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

Abstract

The expression of the cyclin-dependent kinase inhibitor (CDKI) p27 protein was investigated in relation to (1) the expression of the cell cycle regulators p53, Rb and p16 and (2) the proliferation profile as determined by the expression of Ki67, cyclin A, and cyclin B1 in 80 cases of de novo diffuse large B-cell lymphomas (DLBCL). P27 expression was low/null in large tumor cells in 58/80 cases and intermediate/high in 22/80 cases. Increased expression of p53 protein was observed in 39/80 cases. Decreased expression of Rb and p16 proteins was mutually exclusive and was observed in 5/80 and 14/80 cases, respectively. The analysis of the p27 expression status (low/null versus intermediate/high) with respect to the p53 and/or Rb/p16 expression status showed that low/null p27 expression was significantly correlated with increased p53 expression (P ‫؍‬ .018) and showed a strong trend for correlation with concurrent increased p53 expression and decreased Rb or p16 expression (P ‫؍‬ .050). These findings suggest a tendency for concurrent alterations of the cell cycle regulators p27, p53, and Rb or p16 in DLBCL, which might result in impaired tumor growth control. Indeed, the analysis of the combined p27/p53/ Rb/p16 expression status with respect to the proliferation profile showed that (1) three alterations in the combined p27/p53/Rb/p16 status (i.e., low/null P27 expression, increased expression of p53, and decreased expression of Rb or p16) were significantly correlated with increased expression of cyclin B1 (P ‫؍‬ .005) and (2) two or three alterations were significantly correlated with increased expression of cyclin A (P ‫؍‬ .014). These findings suggest combined impairment of a complex cell-cycle control network involving the CDK inhibitor p27, the P53 pathway, and the Rb1 pathway, which exerts a cooperative effect resulting in enhanced tumor cell proliferation.

Increased Expression of the bcl6 and CD10 Proteins Is Associated with Increased Apoptosis and Proliferation in Diffuse Large B-Cell Lymphomas

“…The apoptotic index (54) could be evaluated in 62 cases (range, 0.26 -9.7%, mean value 2.79% Ϯ 1.97%; Fig 3). The expression of p27, p53, Rb, p16, Ki67, cyclin A, and cyclin B1 proteins was reported in details previously (53). Briefly, positive expression of p27 and p53 proteins was observed in 22/79 (28%) and 38/79 (48%) cases, respectively.…”

“…In this context, the occurrence of aberrations in the p27 expression status and in the p19 (ARF)-p53 and/or Rb-p16-cyclin D growthinhibitory pathways (1,2), which are frequent events in diffuse large B-cell lymphomas (53, 56 -58), might further enhance the proliferative activity of neoplastic cells. Our recent findings are relevant to this assumption because we have shown that low p27 expression combined with altered p53/Rb/p16 expression status is significantly associated with enhanced proliferation in diffuse large B-cell lymphomas (53). In this regard, we asked the question whether bcl6 expression was associated with altered expression of the major cell cycle regulators p27, p53, Rb and p16.…”

“…Pretreatment of the sections with 10 mM sodium citrate buffer (ph 6.0) in a microwave oven was performed for the CD10 and bcl2 immunostaining as we described elsewhere (52). The monoclonal antibodies directed against Ki67, cyclin A, cyclin B1, p53, Rb1, p16, and p27 proteins, the corresponding positive controls, and the evaluation approach for the expression status of these proteins were reported in detail elsewhere (53). Briefly, positive expression of p53 was considered when the expression of this protein in large neoplastic cells was higher than the maximum value of the expression in lymphoid cells in the reactive lymphoid tissues.…”

“…Positive expression of bcl6, CD10 and bcl2 proteins was considered the intermediate/high expression and negative expression was considered the null/low expression. Internal positive control was required and reactive lymph nodes and normal thymuses from our previous studies were also used as positive controls (53,54). Negative controls were included and consisted in the same immunohistochemical method with omission of the primary antibody.…”

Towards whole-organ modelling of tumour growth

“…Although the role played by p27 in normal and cancer cells is the same, its rates of expression differ so that the concentration of p27 is, generally, smaller in cancer cells than in normal cells (Bai et al, 2001;Funk, 1999;Philipp-Staheli et al, 2001). It has also been observed that normal cells in the presence of growth factors exhibit reduced levels of p27 (Leshem and Halevy, 2002;Saito et al, 2001).…”