Abstract
BackgroundTumor 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.MethodsCancerous 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.ResultsAbnormal 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).Conclusionsp16 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.
Highlights
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 Esophageal Squamous CellCarcinoma (ESCC) carcinogenesis
We examined the methylation status of the p16 gene, in 50 ESCC patients using Methylation Specific PCR (MSP) assay. p16, p53 and MDM2 protein expression was assessed to identify the association of p16INK4a gene methylation with the expression of these cell cycle proteins in a population with a high incidence of ESCC in northeastern Iran
Study population and sample collection A total of 50 ESCC patients were recruited from May 2006 to June 2007, from among patients referred to the two main referral oncology centers in northeastern Iran: Atrak clinic, a referral center for upper GI cancers in Golestan province, and Omid Oncology Hospital, referral oncology hospital in northeastern Iran
Summary
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. Esophageal cancer is the fifth leading cause of cancerrelated deaths in Iran [1] It is considered the second most common type of cancer in both males and females in Golestan province of northeastern Iran (Age Standardized Rate: 22.57 in males and 19.89 in females in 105 persons/year) (unpublished data). This region is located in the "Esophageal Cancer Belt," stretching from China westward through central Asia to northern Iran, where there is a high incidence of Esophageal Squamous Cell. Investigation of alterations in oncogenes and tumor suppressor genes implicated in esophageal tumorigenesis may provide molecular markers for early diagnosis and therapeutic intervention[8]
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