Thus, this novel chimeric molecule is more potent and capable of killing a broader spectrum of tumors than the parental p16 and p27 molecules independent of the tumor cell p53 and phenotype and represents a powerful new therapeutic agent for cancer gene therapy.
The essential role of cyclin kinase subunit 1 (Cks1) in Skp2-dependent p27 degradation was recently discovered, but its role in human malignancies is unknown.
Due to the role of p27 in maintaining cellular quiescence, however, loss of its expression can still be a useful partial indicator of the aggressiveness of cancer.
The study aimed at the assessment of expression levels of cyclins D1 and E in surgically removed gastric cancers, including the analysis of this prognostic value parameter, and attempted to determine some correlations between the expression of the examined cyclins and selected histoclinical and molecular parameters such as: patients' age and gender, histological type according to the Lauren classification, cancer stage (TNM), degree of histological malignancy (G) and level of expression of the cell-cycle regulatory genes protein products--P53, P21, P27.
These findings, overall, suggest that Skp2 may play an important role in ACC development through the down-regulation of p27 and that Skp2 siRNA can be a novel modality of cancer gene therapy for suppression of p27 down-regulation in ACC.
Considerable evidence has confirmed that p27 protein plays a negative role in cell-cycle progression from the G1 to the S phase and is considered a tumour suppressor. p27 down-regulation was demonstrated in several malignancies.
Instead, p27 is degraded or relocalized to the cytoplasm in aggressive malignancies, supporting the notion that p27 sequestration from its nuclear cyclin:cyclin-dependent kinase (cdk) targets is critical.
Therefore, knockdown of Skp2 expression by RNAi inhibits breast cancer cell growth and enhances the effect of epirubicin. siRNA-mediated gene silencing of Skp2 could be a novel cancer gene therapy for the suppression of p27 down regulation.
Moreover, we found down-regulation of miR-21, a well-recognized miRNA frequently involved in a wide variety of cancers and up-regulation of cell cycle-dependent kinase inhibitor (CKI) p21 and p27.
Reduced expression of p27 protein is known as an independent prognostic marker in a large variety of cancers and is associated with an unfavorable prognosis.
Moreover, a significant positive correlation between p27 gene expression and rapamycin anti-tumor activity was also observed in mice bearing different human cancer cell xenografts.