Abstract
BackgroundThe cyclin D1 (CCND1) and cyclin D3 (CCND3) are frequently co-overexpressed in pancreatic ductal adenocarcinoma (PDAC). Here we examine their differential roles in PDAC.ResultsCCND1 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.ConclusionsOur 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.
Highlights
The cyclin D1 (CCND1) and cyclin D3 (CCND3) are frequently co-overexpressed in pancreatic ductal adenocarcinoma (PDAC)
Effects of D-cyclin downregulation on G1-S cell cycle regulators The YFP transduction marker was detected at 48 hours in >90% of cells following transduction with lentiviruses containing CCND1 shRNA, CCND3 shRNA or non-specific shRNA in all three pancreatic cancer cell lines BxPC3, HPAC and PANC1 (Figure 1A insert)
We observed that selective E2F gene targets depend on specific D-type cyclin regulation. In this manuscript we show that the loss of cell proliferation in PDAC cell lines is more pronounced following cyclin D3 suppression compared to that of cyclin D1
Summary
The cyclin D1 (CCND1) and cyclin D3 (CCND3) are frequently co-overexpressed in pancreatic ductal adenocarcinoma (PDAC) We examine their differential roles in PDAC. Already implicated in PDAC, including ERBB2/STAT3, NOTCH1/NF-B and sonic hedgehog [9,10,11] It remains unclear whether the transcriptional targets of D-cyclins/ Rb/E2F pathway are limited to regulators of the cell cycle or if they have activities on other pathways in PDAC, including apoptosis, invasion and sensitivity to anti-cancer agents. We have examined the overlap and divergence of CCND1 and CCND3 targets and putative functions in PDAC cell lines BxPC3, HPAC and PANC1, including their roles in cellular proliferation, senescence, migration and global gene transcription. The functional annotation, enrichment and relationship of affected genes were identified using three publicly available databases: Gene Ontology (GO), KEGG pathways, and the Interolog Interaction Database (I2D), a protein-protein interactions database
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