Abstract
BackgroundBoth mechanistic features and recent correlative findings suggest a potential role for protein kinase C-beta (PKC-β) in tumor pathogenesis, particularly in B-cell malignancies. To evaluate the role of this gene in lymphoid malignancies, we analyzed global gene expression data to quantify PKC-β expression across diagnostic groups and, when possible, determined correlations between PKC-β expression and survival.ResultsOur analysis showed that the level of PKC-β expression was highest in chronic lymphocytic leukemia and follicular lymphoma. Within diffuse large-B cell lymphoma (DLBCL), PKC-β expression was significantly higher in activated B-cell- like subtype than germinal center B-cell- like subtype (P < 0.0001). Elevated PKC-β appeared to be associated with worse survival in both of these subtypes. When analyzed within clinically defined risk groups established by the International Prognostic Index (IPI), PKC-β expression was lowest in patients with low IPI scores (0–1). Within intermediate- and high-risk IPI groups, elevated PKC-β expression was associated with worse survival, suggesting that PKC-β may expand the prognostic value of the IPI. Results of global gene expression analyses of DLBCL samples corroborate previous observations that anti-apoptosis, cell proliferation, and B-cell proliferation signaling pathways are functionally related to PKC-β.ConclusionWe present a first detailed pharmacogenomics report comparing PKC-β mRNA expression across different lymphoid malignancies and evaluating it as an outcome predictor. Our findings suggest that DLBCL patients with elevated PKC-β have a worse prognosis, indicating that further evaluation of PKC-β as a chemotherapeutic target for lymphoid malignancies is warranted.ReviewersThis article was reviewed by Dr. Pierre Pontarotti, Dr. Kateryna Makova, and Dr. Matthew Coleman (nominated by Dr. Sandrine Dudoit).
Highlights
Both mechanistic features and recent correlative findings suggest a potential role for protein kinase C-beta (PKC-β) in tumor pathogenesis, in B-cell malignancies
We evaluated PKC-β to determine whether it could predict survival within the clinically defined risk groups established by the International Prognostic Index (IPI) [13]
Analysis of a second dataset derived from Affymetrix arrays [12] showed a similar trend with mean PKC-β expression significantly elevated in follicular lymphoma (FL) relative to diffuse large B-cell lymphoma (DLBCL) samples (P = 0.018)
Summary
Both mechanistic features and recent correlative findings suggest a potential role for protein kinase C-beta (PKC-β) in tumor pathogenesis, in B-cell malignancies. The protein kinase C (PKC) family of serine/threonine kinases has an important role in biological processes related to signal transduction, cell proliferation, and apoptosis. Protein kinase C-beta (PKC-β) is a regulator of the vascular endothelial growth factor (VEGF) signal cascade and angiogenesis [3,4,5,6,7]. Xia et al demonstrated that PKC inhibitors could block VEGF-induced PKC activation and endothelial cell proliferation [7]. BCR stimulation of PKC-β-deficient B cells failed to up-regulate the anti-apoptotic protein Bcl-xl, and quenched cell survival signals [9]. The PKC-β inhibitor enzastaurin has shown activity in xenograft mouse models of diffuse large cell lymphoma [11]. 2. There is no citation for " VEGF-mediated mitogenic effects were blocked by PKC-b inhibitor LY333531, but not by antisense oligonucleotides to PKCa."
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