Novel tumor growth inhibition mechanism by cell cycle regulator cdk2ap1 involves antiangiogenesis modulation

We evaluated the effect of expressing the cell cycle regulator protein cdk2-associating protein1 (cdk2ap1) in inhibiting growth of squamous cell carcinoma (SCC). Expression of cdk2ap1 correlated with reduction in several SCC malignant cell phenotypes, including reduced angiogenesis. We observed several alterations in gene expression consistent with classical functions of cdk2ap1, including upregulation of cell cycle inhibitory genes, and an upregulation in expression of genes belonging to both intrinsic and extrinsic apoptotic cascades. Interestingly, we also uncovered a profile of gene expression and activation of signaling pathways that may suggest new tumor-suppressive functions for cdk2ap1 through downregulation of invasion/metastasis and modulation of antiangiogenesis by upregulation of the TGFβ signaling pathway. Blocking of the TGFβ1 pathway resulted in inhibition of the cdk2ap1 antiangiogenesis phenotype. In combination, these data support the role of cdk2ap1 as a tumor suppressor gene that can regulate SCC tumor growth in a cell autonomous manner through decreases in invasiveness and a non-cell autonomous manner through decreases in angiogenesis phenotypes, and these are novel phenotypes induced by cdk2ap1.