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Published in: Diseases of the Colon & Rectum 9/2008

01-09-2008 | Original Contribution

MDM2 mRNA Expression in the p53 Pathway May Predict the Potential of Invasion and Liver Metastasis in Colorectal Cancer

Authors: Ito Kondo, M.D., Satoru Iida, M.D., Yoko Takagi, Kenichi Sugihara, M.D.

Published in: Diseases of the Colon & Rectum | Issue 9/2008

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Abstract

Purpose

The p53/MDM2/p14ARF pathway is one of the major signaling cascades involved in the regulation of apoptosis. Although many tumors have been reported to show disruption of the p53/MDM2/p14ARF pathway, few studies have examined p53, MDM2, and p14ARF simultaneously in colorectal carcinoma. The present study was undertaken to clarify whether correlations exist among MDM2, p53, and p14ARF in colorectal cancer.

Methods

We determined the presence of mutations in the p53 gene, MDM2 expression, and methylation status of the p14ARF in 97 primary colorectal carcinoma specimens. Associations with survival and clinicopathologic factors were investigated.

Results

At least one abnormality of these three molecules was found in 82 (84 percent) tumors. We observed a significant inverse association between MDM2 expression and tumor invasion (P = 0.01). Furthermore, the presence of liver metastasis was also significantly associated with low MDM2 expression (P = 0.02).

Conclusions

The results suggest that disruption of the p53/MDM2/p14ARF pathway may frequently participate in colonic carcinogenesis and that MDM2 expression status may be a factor in the prediction of potential invasion and liver metastasis of colorectal carcinomas.
Literature
1.
go back to reference Watanabe T, Katayama Y, Yoshino A, Komine C, Yokoyama T. Deregulation of the TP53/p14ARF tumor suppressor pathway in low-grade diffuse astrocytomas and its influence on clinical course. Clin Cancer Res 2003;9:4884–90.PubMed Watanabe T, Katayama Y, Yoshino A, Komine C, Yokoyama T. Deregulation of the TP53/p14ARF tumor suppressor pathway in low-grade diffuse astrocytomas and its influence on clinical course. Clin Cancer Res 2003;9:4884–90.PubMed
2.
3.
go back to reference Soussi T, Caron de Fromentel C, May P. Structural aspects of the p53 protein in relation to gene evolution. Oncogene 1990;5:945–52.PubMed Soussi T, Caron de Fromentel C, May P. Structural aspects of the p53 protein in relation to gene evolution. Oncogene 1990;5:945–52.PubMed
4.
go back to reference Dale AB, Lothe RA, Meling GI, Hainaut P, Rognum T, Skovlund E. TP53 and long-term progression in colorectal cancer: mutations in the L3 zinc-binding domain predict survival. Clin Cancer Res 1998;4:203–10. Dale AB, Lothe RA, Meling GI, Hainaut P, Rognum T, Skovlund E. TP53 and long-term progression in colorectal cancer: mutations in the L3 zinc-binding domain predict survival. Clin Cancer Res 1998;4:203–10.
7.
go back to reference Snyder LC, Feng TY, Francke U, George DL. Molecular analysis and chromosomal mapping of amplified genes isolated from a transformed mouse 3T3 cell line. Somat Cell Mol Genet 1987;13:235–44.CrossRef Snyder LC, Feng TY, Francke U, George DL. Molecular analysis and chromosomal mapping of amplified genes isolated from a transformed mouse 3T3 cell line. Somat Cell Mol Genet 1987;13:235–44.CrossRef
8.
go back to reference Momand J, Jung D, Wilczynski S, Niland J. The MDM2 gene amplification database. Nucleic Acids Res 1998;26:3453–9.PubMedCrossRef Momand J, Jung D, Wilczynski S, Niland J. The MDM2 gene amplification database. Nucleic Acids Res 1998;26:3453–9.PubMedCrossRef
9.
go back to reference Quelle DE, Zindy F, Ashmun RA, Sherr CJ. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 1995;83:993–1000.PubMedCrossRef Quelle DE, Zindy F, Ashmun RA, Sherr CJ. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 1995;83:993–1000.PubMedCrossRef
10.
go back to reference Hibi K, Nakayama H, Koike M, Kasai Y, Ito K, Akiyama S, Nakao A. Colorectal cancers with both p16 and p14 methylation show invasive characteristics. Jpn J Cancer Res 2002;93:883–7.PubMed Hibi K, Nakayama H, Koike M, Kasai Y, Ito K, Akiyama S, Nakao A. Colorectal cancers with both p16 and p14 methylation show invasive characteristics. Jpn J Cancer Res 2002;93:883–7.PubMed
11.
go back to reference Greene FL, Page DL, Fleming ID. AJCC cancer staging manual. 6th ed. New York: Springer-Verlag, 2002. Greene FL, Page DL, Fleming ID. AJCC cancer staging manual. 6th ed. New York: Springer-Verlag, 2002.
12.
go back to reference Pinyol M, Hernandes L, Martinez A, et al. INK4a/ARF locus alterations in human non-Hodgkin’s lymphomas mainly occur in tumors with wild-type p53 gene. Am J Pathol 2000;156:1987–96.PubMed Pinyol M, Hernandes L, Martinez A, et al. INK4a/ARF locus alterations in human non-Hodgkin’s lymphomas mainly occur in tumors with wild-type p53 gene. Am J Pathol 2000;156:1987–96.PubMed
13.
go back to reference Dowell SP, Wilson PO, Derias NW, Lane P, Hall PA. Clinical utility of the immunocytochemical detection of p53 protein in cytological specimens. Cancer Res 1994;54:2914–21.PubMed Dowell SP, Wilson PO, Derias NW, Lane P, Hall PA. Clinical utility of the immunocytochemical detection of p53 protein in cytological specimens. Cancer Res 1994;54:2914–21.PubMed
14.
go back to reference Inoue H, Kimura A, Tuji T. Degradation profile of mRNA in a dead rat body: basic semi-quantification study. Forensic Sci Int 2002;130:127–32.PubMedCrossRef Inoue H, Kimura A, Tuji T. Degradation profile of mRNA in a dead rat body: basic semi-quantification study. Forensic Sci Int 2002;130:127–32.PubMedCrossRef
15.
go back to reference Ishida K, Zhu BL, Maeda H. Novel approach to quantitative reverse transcription PCR assay of mRNA component in autopsy materials using the TaqMan fluorogenic detection system: dynamics of pulmonary surfactant apoprotein A. Forensic Sci Int 2000;113:127–31.PubMedCrossRef Ishida K, Zhu BL, Maeda H. Novel approach to quantitative reverse transcription PCR assay of mRNA component in autopsy materials using the TaqMan fluorogenic detection system: dynamics of pulmonary surfactant apoprotein A. Forensic Sci Int 2000;113:127–31.PubMedCrossRef
16.
go back to reference Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 1996;93:9821–6.PubMedCrossRef Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 1996;93:9821–6.PubMedCrossRef
17.
18.
go back to reference Wurl P, Meye A, Schmidt H, et al. High prognostic significance of Mdm2/p53 co-overexpression in soft tissue sarcomas of the extremities. Oncogene 1998;16:1183–5.PubMedCrossRef Wurl P, Meye A, Schmidt H, et al. High prognostic significance of Mdm2/p53 co-overexpression in soft tissue sarcomas of the extremities. Oncogene 1998;16:1183–5.PubMedCrossRef
19.
go back to reference Schiebe M, Ohneseit P, Hoffmann W, Meyemann R, Rodemann HP, Bamberg M. Analysis of mdm2 and p53 gene alterations in glioblastomas and its correlation with clinical factors. J Neurooncol 2000;49:197–203.PubMedCrossRef Schiebe M, Ohneseit P, Hoffmann W, Meyemann R, Rodemann HP, Bamberg M. Analysis of mdm2 and p53 gene alterations in glioblastomas and its correlation with clinical factors. J Neurooncol 2000;49:197–203.PubMedCrossRef
20.
go back to reference Gustafsson B, Axelsson B, Gustafsson B, Christensson B, Winiarski J. MDM2 and p53 in childhood acute lymphoblastic leukemia: higher expression in childhood leukemias with poor prognosis compared to long-term survivors. Pediatr Hematol Oncol 2001;18:497–508.PubMedCrossRef Gustafsson B, Axelsson B, Gustafsson B, Christensson B, Winiarski J. MDM2 and p53 in childhood acute lymphoblastic leukemia: higher expression in childhood leukemias with poor prognosis compared to long-term survivors. Pediatr Hematol Oncol 2001;18:497–508.PubMedCrossRef
21.
go back to reference Lukas J, Gao DQ, Kashmeshian M, et al. Alternative and aberrant messenger RNA splicing of the mdm2 oncogene in invasive breast cancer. Cancer Res 2001;61:3212–9.PubMed Lukas J, Gao DQ, Kashmeshian M, et al. Alternative and aberrant messenger RNA splicing of the mdm2 oncogene in invasive breast cancer. Cancer Res 2001;61:3212–9.PubMed
22.
go back to reference Hori M, Shimazaki J, Inagawa S, Itabashi M, Hori M. Overexpression of MDM2 oncoprotein correlates with possession of estrogen receptor alpha and lack of MDM2 mRNA splice variants in human breast cancer. Breast Cancer Res Treat 2002;71:77–83.PubMedCrossRef Hori M, Shimazaki J, Inagawa S, Itabashi M, Hori M. Overexpression of MDM2 oncoprotein correlates with possession of estrogen receptor alpha and lack of MDM2 mRNA splice variants in human breast cancer. Breast Cancer Res Treat 2002;71:77–83.PubMedCrossRef
23.
go back to reference Higashiyama M, Doi O, Kodama K, et al. 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 1997;75:1302–8.PubMed Higashiyama M, Doi O, Kodama K, et al. 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 1997;75:1302–8.PubMed
24.
go back to reference Polsky D, Bastian BC, Hazan C, et al. HDM2 protein overexpression, but not gene amplification, is related to tumorigenesis of cutaneous melanoma. Cancer Res 2001;61:7642–6.PubMed Polsky D, Bastian BC, Hazan C, et al. HDM2 protein overexpression, but not gene amplification, is related to tumorigenesis of cutaneous melanoma. Cancer Res 2001;61:7642–6.PubMed
25.
go back to reference Polsky D, Melzer K, Hazan C, et al. HDM2 protein overexpression and prognosis in primary malignant melanoma. J Natl Cancer Inst 2002;94:1803–6.PubMed Polsky D, Melzer K, Hazan C, et al. HDM2 protein overexpression and prognosis in primary malignant melanoma. J Natl Cancer Inst 2002;94:1803–6.PubMed
26.
go back to reference Millon R, Muller D, Schultz I, et al. Loss of MDM2 expression in human head and neck squamous cell carcinomas and clinical significance. Oral Oncol 2001;37:620–31.PubMedCrossRef Millon R, Muller D, Schultz I, et al. Loss of MDM2 expression in human head and neck squamous cell carcinomas and clinical significance. Oral Oncol 2001;37:620–31.PubMedCrossRef
27.
go back to reference Iwakuma T, Lozano G. MDM2, an introduction. Mol Cancer Res 2003;1:993–1000.PubMed Iwakuma T, Lozano G. MDM2, an introduction. Mol Cancer Res 2003;1:993–1000.PubMed
28.
go back to reference Evans SC, Viswanathan M, Grier JD, Narayama M, El-Naggar AK, Lozano G. An alternatively spliced HDM2 product increases p53 activity by inhibiting HDM2. Oncogene 2001;20:4041–9.PubMedCrossRef Evans SC, Viswanathan M, Grier JD, Narayama M, El-Naggar AK, Lozano G. An alternatively spliced HDM2 product increases p53 activity by inhibiting HDM2. Oncogene 2001;20:4041–9.PubMedCrossRef
29.
go back to reference Girnita L, Girnita A, Larsson O. Mdm2-dependent ubiquitination and degradation of the insulin-like growth factor 1 receptor. Proc Natl Acad Sci USA 2003;100:8247–57.PubMedCrossRef Girnita L, Girnita A, Larsson O. Mdm2-dependent ubiquitination and degradation of the insulin-like growth factor 1 receptor. Proc Natl Acad Sci USA 2003;100:8247–57.PubMedCrossRef
30.
go back to reference Yoeli-Lerner M, Yiu GK, Rabinovitz I, Erhardt P, Jauliac S, Toker A. Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT. Mol Cell 2005;20:539–50.PubMedCrossRef Yoeli-Lerner M, Yiu GK, Rabinovitz I, Erhardt P, Jauliac S, Toker A. Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT. Mol Cell 2005;20:539–50.PubMedCrossRef
31.
go back to reference Salcedo A, Mayor F Jr, Penela P. Mdm2 is involved in the ubiquitination and degradation of G-protein-coupled receptor kinase 2. EMBO J 2006;25:4752–62.PubMedCrossRef Salcedo A, Mayor F Jr, Penela P. Mdm2 is involved in the ubiquitination and degradation of G-protein-coupled receptor kinase 2. EMBO J 2006;25:4752–62.PubMedCrossRef
32.
go back to reference Esteller M, Tortola S, Toyota M, et al. Hypermethylation-associated inactivation of p14(ARF) is independent of p16(INK4a) methylation and p53 mutational status. Cancer Res 2000;60:129–33.PubMed Esteller M, Tortola S, Toyota M, et al. Hypermethylation-associated inactivation of p14(ARF) is independent of p16(INK4a) methylation and p53 mutational status. Cancer Res 2000;60:129–33.PubMed
33.
go back to reference Esteller M, Cardo CC, Corn PG, et al. p14ARF silencing by promoter hypermethylation mediates abnormal intracellular localization of MDM2. Cancer Res 2001;61:2816–21.PubMed Esteller M, Cardo CC, Corn PG, et al. p14ARF silencing by promoter hypermethylation mediates abnormal intracellular localization of MDM2. Cancer Res 2001;61:2816–21.PubMed
34.
go back to reference Esteller M, Ganzalez S, Risques RA, et al. K-ras and p16 aberrations confer poor prognosis in human colorectal cancer. J Clin Oncol 2001;19:299–304.PubMed Esteller M, Ganzalez S, Risques RA, et al. K-ras and p16 aberrations confer poor prognosis in human colorectal cancer. J Clin Oncol 2001;19:299–304.PubMed
35.
go back to reference Bartek J, Lukas J. Pathways governing G1/S transition and their response to DNA damage. FEBS Lett 2001;490:117–22.PubMedCrossRef Bartek J, Lukas J. Pathways governing G1/S transition and their response to DNA damage. FEBS Lett 2001;490:117–22.PubMedCrossRef
36.
37.
go back to reference Tannapfel A, Busse C, Weinans L, et al. INK4a-ARF alterations and p53 mutations in hepatocellular carcinomas. Oncogene 2001;20:7104–9.PubMedCrossRef Tannapfel A, Busse C, Weinans L, et al. INK4a-ARF alterations and p53 mutations in hepatocellular carcinomas. Oncogene 2001;20:7104–9.PubMedCrossRef
38.
go back to reference Fulci G, Labuhn M, Maier D, et al. p53 gene mutation and ink4a-arf deletion appear to be two mutually exclusive events in human glioblastoma. Oncogene 2000;19:3816–22.PubMedCrossRef Fulci G, Labuhn M, Maier D, et al. p53 gene mutation and ink4a-arf deletion appear to be two mutually exclusive events in human glioblastoma. Oncogene 2000;19:3816–22.PubMedCrossRef
39.
go back to reference Gazzeri S, Valle VD, Chaussade L, Brambilla C, Larsen CJ, Brambilla E. The human p19ARF protein encoded by the beta transcript of the p16INK4a gene is frequently lost in small cell lung cancer. Cancer Res 1998;58:3926–31.PubMed Gazzeri S, Valle VD, Chaussade L, Brambilla C, Larsen CJ, Brambilla E. The human p19ARF protein encoded by the beta transcript of the p16INK4a gene is frequently lost in small cell lung cancer. Cancer Res 1998;58:3926–31.PubMed
40.
go back to reference Iida S, Akiyama Y, Nakagima T, et al. Alterations and hypermethylation of the p14(ARF) gene in gastric cancer. Int J Cancer 2000;87:654–8.PubMedCrossRef Iida S, Akiyama Y, Nakagima T, et al. Alterations and hypermethylation of the p14(ARF) gene in gastric cancer. Int J Cancer 2000;87:654–8.PubMedCrossRef
41.
go back to reference Eischen CM, Alt JR, Wang P. Loss of one allele of ARF rescues Mdm2 haploinsufficiency effects on apoptosis and lymphoma development. Oncogene 2004;23:8931–40.PubMedCrossRef Eischen CM, Alt JR, Wang P. Loss of one allele of ARF rescues Mdm2 haploinsufficiency effects on apoptosis and lymphoma development. Oncogene 2004;23:8931–40.PubMedCrossRef
Metadata
Title
MDM2 mRNA Expression in the p53 Pathway May Predict the Potential of Invasion and Liver Metastasis in Colorectal Cancer
Authors
Ito Kondo, M.D.
Satoru Iida, M.D.
Yoko Takagi
Kenichi Sugihara, M.D.
Publication date
01-09-2008
Publisher
Springer-Verlag
Published in
Diseases of the Colon & Rectum / Issue 9/2008
Print ISSN: 0012-3706
Electronic ISSN: 1530-0358
DOI
https://doi.org/10.1007/s10350-008-9382-5

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