Skip to main content
SpringerLink
Log in

Hypermethylation of p14ARF promoter region and expresion of p14ARF gene product in non-small cell lung cancer

  • Published:
Chinese Journal of Cancer Research

Abstract

Objective

This study was designed to investigate promoter methylation status and protein expression of p14ARF gene in non-small cell lung cancer, and value the role of p14ARF promoter methylation in carcinogenesis of non-small cell lung cancer.

Methods

Promoter methylation status and protein expression of p14ARF gene in 40 cases of non-small cell lung cancer were analyzed by methylation specific polymerase china reaction (MSP), restriction enzyme-related polymerase chain reaction (RE-PCR) and immunohistochemistry (IHC).

Results

The positive rates of p14ARF promoter methylation in tumor tissues and normal tissues adjacent to cancer were 17.5% (7/40) and 2.5% (1/40) respectively. There were statistically significant differences between them, P<0.05. The results of RE-PCR were consistent with that of MSP. The expression rate of p14ARF protein in tumor tissues was significantly lower than that in normal tissues adjacent to cancer, p<0.01. Promoter methylation status and protein expression of p14ARF gene in non-small cell lung cancer showed significantly an inverse correlation (r=−0.56, P<0.01), and both of them did not relate statistically with the clinicopathologic characteristics of patients such as histological classification, clinical stage, differentiation grade and lymph node involvement.

Conclusion

Promoter methylation is a crucial mechanism of inactivation of p14ARF gene. Promoter methylation of p14ARF gene might be involved in carcinogenesis of non-small cell lung cancer, and is an early event in development process of non-small cell lung cancer. It might be used as a new target in gene treatments in the future.

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

Similar content being viewed by others

References

  1. Kaye FJ. RB and cyclin dependent kinase pathways: defining a distinction between Rb and p16 loss in lung cancer [J]. Oncogene 2002; 21:6908–6914.

    Article  PubMed  CAS  Google Scholar 

  2. Divine KK, Pulling LC, Marron-Terada PG, et al. Multiplicity of abnormal promoter methylation in lung adenocarcinomas from smokers and never smokers[J]. Int J Cancer 2005; 114:400–405.

    Article  PubMed  CAS  Google Scholar 

  3. Park MJ, Shimizu K, Nakano T, et al. Pathogenetic and biologic significance o TP14ARF alterations in nonsmall cell lung carcinoma[J]. Cancer Genet Cytogenet 2003; 141:5–13.

    Article  PubMed  CAS  Google Scholar 

  4. Serrano M. The INK4A/ARF locus in murine tumorigenesis[J]. Carcinogeenesis 2000; 21:865–869.

    Article  CAS  Google Scholar 

  5. Quelle DE, Ashmun RA, Hannon GJ, et al. Cloning and characterization of murine p16INK4a and p15INK4b genes[J]. Oncogene 1995; 111:635–645.

    Google Scholar 

  6. Kamijo T, Zindy F, Roussel MF, et al. Tumor suppression att the mouse INK4a locus mediated by the alternative reading frame product p19ARF[J]. Cell 1997; 91:649–659.

    Article  PubMed  CAS  Google Scholar 

  7. Zhang Y, Xiong Y, Yarbrough WG. ARF promoes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p35 tumor suppression pathways[J]. 1998; 92:725–734.

    CAS  Google Scholar 

  8. Belinsky SA, Palmisano WA, Gilliland FD, et al. Aberrant promoter methylation in bronchial epithelium and sputum from current and former smokers[J]. Cancer Res 2002; 21; 7421–7434.

    Google Scholar 

  9. Osada H, Takahashi T. Genetic alterations of multiple tumor suppressors and oncogenes in the carcinogenesis and progression of lung cancer[J]. Oncogene 2002; 21:7421–7434.

    Article  PubMed  CAS  Google Scholar 

  10. Robertson KD, Jones PA. The human ARF cell cycle regulatory gene promoter is a CpG island which can be silenced by DNA methylation and downregulated by wild-type p53[J]. Mol Cell Biol 1998; 18:6457–6473.

    PubMed  CAS  Google Scholar 

  11. Tanaka R, Wang D, Morishita Y, et al. Loss of function of p16 gene and prognosis of pulmonary adenocarcinoma[J]. Cancer 2005; 103:608–615.

    Article  PubMed  CAS  Google Scholar 

  12. Toyota M, Ho C, Ahuja N, et al. Identification of differentially methylated sequences in colorectal cancer by methylated CpG island amplification[J]. Cancer Res 1999; 59:2307–2305.

    PubMed  CAS  Google Scholar 

  13. Herman JG, Umar A, Polyak K, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma[J]. Proc Natl Acad Sci USA 1998; 95:6870–6875.

    Article  PubMed  CAS  Google Scholar 

  14. Esteller M, Corn PG, Urena JM, et al. Inactivation of glutathione S-transferase P1 gene by promoter hypermethylation in human neoplasia[J]. Cancer Res 1998; 58:4515–4518.

    PubMed  CAS  Google Scholar 

  15. Esteller M, Hamilton SR, Burger PC, et al. Inactivation of the DNA repair gene the DNA repair gene 06-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia[J]. Cancer Res 1999; 59:793–797.

    PubMed  CAS  Google Scholar 

  16. Herman JG, Graff JR, Myohanen S, et al. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands[J]. Proc Natl Acad Scil USA 1996; 93:9821–9826.

    Article  CAS  Google Scholar 

  17. Chaubert P, Garyer R, Zimmermann A, et al. Germ-line mutations of the p16INK4a (MTS1) gene occur in a subset of patients with hepatocellular carcinoma[J]. Hepatology 1997; 25:1376–1381.

    Article  PubMed  CAS  Google Scholar 

  18. Esteller M, Tortola S, Toyota M, et al. Hypermethylation-associated inactivation of p14ARF is independent of p16INK4a methylation and pp53 mutational status[J]. Cancer Res 2000; 60:129–133.

    PubMed  CAS  Google Scholar 

  19. Weihrauch M, Markwarth A, Lehnert G, et al. Abnormalities of the ARF-p53 pathway in primary angiosarcomas of the liver[J]. Hum Pathol 2002; 33:884–892.

    Article  PubMed  CAS  Google Scholar 

  20. Park MJ, Shimizu K, Nakano T, et al. Pathogenetic and biologic significance of TP14ARF alterations in nonsmall cell lung carcinoma[J]. Cancer Genetics Cytognetics 2003; 141:5–13.

    Article  CAS  Google Scholar 

  21. Kim DH, Kim JS, Ji YI, et al. Hypermethylation of RASSF1A promoter is associated with the age at starting smoking and a poor prognosis in primary ono-small cell lung cancer[J]. Cancer Res 2003; 63:3743–3746.

    PubMed  CAS  Google Scholar 

  22. Zochbauer Muller S, Fong KM, Virmani AK, et al. Aberrant promoter methylation of multiple genes in non-small cell lung cancers[J]. Cancer Res 2001; 61:249–255.

    PubMed  CAS  Google Scholar 

  23. Gonzalgo ML, Hayashida T, Bender CM, et al. The role of DNA methylation in expression of p19/p16 locus in human bladder cancer cell line[J]. Cancer Res 1998; 58:1245–1252.

    PubMed  CAS  Google Scholar 

  24. Paz MF, Avila S, Fraga MF, et al. Germ-line variants in methy1-guoup metabolism genes and susceptibility to DNA methylation in normal tissues and human primary tumors[[J]. Cancer Res 2002; 62:4519–4524.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of General Thoracic Surgery, The Affiliated Hospital of Qingdao University Medical College, Qingdao, 266003, China

    Tian Kai-hua  (田凯华), Shen Yi  (沈毅), Luo Yi-rne  (罗宜人) & Wang Ming-zhao  (王明钊)

  2. Dipartment of General Thoracic Surgery, The First Affiliated Hospital, China Medical University, Shenyang, 110001, China

    Liu Hong-xu  (刘宏旭), Zhao Hui-ru  (赵惠儒) & Zhang Lin  (张林)

Authors
  1. Tian Kai-hua  (田凯华)
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shen Yi  (沈毅)
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Luo Yi-rne  (罗宜人)
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wang Ming-zhao  (王明钊)
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Liu Hong-xu  (刘宏旭)
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhao Hui-ru  (赵惠儒)
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zhang Lin  (张林)
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tian Kai-hua  (田凯华).

Additional information

Biography: Tian Kai-hua (1971–), male, doctor of medicine, The Affiliated Hospital of Qingdao University Medical College, majors in research on thoracic cancer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tian, Kh., Shen, Y., Luo, Yr. et al. Hypermethylation of p14ARF promoter region and expresion of p14ARF gene product in non-small cell lung cancer. Chin. J. Cancer Res. 18, 276–281 (2006). https://doi.org/10.1007/s11670-006-0276-6

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11670-006-0276-6

Key words

CLC number

Search

Navigation