Ontario Cancer Institute and Princess Margaret Hospital, University Health Network, Toronto, Ontario M5G 2M9, Canada.
Mol Cancer. 2010 Feb 1;9:24. doi: 10.1186/1476-4598-9-24.
The cyclin D1 (CCND1) and cyclin D3 (CCND3) are frequently co-overexpressed in pancreatic ductal adenocarcinoma (PDAC). Here we examine their differential roles in PDAC.
CCND1 and CCND3 expression were selectively suppressed by shRNA in PDAC cell lines with expression levels of equal CCND1 and CCND3 (BxPC3), enhanced CCND1 (HPAC) or enhanced CCND3 (PANC1). Suppression of cell proliferation was greater with CCND3 than CCND1 downregulation. CCND3 suppression led to a reduced level of phosphorylated retinoblastoma protein (Ser795p-Rb/p110) and resulted in decreased levels of cyclin A mRNA and protein. A global gene expression analysis identified deregulated genes in D1- or D3-cyclin siRNA-treated PANC1 cells. The downregulated gene targets in CCND3 suppressed cells were significantly enriched in cell cycle associated processes (p < 0.005). In contrast, focal adhesion/actin cytoskeleton, MAPK and NF B signaling appeared to characterize the target genes and their interacting proteins in CCND1 suppressed PANC1 cells.
Our results suggest that CCND3 is the primary driver of the cell cycle, in cooperation with CCND1 that integrates extracellular mitogenic signaling. We also present evidence that CCND1 plays a role in tumor cell migration. The results provide novel insights for common and differential targets of CCND1 and CCND3 overexpression during pancreatic duct cell carcinogenesis.
细胞周期蛋白 D1（CCND1）和细胞周期蛋白 D3（CCND3）在胰腺导管腺癌（PDAC）中经常共同过表达。在这里，我们研究了它们在 PDAC 中的差异作用。
在表达水平相等的 CCND1 和 CCND3（BxPC3）、增强的 CCND1（HPAC）或增强的 CCND3（PANC1）的 PDAC 细胞系中，通过 shRNA 选择性抑制了 CCND1 和 CCND3 的表达。与 CCND1 下调相比，CCND3 的抑制导致细胞增殖减少。CCND3 抑制导致磷酸化视网膜母细胞瘤蛋白（Ser795p-Rb/p110）水平降低，并导致 cyclin A mRNA 和蛋白水平降低。全基因表达分析鉴定了 D1 或 D3 细胞周期蛋白 siRNA 处理的 PANC1 细胞中失调的基因。在 CCND3 抑制细胞中下调的基因靶标在细胞周期相关过程中显著富集（p < 0.005）。相比之下，焦点粘附/肌动蛋白细胞骨架、MAPK 和 NF B 信号似乎描述了 CCND1 抑制 PANC1 细胞中的基因靶标及其相互作用蛋白。
我们的结果表明，CCND3 是细胞周期的主要驱动因素，与整合细胞外有丝分裂信号的 CCND1 合作。我们还提供了证据表明，CCND1 在肿瘤细胞迁移中起作用。这些结果为胰腺导管细胞癌变过程中 CCND1 和 CCND3 过表达的共同和差异靶标提供了新的见解。
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