14-3-3sigma Modulates pancreatic cancer cell survival and invasiveness.

Purpose: The purpose of the present study was to investigate the potential role of 14-3-3sigma in pancreatic ductal adenocarcinoma (PDAC).

Experimental Design: 14-3-3 isoform expression was determined by real-time quantitative PCR in laser capture normal pancreatic ductal cells and pancreatic cancer cells and in 5 pancreatic cancer cell lines. PANC-1 cells, with low levels of 14-3-3sigma, were stably transfected with a human 14-3-3sigma cDNA. Conversely, high endogenous 14-3-3sigma levels in T3M4 cells were suppressed by specific short hairpin RNA. Apoptosis, motility, and invasiveness were studied.

Results: The cancer cells in 7 PDAC samples expressed high levels of 14-3-3sigma mRNA by quantitative PCR when compared with normal pancreatic duct cells. 14-3-3sigma protein levels were high in BxPC3, COLO-357, and T3M4 cells, intermediate in ASPC-1 cells, and low in PANC-1 cells. Most cell lines released detectable amount of 14-3-3sigma into conditioned medium. Overexpression of 14-3-3sigma in PANC-1 cells led to resistance to cisplatinum-induced apoptosis, increased basal migration, and increased invasion in response to epidermal growth factor and insulin-like growth factor-I. By contrast, short hairpin RNA-mediated knockdown of endogenous 14-3-3sigma in T3M4 cells did not alter migration but led to enhanced cisplatinum sensitivity, increased invasiveness in response to epidermal growth factor, and decreased invasiveness in response to insulin-like growth factor-I.

Conclusions: 14-3-3sigma contributes to the chemoresistance of pancreatic cancer cells and exerts cell type-dependent effects on cell migration and invasion. Therefore, strategies aimed at suppressing 14-3-3sigma expression and function may have a therapeutic benefit in subgroups of patients with PDAC.