Abstract
s / Pancreatology 13 (2013) e1–e94 e28 develop advanced PanIN lesions that progress to PDAC with high frequency. By array analysis of PDAC arising in Rb/K mice we determined that these tumors express high levels of Agr2 mRNA and high levels of transforming growth factor-beta (TGF-b). Paradoxically, TGF-b1 decreased AGR2 mRNA and protein levels in TGF-b1-responsive COLO-357 and PANC-1 human pancreatic cancer cells. Moreover, TGF-b1 decreased AGR2 luciferase/promoter activity in these cell lines, and mutation of two Smad binding elements in the AGR2 promoter was sufficient to abrogate TGFb1’s actions. By contrast, TGF-b1 did not alter AGR2 expression in BxPC3 cells, which are null for Smad4. Taken together, these data suggest that in vivo, RB loss enhances Agr2 through loss of repression from perturbations in TGF-b signaling, thus contributing to accelerated PDAC progression.
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