. 2.
    Legler J, Ries L, Ma, Warren J, Heineman E, Kaplan R, Linet MJJNCI (2000) Brain and other central nervous system cancers: recent trends in incidence and mortality. Journal of the National Cancer Institute 92(1):1382–1390CrossRefGoogle Scholar
  3. 3.
    Van Meir EG, Hadjipanayis CG, Norden AD, Hui-Kuo S, Wen PY, Olson JJ (2010) Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin 60(3):166–193CrossRefGoogle Scholar
  4. 4.
    Takano S, Yamashita T, Ohneda OJJO (2010) Molecular therapeutic targets for glioma angiogenesis. Journal of oncology 2010(9):351908CrossRefGoogle Scholar
  5. 5.
    Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, Hahn WC, Ligon KL, Louis DN, CJG B (2007) Genes Dev. Malignant astrocytic glioma: genetics, biology, and paths to treatment 21(21):2683–2710Google Scholar
  6. 6.
    Heiss NS, Knight SW, Vulliamy TJ, Klauck SM, Wiemann S, Mason PJ, Poustka A, Dokal I (1998) X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Genet 19(1):32–38CrossRefGoogle Scholar
  7. 7.
    Kirwan M, Dokal I (2010) Dyskeratosis congenita: a genetic disorder of many faces. Clin Genet 73(2):103–112CrossRefGoogle Scholar
  8. 8.
    Montanaro L, Brigotti M, Clohessy J, Barbieri S, Ceccarelli C, Santini D, Taffurelli M, Calienni M, Teruyafeldstein J, Trerè DJJP (2006) Dyskerin expression influences the level of ribosomal RNA pseudo-uridylation and telomerase RNA component in human breast cancer. J Pathol 210(1):10–18CrossRefGoogle Scholar
  9. 9.
    Martin H, Nahum SJNRMCB (2005) Translational control in stress and apoptosis. Nature reviews Molecular cell biology 6(4):318CrossRefGoogle Scholar
  10. 10.
    Davide R, Silvia G, Francesco P, Eduardo R, Francesca M, Rao PH, Carlos CC, Pier Paolo PJS (2003) Dyskeratosis congenita and cancer in mice deficient in ribosomal RNA modification. Science 299(5604):259CrossRefGoogle Scholar
  11. 11.
    Liu B, Zhang J, Huang C, Liu HJPO (2012) Dyskerin overexpression in human hepatocellular carcinoma is associated with advanced clinical stage and poor patient prognosis. PLoS One 7(8):e43147CrossRefGoogle Scholar
  12. 12.
    Alawi F, Lee MN (2007) DKC1 is a direct and conserved transcriptional target of c-MYC. Biochem Biophys Res Commun 362(4):893–898CrossRefGoogle Scholar
  13. 13.
    Montanaro L, Brigotti M, Clohessy J, Barbieri S, Ceccarelli C, Santini D, Taffurelli M, Calienni M, Teruya-Feldstein J, Trerè D (2010) Dyskerin expression influences the level of ribosomal RNA pseudo-uridylation and telomerase RNA component in human breast cancer. J Pathol 210(1):10–18CrossRefGoogle Scholar
  14. 14.
    Poncet D, Belleville A, T'Kint dRC, Roborel dCA, Ben SE, Merle-Beral H, Callet-Bauchu E, Salles G, Sabatier L, Delic JJB (2008) Changes in the expression of telomere maintenance genes suggest global telomere dysfunction in B-chronic lymphocytic leukemia. Blood 111(4):2388CrossRefGoogle Scholar
  15. 15.
    Huang LE, Gu J, Schau M, Bunn HF (1998) Regulation of hypoxia-inducible factor 1α is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA 95(14):7987–7992CrossRefGoogle Scholar
  16. 16.
    Fredlund E, Ringnér M, Maris JM, Påhlman S (2008) High Myc pathway activity and low stage of neuronal differentiation associate with poor outcome in neuroblastoma. Proc Natl Acad Sci USA 105(37):14094–14099CrossRefGoogle Scholar
  17. 17.
    Besson A, Dowdy SF, Roberts JM (2008) CDK inhibitors: cell cycle regulators and beyond. Dev Cell 14(2):159–169CrossRefGoogle Scholar
  18. 18.
    Malumbres M, Barbacid M (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9(3):153–166CrossRefGoogle Scholar
  19. 19.
    O'Brien R, Tran SL, Maritz M, Liu B, Kong CF, Purgato S, Yang C, Murray J, Russel AJ, Flemming CLJCR (2016) MYC-driven neuroblastomas are addicted to a telomerase-independent function of dyskerin. Cancer Res 76(12):3604–3617CrossRefGoogle Scholar
  20. 20.
    Maria B, Aya P, Ornella Z, Maria C, Nadya K, Eduardo R, Rao PH, Ruggero D (2008) Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency. Nature 456(7224):971–975CrossRefGoogle Scholar
  21. 21.
    Nie E, Zhang X, Xie S, Shi Q, Hu J, Meng Q, Zhou X, Yu R (2015) Β-catenin is involved in Bex2 down-regulation induced glioma cell invasion/migration inhibition. Biochem Biophys Res Commun 456(1):494–499CrossRefGoogle Scholar
  22. 22.
    Sawaya RE, Yamamoto M, Gokaslan ZL, Wang SW, Mohanam S, Fuller GN, Mccutcheon IE, Stetlerstevenson WG, Nicolson GL, Rao JS (1996) Expression and localization of 72 kDa type IV collagenase (MMP-2) in human malignant gliomas in vivo. Clin Exp Metastasis 14(1):35–42CrossRefGoogle Scholar
  23. 23.
    Wang L, Zhang ZG, Zhang RL, Gregg SR, Hozeskasolgot A, Letourneau Y, Wang Y, Chopp M (2006) Matrix metalloproteinase 2 (MMP2) and MMP9 secreted by erythropoietin-activated endothelial cells promote neural progenitor cell migration. J Neurosci 26(22):5996–6003CrossRefGoogle Scholar
  24. 24.
    Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–890.  https://doi.org/10.1016/j.cell.2009.11.007 CrossRefPubMedGoogle Scholar
  25. 25.
    Asano K, Asano K, Duntsch CD, Zhou Q, Weimar JD, Bordelon D, Robertson JH, Pourmotabbed T (2004) Correlation of N-cadherin expression in high grade gliomas with tissue invasion. J Neuro-Oncol 70(1):3–15CrossRefGoogle Scholar
  26. 26.
    Smith TG, Robbins PA, Ratcliffe PJ (2008) The human side of hypoxia-inducible factor. Br J Haematol 141(3):325–334CrossRefGoogle Scholar
  27. 27.
    Méndez O, Zavadil J, Esencay M, Lukyanov Y, Santovasi D, Wang S-C, Newcomb EW, Zagzag D (2010) Knock down of HIF-1α in glioma cells reduces migration in vitro and invasion in vivo and impairs their ability to form tumor spheres. Mol Cancer 9(1):133CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of NeurosurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
  2. 2.Department of NeurosurgeryAffiliated Hospital of Xuzhou Medical UniversityXuzhouChina
  3. 3.Cancer InstituteXuzhou Medical UniversityXuzhouChina
  4. 4.Department of Occupational Medicine and Environmental Health, School of Public HealthNanjing Medical UniversityNanjingChina
  5. 5.Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer InstituteXuzhou Medical UniversityXuzhouChina
  6. 6.Department of NeurosurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina

Personalised recommendations