Differential roles of cyclin D1 and D3 in pancreatic ductal adenocarcinoma.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Radulovich
Nikolina
N
Ontario Cancer Institute and Princess Margaret Hospital, University Health Network, Toronto, Ontario M5G 2M9, Canada.
Pham
Nhu-An
NA
Strumpf
Dan
D
Leung
Lisa
L
Xie
Wing
W
Jurisica
Igor
I
Tsao
Ming-Sound
MS
D000199:Actins / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D056743:Cyclin D3 / Q000235:genetics* / Q000378:metabolism; D003599:Cytoskeleton / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D022001:Focal Adhesions / Q000235:genetics; D016193:G1 Phase / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016196:S Phase / Q000235:genetics
D000199:Actins; C530104:CCND1 protein, human; C534696:CCND3 protein, human; D056743:Cyclin D3; D019938:Cyclin D1; D020928:Mitogen-Activated Protein Kinases