| Cancer is caused by uncontrolled proliferation of cells which is itself caused by abnormality of cell cycle regulatory mechanisms, mainly in Rb pathway. Retinoblastoma (Rb), located at 13q14, is a key tumor suppressor gene. Rb family of proteins, pRb, p107 and p130 are thought ultimately regulate G1-S checkpoint of the cell cycle. At the beginning of G1, Rb proteins exist as unphosphorylated stat that allow them to bind more than 80 kinds of proteins including E2F which is essential for cell cycle progression. The activity of the Rb proteins is primarily controlled by phosphorylation events. Rb phosphorylation at G1-S transition is driven by Cdks Cdk4 and Cdk6, in protein complexes with cyclinD1 which contains nuclear localization signals and target the Ckd4/Cdk6 to the nucleus. These complexes are controlled by the Cdk inhibitors, p16 family of proteins, p16INK4a, p15INK4B and p18INK4C. The Rb/cyclinD1/cdk4/p16 pathway is obtained by substituting events. Each of these alteration has variety of mechanisms, but all of these alterations have the same result that irregulation of transcription factor such as E2F.Studies concerning about the expression of Rb, cyclinD1, p16 gene and the clinical pathology factors have been performed. But not all research showed positive existence among over-expression of cyclinD1, absence of Rb, p16 and poor prognosis. At the same time, these protein expression rates are quite different even in the same tissue and by the same method. In oral squamous cell carcinoma (OSCC), several studies between clinical pathology factors and expression of Rb, cyclinD1, p16 gene have been reported with controversial results.In this study, the expression of retinoblastoma protein (pRb), cyclinD1 and p16 in 37 OSCC was performed to analysis such a relationship in formalin fixed-paraffin embedded archival material by streptavidin-biotin-peroxidase immunohistochemical method with Mouse monoclonal anti p16 antibody (F12, Santa Cruz, 1:200), anti Rb antibody (1F8, DAKO Italy, 1:40) and anti cyclinD1 antibody (DCS-6, DAKO Italy, 1:50). The results were expressed as the percentage of positive cells counted. The percentage of positive cells in each case was semiquantitatively evaluated. In the present study, cyclinD1, p16 and Rb immunoreactivities were classified into four categories according to the percentage of positive cell: -:0-5%, +: 5%-25%, ++: 25-50%, +++: 50-75%, ++++:≧75%. Relationships between immunohistochemical results with various clinical and pathological features were analyzed by Fisher's exact test.Alteration of Rb expression, positive cyclinD1 expression and loss of p16 expression were demonstrated in 9 (24%) patients, 21 (57%) patients, and 19 (51%) patients, respectively. An inverse correlation was found between p16 expression and Rb expression (p=0.02). cyclinD1 over-expression was associated with tumor size (p = 0.02) and lymph node metastases (p = 0.01). p16 expression was lower in the elderly group (over 60 years) as compared with the younger group (less than 60 years) (p=0.02).In our series, loss of the Rb expression was similar to the Dokiya et al 21 of 72 (29)% in OSCC. We found loss of p16 expression was 51%, which is consistent with Jares et al 24 of 42 (57%). Our studied showed cyclinD1 over-expression was observed in 57%, which is in line with Masuda et al 55% and Muller et al 58% in OSCC.If the expression of these proteins is looked at together, all but 5 tumors contained at least one abnormality in the expression of Rb, cyclinD1 and p16. This observation confirms the fundamental roles of the Rb/cyclinD1/p16 pathway in OSCC turmorgenesis and suggests alteration in at least one of these genes might be required for OSCC development and progression.We found 2 inverse correlations between Rb and p16, p16 and age. These observations confirm the critical importance of Rb/cyclinD1/p16 pathway in the progression of OSCC. It suggest that (1) loss of the p16 protein may constitute an early event in the development of these OSCC, (2) the reciprocal expression... |
