Skip to main content

Advertisement

Log in

Correlation of p53, MDM2 and p14ARF protein expression in human esophageal squamous cell carcinoma

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

To determine the interrelationships of p53, MDM2, and p14ARF protein expression in primary esophageal squamous cell carcinoma (ESCC) and their prognostic value in ESCC.

Methods

In total, 119 patients treated for ESCC with esophagectomy were enrolled in this study. Demographic and clinical data including gender, age, depth of tumor invasion, lymph node involvement, and 5-year survival rate were collected by chart review. p53, MDM2, and p14ARF were detected immunohistochemically in the resected tumors to evaluate their usefulness as biomarkers of clinical outcome.

Results

p53, MDM2, and p14ARF were expressed in 61 (51.3%), 34 (28.6%), and 22 (18.5%) of 119 tumor specimens, respectively. Overall, p53 protein expression was positively correlated with MDM2 (P = 0.024) and p14ARF expression (P = 0.026). In addition, p14ARF expression was most often found in specimens that were positive for both p53 and MDM2. Changes in the p53, MDM2, and p14ARF protein levels were not correlated with 5-year survival rate.

Conclusions

Expression of p53 protein correlates with increased MDM2 and p14ARF protein levels in ESCC. In addition, status of p53 (wild-type versus mutant) rather than expression level of p53, MDM2, or p14ARF is likely to be the more critical determinant of clinical outcome.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  • Agrawal A, Yang J, Murphy RF, Agrawal DK (2006) Regulation of the p14ARF-Mdm2-p53 pathway: an overview in breast cancer. Exp Mol Pathol 81:115–122. doi:10.1016/j.yexmp.2006.07.001

    Article  PubMed  CAS  Google Scholar 

  • Arora S, Mathew R, Mathur M, Chattopadhayay TK, Ralhan R (2001) Alterations in MDM2 expression in esophageal squamous cell carcinoma: relationship with p53 status. Pathol Oncol Res 7:203–208

    Article  PubMed  CAS  Google Scholar 

  • Capoulade C, Bressac-de Paillerets B, Lefrere I, Ronsin M, Feunteun J, Tursz T, Wiels J (1998) Overexpression of MDM2, due to enhanced translation, results in inactivation of wild-type p53 in Burkitt’s lymphoma cells. Oncogene 16:1603–1610. doi:10.1038/sj.onc.1201702

    Article  PubMed  CAS  Google Scholar 

  • Cordon-Cardo C, Latres E, Drobnjak M, Oliva MR, Pollack D, Woodruff JM, Marechal V, Chen J, Brennan MF, Levine AJ (1994) Molecular abnormalities of mdm2 and p53 genes in adult soft tissue sarcomas. Cancer Res 54:794–799

    PubMed  CAS  Google Scholar 

  • Culjkovic B, Topisirovic I, Skrabanek L, Ruiz-Gutierrez M, Borden KL (2006) eIF4E is a central node of an RNA regulon that governs cellular proliferation. J Cell Biol 175:415–426. doi:10.1083/jcb.200607020

    Article  PubMed  CAS  Google Scholar 

  • Fahn HJ, Wang LS, Huang BS, Huang MH, Chien KY (1994) Tumor recurrence in long-term survivors after treatment of carcinoma of the esophagus. Ann Thorac Surg 57:677–681

    Article  PubMed  CAS  Google Scholar 

  • Gallagher S, Kefford RF, Rizos H (2005) Enforced expression of p14ARF induces p53-dependent cell cycle arrest but not apoptosis. Cell Cycle 4:465–472

    PubMed  CAS  Google Scholar 

  • Greene FL, Page DL, Fleming ID, Fritz A, Balch CM, Haller DG, Morrow M (2002) AJCC cancer staging manual. Springer, New York

    Book  Google Scholar 

  • Harris SL, Levine AJ (2005) The p53 pathway: positive and negative feedback loops. Oncogene 24:2899–2908. doi:10.1038/sj.onc.1208615

    Article  PubMed  CAS  Google Scholar 

  • Higashiyama M, Doi O, Kodama K, Yokouchi H, Kasugai T, Ishiguro S, Takami K, Nakayama T, Nishisho I (1997) MDM2 gene amplification and expression in non-small-cell lung cancer: immunohistochemical expression of its protein is a favourable prognostic marker in patients without p53 protein accumulation. Br J Cancer 75:1302–1308

    PubMed  CAS  Google Scholar 

  • Honda R, Tanaka H, Yasuda H (1997) Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett 420:25–27. doi:10.1016/S0014-5793(97)01480-4

    Article  PubMed  CAS  Google Scholar 

  • Hsu HS, Wang YC, Tseng RC, Chang JW, Chen JT, Shih CM, Chen CY (2004) 5′ cytosine-phospho-guanine island methylation is responsible for p14ARF inactivation and inversely correlates with p53 overexpression in resected non-small cell lung cancer. Clin Cancer Res 10:4734–4741. doi:10.1158/1078-0432.CCR-03-0704

    Article  PubMed  CAS  Google Scholar 

  • Ikeda G, Isaji S, Chandra B, Watanabe M, Kawarada Y (1999) Prognostic significance of biologic factors in squamous cell carcinoma of the esophagus. Cancer 86:1396–1405. doi:10.1002/(SICI)1097-0142(19991015)86:8<1396::AID-CNCR3>3.0.CO;2-H

    Article  PubMed  CAS  Google Scholar 

  • Ikeguchi M, Ueda T, Fukuda K, Yamaguchi K, Tsujitani S, Kaibara N (2002) Expression of the murine double minute gene 2 oncoprotein in esophageal squamous cell carcinoma as a novel marker for lack of response to chemoradiotreatment. Am J Clin Oncol 25:454–459. doi:10.1097/00000421-200210000-00006

    Article  PubMed  Google Scholar 

  • Landers JE, Cassel SL, George DL (1997) Translational enhancement of mdm2 oncogene expression in human tumor cells containing a stabilized wild-type p53 protein. Cancer Res 57:3562–3568

    PubMed  CAS  Google Scholar 

  • Leach FS, Tokino T, Meltzer P, Burrell M, Oliner JD, Smith S, Hill DE, Sidransky D, Kinzler KW, Vogelstein B (1993) p53 Mutation and MDM2 amplification in human soft tissue sarcomas. Cancer Res 53:2231–2234

    PubMed  CAS  Google Scholar 

  • Lianes P, Orlow I, Zhang ZF, Oliva MR, Sarkis AS, Reuter VE, Cordon-Cardo C (1994) Altered patterns of MDM2 and TP53 expression in human bladder cancer. J Natl Cancer Inst 86:1325–1330. doi:10.1093/jnci/86.17.1325

    Article  PubMed  CAS  Google Scholar 

  • Mandard AM, Hainaut P, Hollstein M (2000) Genetic steps in the development of squamous cell carcinoma of the esophagus. Mutat Res 462:335–342. doi:10.1016/S1383-5742(00)00019-3

    Article  PubMed  CAS  Google Scholar 

  • Matsumoto M, Furihata M, Kurabayashi A, Araki K, Sasaguri S, Ohtsuki Y (2003) Association between inducible nitric oxide synthase expression and p53 status in human esophageal squamous cell carcinoma. Oncology 64:90–96. doi:10.1159/000066519

    Article  PubMed  CAS  Google Scholar 

  • Momand J, Zambetti GP, Olson DC, George D, Levine AJ (1992) The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69:1237–1245. doi:10.1016/0092-8674(92)90644-R

    Article  PubMed  CAS  Google Scholar 

  • Nathan CO, Sanders K, Abreo FW, Nassar R, Glass J (2000) Correlation of p53 and the proto-oncogene eIF4E in larynx cancers: prognostic implications. Cancer Res 60:3599–3604

    PubMed  CAS  Google Scholar 

  • Robert V, Michel P, Flaman JM, Chiron A, Martin C, Charbonnier F, Paillot B, Frebourg T (2000) High frequency in esophageal cancers of p53 alterations inactivating the regulation of genes involved in cell cycle and apoptosis. Carcinogenesis 21:563–565. doi:10.1093/carcin/21.4.563

    Article  PubMed  CAS  Google Scholar 

  • Rosa AR, Schirmer CC, Gurski RR, Meurer L, Edelweiss MI, Kruel CD (2003) Prognostic value of p53 protein expression and vascular endothelial growth factor expression in resected squamous cell carcinoma of the esophagus. Dis Esophagus 16:112–118. doi:10.1046/j.1442-2050.2003.00309.x

    Article  PubMed  CAS  Google Scholar 

  • Saito H, Tsujitani S, Oka S, Ikeguchi M, Maeta M, Kaibara N (2002) The expression of murine double minute 2 is a favorable prognostic marker in esophageal squamous cell carcinoma without p53 protein accumulation. Ann Surg Oncol 9:450–456. doi:10.1007/BF02557267

    Article  PubMed  Google Scholar 

  • Shibagaki I, Tanaka H, Shimada Y, Wagata T, Ikenaga M, Imamura M, Ishizaki K (1995) p53 mutation, murine double minute 2 amplification, and human papillomavirus infection are frequently involved but not associated with each other in esophageal squamous cell carcinoma. Clin Cancer Res 1:769–773

    PubMed  CAS  Google Scholar 

  • Smeds J, Berggren P, Ma X, Xu Z, Hemminki K, Kumar R (2002) Genetic status of cell cycle regulators in squamous cell carcinoma of the oesophagus: the CDKN2A (p16(INK4a) and p14(ARF)) and p53 genes are major targets for inactivation. Carcinogenesis 23:645–655. doi:10.1093/carcin/23.4.645

    Article  PubMed  CAS  Google Scholar 

  • Stott FJ, Bates S, James MC, McConnell BB, Starborg M, Brookes S, Palmero I, Ryan K, Hara E, Vousden KH, Peters G (1998) The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J 17:5001–5014. doi:10.1093/emboj/17.17.5001

    Article  PubMed  CAS  Google Scholar 

  • Volant A, Nousbaum JB, Giroux MA, Roue-Quintin I, Metges JP, Ferec C, Gouerou H, Robaszkiewicz M (1995) p53 protein accumulation in oesophageal squamous cell carcinomas and precancerous lesions. J Clin Pathol 48:531–534. doi:10.1136/jcp.48.6.531

    Article  PubMed  CAS  Google Scholar 

  • Wang YC, Lin RK, Tan YH, Chen JT, Chen CY (2005) Wild-type p53 overexpression and its correlation with MDM2 and p14ARF alterations: an alternative pathway to non-small-cell lung cancer. J Clin Oncol 23:154–164. doi:10.1200/JCO.2005.03.139

    Article  PubMed  CAS  Google Scholar 

  • Weber JD, Taylor LJ, Roussel MF, Sherr CJ, Bar-Sagi D (1999) Nucleolar Arf sequesters Mdm2 and activates p53. Nat Cell Biol 1:20–26. doi:10.1038/8991

    Article  PubMed  CAS  Google Scholar 

  • Xing EP, Nie Y, Song Y, Yang GY, Cai YC, Wang LD, Yang CS (1999) Mechanisms of inactivation of p14ARF, p15INK4b, and p16INK4a genes in human esophageal squamous cell carcinoma. Clin Cancer Res 5:2704–2713

    PubMed  CAS  Google Scholar 

  • Xue Q, Sano T, Kashiwabara K, Oyama T, Nakajima T (2001) Aberrant expression of pRb, p16, p14ARF, MDM2, p21 and p53 in squamous cell carcinomas of lung. Jpn J Cancer Res 92:285–292

    PubMed  CAS  Google Scholar 

  • Zhu N, Gu L, Findley HW, Zhou M (2005) Transcriptional repression of the eukaryotic initiation factor 4E gene by wild type p53. Biochem Biophys Res Commun 335:1272–1279. doi:10.1016/j.bbrc.2005.08.026

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The study was supported by grants from the National Science Council of Taiwan to HS Hsu (NSC-96-2314-B-075-027) and TH Cheng (NSC-93-2320-B-010-063).

Conflict of interest statement

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Han-Shui Hsu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cheng, TH., Hsu, PK., Li, A.FY. et al. Correlation of p53, MDM2 and p14ARF protein expression in human esophageal squamous cell carcinoma. J Cancer Res Clin Oncol 135, 1577–1582 (2009). https://doi.org/10.1007/s00432-009-0605-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-009-0605-5

Keywords

Navigation