Expression of p16 and Cyclin D1 in Bladder Cancer and Correlation in Cancer Progression

Abstract

Introduction: Gene p16 encodes a cyclin-dependent kinase inhibitor which functions to regulate cyclin D1, cell cycle progression and malignancies. The relationship between p16 and cyclin D1 is thought to alter bladder cancer formation and tumor progression. We aimed to investigate the expression of p16 and cyclin D1 genes in order to evaluate their clinical significance in bladder cancer. Materials and Methods: Tissue samples from 67 patients with transitional cell carcinoma were examined with an immunohistochemical stain for the expression of p16 and cyclin D1 genes. The expression rate was compared to 12 normal urinary bladder mucosa samples obtained from transurethral surgery from noncancer patients. Results: The results revealed significant differences between normal bladder mucosa (100%) and cancer tissue (40.3%) for the positive staining of p16 protein (p < 0.001), while positive staining for the cyclin D1 protein in the patient group (67.2%) was significantly higher (p = 0.003) than that in the control group (16.7%). With the progression of tumor grade and clinical staging the positive rate of p16 gene expression increased, whereas, that of cyclin D1 decreased. Expression of the p16 gene in the non-invasive group was greater than that in the invasive group and a lower expression rate of the cyclin D1 gene in the non-invasive group compared to the invasive group. Conclusions: The results revealed that expression of the p16 gene is inversely proportional to the expression of the cyclin D1 gene. Therefore, abnormal expression of the p16 and cyclin D1 genes play important roles in tumorigenesis and tumor progression.

Evaluation of different p16 immunostaining methods and the prognostic role of p16/Ki-67 combined expression in non-muscle invasive bladder cancers

“…As with many tissue section studies, there are various approaches to immunohistochemical evaluation of p16 in the bladder. p16, which is more difficult to evaluate than cell cycle proteins, such as Ki-67 and p53, is a valuable marker for predicting the clinical course [1,19].…”

“…In other studies, expression below 10% was regarded as abnormal, while that above 10% was considered normal [18][19][20]. Another study interpreted p16 expression below 5% as negative staining for p16 [1]. Some authors regarded expression loss (no staining) and overexpression (staining > 50%) as abnormal and moderate staining as normal [21][22][23][24].…”

“…However, the functional and biological importance of cytoplasmic staining is not yet understood [35]. Some studies on p16 expression take into account only nuclear staining [1,24,36], while others consider both nuclear and cytoplasmic staining [18,19,23]. Han et al compared endocervical carcinomas and endometrial adenocarcinomas in terms of p16 expression.…”

“…P16c: Expression below 5% was regarded as abnormal while expression ≥ 5% was regarded as normal [1].…”

“…Bladder cancer is a complex and multi-factorial cancer involving both environmental and genetic factors [1]. During diagnosis, nearly 75% of bladder cancers are superficial which are confined to the mucosa or lamina propria [2][3][4].…”