p16INK4a hypermethylation and p53, p16 and MDM2 protein expression in esophageal squamous cell carcinoma.
BACKGROUND
Tumor suppressor genes p53 and p16INK4a and the proto-oncogene MDM2 are considered to be essential G1 cell cycle regulatory genes whose loss of function is associated with ESCC carcinogenesis. We assessed the aberrant methylation of the p16 gene and its impact on p16INK4a protein expression and correlations with p53 and MDM2 protein expressions in patients with ESCC in the Golestan province of northeastern Iran in which ESCC has the highest incidence of cancer, well above the world average.


METHODS
Cancerous tissues and the adjacent normal tissue obtained from 50 ESCC patients were assessed with Methylation-Specific-PCR to examine the methylation status of p16. The expression of p16, p53 and MDM2 proteins was detected by immunohistochemical staining.


RESULTS
Abnormal expression of p16 and p53, but not MDM2, was significantly higher in the tumoral tissue. p53 was concomitantly accumulated in ESCC tumor along with MDM2 overexpression and p16 negative expression. Aberrant methylation of the p16INK4a gene was detected in 31/50 (62%) of esophageal tumor samples, while two of the adjacent normal mucosa were methylated (P < 0.001). p16INK4a aberrant methylation was significantly associated with decreased p16 protein expression (P = 0.033), as well as the overexpression of p53 (P = 0.020).


CONCLUSIONS
p16 hypermethylation is the principal mechanism of p16 protein underexpression and plays an important role in ESCC development. It is associated with p53 protein overexpression and may influence the accumulation of abnormally expressed proteins in p53-MDM2 and p16-Rb pathways, suggesting a possible cross-talk of the involved pathways in ESCC development.
Taghavi
Noushin
N
National Institute of Genetic Engineering and Biotechnology, Tehran, Iran.
Biramijamal
Firouzeh
F
Sotoudeh
Masoud
M
Khademi
Hooman
H
Malekzadeh
Reza
R
Moaven
Omeed
O
Memar
Bahram
B
A'rabi
Azadeh
A
Abbaszadegan
Mohammad Reza
MR
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000737:chemistry* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016009:Chi-Square Distribution; D018899:CpG Islands; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis / Q000235:genetics*; D019175:DNA Methylation; D004938:Esophageal Neoplasms / Q000737:chemistry* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007492:Iran; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D000090063:Proto-Oncogene Mas; D051736:Proto-Oncogene Proteins c-mdm2 / Q000032:analysis*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*
D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
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