Loss of Expression of Tumor Suppressor p16^INK4 Protein in Human Primary Gastric Cancer Is Related to the Grade of Differentiation

Abstract

Background: Recent research has revealed a rapid increase in the number of alterations underlying oncogenesis and the proteins which regulate the cell cycle. p16 is a cell cycle regulatory protein acting as a cyclin-dependent kinase inhibitor (CDKI). Because of its antiproliferative effect, p16 has been suggested to be a tumor suppressor gene. Deletions, mutations and functional inactivation of p16 occur with a frequency second only to p53 in most human malignancies. Aim: to evaluate the p16 protein expression in primary gastric cancer in order to understand the possible differences in relation to histotype and grade of tumors. Material and Methods: Immunohistochemical expression of p16 was investigated in matched normal and cancerous tissues from 70 patients with gastric cancer (52 intestinal and 18 diffuse type). Results: In non-cancerous gastric tissues the immunostaining of p16 was weak and limited to antral glands. In gastric cancer tissues, the enhanced immunoreactivity of p16 was not significantly different in intestinal and diffuse type of gastric cancer. However, the intensity of immunostaining was inversely related to the grade of differentiation of these tumours. Conclusions: The overexpression of p16 seems to be a common event in the development of both intestinal and diffuse type of gastric cancer and it is likely that it may be driven by features of the neoplastic state. Likewise, the absence of p16 in the lowest grade of differentiation may reflect increased selection pressure and clonal expansion of the cells with a more aggressive phenotype.

Expressão do P16 e do PDGFR-Beta no adenocarcinoma gástrico

“…Concerning to Lauren histological type, against expectations the diffuse type was predominant, 1,[26][27][28] no statistical difference between Lauren histological type and p16 expression in the two thresholds studied was found as previously reported, 12 although no agreement on this issue have been reached 7,27 . Although it is known that tumours with p16 loss tend to have a higher metastatic potential immunohistochemistry to p16 in lymph nodes was not carried out in this study, since overall p16 expression is much lower in metastatic lymph nodes than in primary lesion 6 .…”

“…Expression of p16 is decreased in node metastasis 6 . Apparently there is no difference in expression between intestinal and diffuse-type gastric adenocarcinoma 12 …”

“…Recent papers have demonstrated relation between p16 inactivation and development of stomach cancer. Forty to ninety per cent of gastric adenocarcinomas show inactivation of p16, [6][7][8][9][10][11] appearing to have relation with cellular differentiation 7,10,12 . Expression of p16 is decreased in node metastasis 6 .…”

Association of low p16INK4a and p15INK4b mRNAs expression with their CpG islands methylation with human hepatocellular carcinogenesis

“…Interestingly, the correlation of loss of p16 protein expression with the cellular differentiation of HCC and gastric cancer has been reported [23,24] . Park et al also noted that inactivation of p16 exon 1 by DNA hypermethylation occurred during the progression of tumor cells to poorly differentiated HCC, which was induced by diethylnitrosamine plus thioacetamide in Fischer 344 rats [25] .…”

Differences in proximal (cardia) versus distal (antral) gastric carcinogenesis via retinoblastoma pathway

“…Other studies on (distal) gastric carcinogenesis have shown a similar p16 'overexpression' in gastric carcinomas [16,17] with weak staining in non-involved mucosa. However, a recent immunohistochemical study found a progressive p16 decrease and a pRb increase from gastritis to dysplasia [12] in samples from the cardia.…”