Pancreatic ductal adenocarcinoma (PDA) is an extremely aggressive malignancy, which carries a dismal prognosis. Activating mutations of the Kras gene are common to the vast majority of human PDA. In addition, recent studies have demonstrated that embryonic signaling pathway such as Hedgehog and Notch are inappropriately upregulated in this disease. The role of another embryonic signaling pathway, namely the canonical Wnt cascade, is still controversial. Here, we use gene array analysis as a platform to demonstrate general activation of the canonical arm of the Wnt pathway in human PDA. Furthermore, we provide evidence for Wnt activation in mouse models of pancreatic cancer. Our results also indicate that Wnt signaling might be activated downstream of Hedgehog signaling, which is an early event in PDA evolution. Wnt inhibition blocked proliferation and induced apoptosis of cultured adenocarcinoma cells, thereby providing evidence to support the development of novel therapeutical strategies for Wnt inhibition in pancreatic adenocarcinoma.

Recent studies have suggested that ␤-catenin is involved in the regulation of hepatocyte proliferation in multiple contexts, including organ development and tumorigenesis. We explored the role of ␤-catenin during liver regeneration using T cell factor/lymphoid enhancer factor (TCF/LEF)-reporter mice (TOPGal mice) and liver-specific ␤-catenin knockout mice. Liver-specific ␤-catenin knockout mice showed a delayed onset of DNA synthesis after hepatectomy, whereas recovery of liver mass was not affected. Among putative ␤-catenin target genes examined, the induction of Ccnd1 expression was reduced, whereas the expression of Myc and Egfr was unaffected. Furthermore, cyclin D1 protein levels were not induced, and the expression of cyclins A, E, and proliferating cell nuclear antigen was delayed. Intriguingly, the analysis of TOPGal mice showed that hepatocytes with active TCF/LEF transcription are confined to the pericentral zone and are not increased in number during regeneration, indicating an uncoupling between ␤-catenin/TCF signaling activity and hepatocyte proliferation. Conclusion: Our results indicate that ␤-catenin is critical for the proper regulation of hepatocyte proliferation during liver regeneration; however, the activity of ␤-catenin/TCF signaling does not correlate with hepatocyte proliferation, suggesting that this regulation might be indirect/secondary. (HEPATOLOGY 2007;45:361-368.)

Mutations of chromosome replication genes can be one of the early events that promote genomic instability. Among genes that are involved in chromosomal replication, DNA polymerase α is essential for initiation of replication and lagging-strand synthesis. Here we examined the effect of two mutations in S. cerevisiae POL1, pol1-1 and pol1-17, on a microsatellite (GT)16 tract. The pol1-17 mutation elevated the mutation rate 13-fold by altering sequences both inside and downstream of the (GT)16 tract, whereas the pol1-1 mutation increased the mutation rate 54-fold by predominantly altering sequences downstream of the (GT)16 tract in a RAD52-dependent manner. In a rad52 null mutant background pol1-1 and pol1-17 also exhibited different plasmid and chromosome loss phenotypes. Deletions of mismatch repair (MMR) genes induce a differential synergistic increase in the mutation rates of pol1-1 and pol1-17. These findings suggest that perturbations of DNA replication in these two pol1 mutants are caused by different mechanisms, resulting in various types of mutations. Thus, mutations of POL1 can induce a variety of mutator phenotypes and can be a source of genomic instability in cells.