Altered Expression of the Cell Cycle Regulatory Molecules pRb, p53 and MDM2 Exert a Synergetic Effect on Tumor Growth and Chromosomal Instability in Non-small Cell Lung Carcinomas (NSCLCs)

Abstract

Background: Recent in vitro studies provide evidence that the cell cycle molecules pRb, p53 and MDM2 form a tightly regulated protein network. In this study, we examined the relationship of this protein network in a series of non-small cell lung carcinomas (NSCLCs), with the kinetic parameters, including proliferative activity or proliferation index (PI) and apoptotic index (AI), and ploidy status of the tumors. Material and Methods: A total of 87 NSCLCs were examined using immunohistochemical and molecular methods in order to estimate the status of the pRb-p53-MDM2 network. The kinetic parameters and the ploidy status of the tumors were assessed by in situ assays. The possible associations between alterations of the network, kinetic parameters and ploidy status of the carcinomas were assessed with a series of statistical methods. Results: Aberrant expression of pRb (Ab) and overexpression of p53 (P) and MDM2 (P) proteins were observed in 39%, 57%, and 68% of the carcinomas, respectively. The comprehensive analysis revealed that concurrent alterations in all three cell cycle regulatory molecules were the most frequent pattern, pRb(Ab)/p53(P)/MDM2(P); this "full abnormal" phenotype represented approximately 27% of the cases. This immunoprofile obtained the highest

Genomic Alterations in the RB Pathway Indicate Prognostic Outcomes of Early-Stage Lung Adenocarcinoma

“…When Rb is phosphorylated to pRb by cyclindependent kinases, it is unable to form a complex with E2F, which allows E2F to promote cell-cycle progression (44). In this study, lower levels of pRb and cyclin D1 and higher levels of E2F1, a member of the E2F family, were detected in tumors with RB1 alterations compared with tumors without RB1 alterations.…”

Low Expression of p27 Protein Combined with Altered p53 and Rb/p16 Expression Status Is Associated with Increased Expression of Cyclin A and Cyclin B1 in Diffuse Large B-Cell Lymphomas

“…Moreover, there is accumulating evidence that concurrent alterations of the status of p27, Rb, and p53 may have cooperative effects resulting in uncontrolled tumor cell proliferation and aggressive malignancies. Indeed, (1) experimental evidence showed that Rb(ϩ/Ϫ)/P27(Ϫ/Ϫ) mice developed pituitary adenocarcinoma with loss of the remaining allele of Rb and a high-grade thyroid C-cell carcinoma that was more aggressive than the disease in either Rb(Ϯ) or P27(Ϫ/Ϫ) mice (41), (2) decreased expression of p27 and overexpression of p53 protein, alone or combined, were predictors of metastatic potential in early invasive colorectal cancer (42), (3) altered p16/INKA4, Rb, and p53 protein status in non-small cell lung carcinomas exert synergistic effect in proliferative activity (45,46), and (4) concurrent disruption of p16/INKA4 and ARF-p53 pathways was an independent negative prognostic factor in DLBCL, whereas selective disruption of either p16/INKA4 or ARF-p53 pathway did not significantly influence the clinical outcome in that series (32). Because of these aforementioned cooperative effects, we have analyzed (1) the relationship of p27 with the p53 and Rb/p16 expression status and (2) the combined p27/p53/ Rb/p16 expression status with respect to the proliferation profile in DLBCL.…”

The expression of COX-2, hTERT, MDM2, LATS2 and S100A2 in different types of non-small cell lung cancer (NSCLC)

“…The correlation between the higher expression of COX-2 and hTERT in NSCLC was already discussed and proposed as a prognostic marker [18]. The MDM2 oncogene, mostly over-expressed in NSCLC, is the main negative regulator of p53 [19][20][21]. As such, it promotes cell survival and cell cycle progression by binding the amino-terminal transactivation domain of the p53 tumour suppressor protein.…”