Expression patterns of cyclins D1, E and cyclin-dependent kinase inhibitors p21waf1/cip1, p27kip1 in colorectal carcinoma: correlation with other cell cycle regulators (pRb, p53 and Ki-67 and PCNA) and clinicopathological features

Abstract

Aberrations in the cell cycle regulators are common features of many tumours and several have been shown to have prognostic significant in colorectal cancer. The expression patterns of cyclins D1 and E as well as cyclin-dependent kinase (CDK) inhibitors p21waf1/cip1 and p27kip1 and their interrelationship with other cell cycle checkpoint proteins [p53, pRb, Ki-67 and proliferative cell nuclear antigen (PCNA)] were investigated in colorectal cancer in order to ascertain coregulation and influence on tumour behaviour or survival. These molecular markers were localisated immunohistochemically using the monoclonal antibodies anticyclin D1 (DCS-6), anticyclin E (13A3), anti-p21 (4D10), anti-p27 (1B4), anti-p53 (DO7), anti-Rb (AB-5), MIB1 and PC10 in colorectal cancer tissue from 97 patients. Data were analysed statistically using the spss software program. Overexpression of cyclin D1, cyclin E and p21waf1/cip1 proteins (>5% positive neoplastic cells) was observed in 5.9%, 30% and 7.2% of the cases respectively. Increased levels of cyclin D1 (p = 0.0001) and p21waf1/cip1 protein (p = 0.03) in tumours with mucous differentiation were observed. Overexpression of cyclin D1 was correlated with tumour stage (p = 0.03), the lymph node involvement (p = 0.02), as well as p21waf1/cip1 protein expression (p < 0.0001). Cyclin E was positively correlated with p21waf1/cip1 (p = 0.014), as well as with the cell proliferation as measured by PCNA-labelling index (p = 0.011) and Ki-67 score (p = 0.007). A positive relationship of p21waf1/cip1 expression with the proliferative-associated index Ki-67 was noted (p = 0.005). Downregulation of p27kip1 was observed in 47.4% of the cases and was correlated with downregulation of pRb (p = 0.002) and PCNA score (p = 0.004). The prognostic significance of cyclins D1, E and CDK inhibitors p21waf1/cip1, p27kip1 in determining the risk of recurrence and overall survival with both univariate (long-rang test) and multivariate (Cox regression) methods of analysis showed no statistically significance differences. In conclusion, these findings suggest that, the levels of the cell cycle regulators studied, do not seems to have a prognostic value, in terms of predicting the risk of early recurrence and overall survival. In addition, the interrelationships, probably means their contribution to the regulation of cell growth, through different pathways in colorectal carcinogenesis.

A genetic view of laryngeal cancer heterogeneity

“…31 Cyclin D1 overexpression has been reported in laryngeal carcinoma and might be implicated in regulating cell proliferation by the critical G1/S checkpoint. 32 P63 is a p53 homolog and a potential oncogene in squamous cell cancer that has been found in the distal arm of 3q. 33 Loss of chromosomes 3p, 5q, 8p, 9p, 18q and 21q are commonly identified as well, where loss of 18q could indicate poor prognosis tumors.…”

Tumor suppressor pRb2/p130 gene and its derived product Spa310 spacer domain as perspective candidates for cancer therapy

“…Several factors come into play in the regulation of cdk2 activity, such as binding of cdk2 inhibitors as p21 waf1 , p27 Kip1 , and p57 Kip2 (Malumbers and Barbacid, 2005), the already mentioned transient associations with cyclins A and E (Giordano et al, 1989(Giordano et al, , 1991Koff et al, 1992;Bates et al, 1994) and phosphorylation of specific tyrosine and threonine residues (Gu et al, 1992). The constitutive activation of cdk2/cyclin E complexes is often associated with the deregulation of G1 to S transition and tumor progression (Fujii et al, 1998;Harwell et al, 2004;Ioachim et al, 2004;Liao et al, 2004;Sunters et al, 2004;Peschos et al, 2005;Tenderenda, 2005). On these grounds, the targeting of cdk2 activity can have important implications for the development of therapeutics for cancer treatment.…”

Expression of cyclin E in stage III colorectal carcinoma

“…The detection of such markers may aid in risk stratification and cyclin E may be included in the list of possible candidates. The role of cyclin E in colon tumorgenesis is supported by certain studies which revealed overexpression of cyclin E in early stages of tumor development (17,23). Positive cyclin E staining was correlated with Ki-67 antigen (a marker of proliferative activity of malignant cells) and p53 protein level in these cells (3,24).…”