DOI QR코드

DOI QR Code

CCNG2 Suppressor Biological Effects on Thyroid Cancer Cell through Promotion of CDK2 Degradation

  • Li, Wei-Juan (Department of Endocrinology (Section I), Tangshan Workers Hospital) ;
  • Liu, Ge-Ling (Department of Endocrinology (Section I), Tangshan Workers Hospital) ;
  • Yu, Fang (Department of Endocrinology (Section I), Tangshan Workers Hospital) ;
  • Xiang, Xiu-Xiu (Department of Endocrinology (Section I), Tangshan Workers Hospital) ;
  • Lu, Yi-Fang (Department of Endocrinology (Section I), Tangshan Workers Hospital) ;
  • Xiao, Hong-Zhen (Department of Endocrinology (Section I), Tangshan Workers Hospital) ;
  • Shi, Yan-Ping (Department of Endocrinology (Section I), Tangshan Workers Hospital)
  • Published : 2013.10.30

Abstract

This study aimed to analyze the expression and clinical significance of cyclin G2 (CCNG2) in thyroid carcinoma and the biological effects of CCNG2 overexpression in a cell line. Immunohistochemistry and Western blotting were used to analyze CCNG2 protein expression in 63 cases of thyroid cancer and normal tissues to allow the relationship with clinical factors to be assessed. CCNG2 lentiviral and empty vectors were transfected into the thyroid cancer K1 cell line. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were applied to detect the mRNA and protein levels of CCNG2. MTT assay and cell cycle were also conducted to assess the influence of up-regulated expression of CCNG2 on K1 cell biology. The level of CCNG2 protein expression was found to be significantly lower in thyroid cancer tissue than normal tissues (P<0.05). Western blot: The relative amount of CCNG2 protein in thyroid cancer tissue was respectively found to be significantly lower than in normal tissues (P<0.05), correlating with lymph node metastasis, clinic stage and histological grade (P<0.05), but not gender, age or tumor size (P>0.05). Loss of CCNG2 expression correlated significantly with poor overall survival time on Kaplan-Meier analysis (P<0.05). The results for biological functions showed that K1 cell transfected CCNG2 had a lower survival fraction, a greater percentage in the G0/G1 phases, and lower cyclin-dependent kinase 2 (CDK2) protein expression compared with K1 cells non-transfected with CCNG2 (P<0.05). CCNG2 expression decreased in thyroid cancer and correlated significantly lymph node metastasis, clinic stage, histological grade and poor overall survival, suggesting that CCNG2 may play important roles as a negative regulator in thyroid cancer K1 cells by promoting degradation of CDK2.

Keywords

References

  1. Ahmed S, Al-Saigh S, Matthews J (2012). FOXA1 is essential for aryl hydrocarbon receptor-dependent regulation of cyclin G2. Mol Cancer Res, 10, 636-48. https://doi.org/10.1158/1541-7786.MCR-11-0502
  2. Arachchige DonAS, Dallapiazza RF, et al (2006). CyclinG2 is a centrosome-associated nucleocytoplasmic shuttling protein that influences microtubule stability and induces a P53-dependent cell cycle arrest. Exp Cell Res, 312, 4181-204. https://doi.org/10.1016/j.yexcr.2006.09.023
  3. Bates S, Rowan S, Vousden KH (1996). Characterization of human cyclin G1 and G2: DNA damage inducible genes. Oneogene, 13, 1103-9.
  4. Bennin DA, DonAS, Brake T, et al (2002). Cyclin G2 associates with protein phosphatase 2A catalytic and regulatory B' subunits in active complexes and induces nuclear aberrations and a Gl/S phase cell cycle arrst.J Biol Chem, 2779, 27449-67.
  5. Cui XF, Liu AJ, Xu ZM (2009). Expression of Cyclin G2 and its clinical significance in laryngeal squamouse cell carcinorna. J Clinic torhinolaryngology, 23, 277-9.
  6. Choi MG, Noh JH, An JY, et al (2009). Expression levels of cyclinG2, but not cyclin E, correlate with gastric progression. J Surg Res, 157, 168-74. https://doi.org/10.1016/j.jss.2008.06.020
  7. Chen J, Yusuf L, Andersen HM, Fruman DA (2006). FOXO transcription factors cooperate $with{\delta}EF1$ to activate growth suppressive genes in B-lymphoeytes. J Immunol, 76, 2711-21.
  8. Cellai C, Laurenzana A, Bianchi E, et al (2009). Mechanistic insight intoWEB-2170-induced apoptosis in human acute myelogenous leukemia cells:the crucial role of PTEN. Exp Hematol, 7, 1176-85.
  9. DeLellis RA, Lloyd RV, Heitz PU, Eng C (2004). World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Endocrine Organs. Lyon: IARC.
  10. Frattini M, Ferrario C, Bressan P, et al (2004). Alternative mutations of BRAF, RET and NTRK1 are associated with similar but distinct gene expression patterns in papillary thyroid cancer. Oncogene, 23, 7436-40. https://doi.org/10.1038/sj.onc.1207980
  11. Gao F, Lin Y, Zhang RR (2012). RNA-DNA differences are rarer in proto- oncogenes than in tumor suppressor genes. Sci Rep, 2, 245.
  12. Horne MC, Goolsby GL, Donaldson KL, et al (1996). Cyclin G1 and cyclinG2 comprise a new family of cyclins with contrasting cycle-regulated expression. J Biol Chem, 271, 6050-61. https://doi.org/10.1074/jbc.271.11.6050
  13. Horne MC, Donaldson KL, Goolsby GL, et al (1997). Cyclin G2 is up-regulated during growth inhibition and B cell antigen recep tormediated cell cycle arrest. J Biol Chem, 272, 12650-61. https://doi.org/10.1074/jbc.272.19.12650
  14. Kimura ET, Nikiforova MN, Zhu Z, et al (2003). High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res, 63, 1454-7.
  15. Kim Y, Shintani S, Kohno Y, Zhang R, Wong DT (2004). Cyclin G2 dysregulation in human oral cancer. Cancer Res, 64, 8980-6. https://doi.org/10.1158/0008-5472.CAN-04-1926
  16. Le XF, Arachchige-Don AS, Mao W, Horne MC, Bast RC Jr. (2007). Roles of human epidermal growth factor receptor 2, c-jun NH2-terminal kinase, phosphoinositide 3-kinase, and p70 S6 kinase pathways in regulation of cyclin G2 expression in human breast cancer cells. Mol CancerTher, 6, 2843-57.
  17. Martinez-Gac L, Marques M, Garcia Z, Campanero MR, Carrera AC (2004). Control of cyclinG2 mRNA expression by forkhead transcription factors: novel mechanism for cell cycle control by phosphoinositide 3-kinase and forkhead. Mol Cell Biol, 4, 2181-9.
  18. Malz M, Pinna F, Schirmacher P, Breuhahn K (2012). Transcriptional regulators in hepatocarcinogenesis--key integrators of malignant transformation. J Hepatol, 57, 186-95. https://doi.org/10.1016/j.jhep.2011.11.029
  19. Nikiforov YE, Biddinger PW, Thompson LDR (2009). Diagnostic pathology and molecular genetcis of the thyroid. Baltimore: Lippincott Williams & Wilkins. 94-102.
  20. Shan G, Shan SG, Zhang XB (2009). Expression and clinical significance of cyclin G1 and cyelinG2 in transitional cell carcinoma of bladder. Chin J Histochemistry Cytochmistry, 18, 268-72.
  21. Shi W, Yu KR, Wu GY, Zhang H (2011). Expression of CCNG2 in gastric carcinorna and its relationship with prognosis. Chin J Cell Boil, 33, 994-7.
  22. Song YL, Hu GH (2006). CyclinG2: Correlation with head and neck neoplasms. Int J Otolaryngol Head Neck Surg, 30, 8-11.
  23. Xu G, Bernaudo S, Fu G, et al (2008). CyclinG2 is degraded through the ubiquitin-proteasome pathway and mediates the antiproliferative effect of activin receptor-like kilase 7. Mol Biol Cell, 9, 4968-79.
  24. van Duijn PW, Ziel-van der Made AC, van der Korput JA, Trapman J (2010). PTEN- mediated Gl cell-cycle arrest in LNCaP prostate cancer cells is associated with altered expression of cell-cycle regulators. Prostate, 70, 135-46.

Cited by

  1. MicroRNA-1246 promotes growth and metastasis of colorectal cancer cells involving CCNG2 reduction vol.13, pp.1, 2015, https://doi.org/10.3892/mmr.2015.4557
  2. Cyclin G2: A novel independent prognostic marker in pancreatic cancer pp.1792-1082, 2015, https://doi.org/10.3892/ol.2015.3667