It is important to note that the three M protein positive p80HT mice used for t

This finding is of interest since there are reports that implicate Sirt1 in the regulation of cellular differentiation ARN-509 956104-40-8 and dedifferenti ation processes, Dedifferentiation and the associ ated phenomenon of epithelial to mesenchymal transition play an essential role in the development of early local and distant tumor spread. Observations that link high Sirt1 ex pression to poorly differentiated cancers were also made by other investigators for hepatocellular carcinoma, prostate cancer and glioblastoma, The association between high Sirt1 expression and poor histological grade may also explain why in our cohort Sirt1 expression is associated with poor outcome regardless of the tumor stage as shown by its prognostic indepen dency in multivariate survival analysis.<br><br> A Sirt1 positive and poorly differentiated tumor may have acquired a biological profile that allows for e. g. early AUY922 747412-49-3 systemic spread of clinically undetectable micrometastases in lymph nodes and distant organs leading to impaired survival regardless of the tumor size and metastases detected at the point of initial tumor diagnosis. A re cent study by Nalls and colleagues showed that SAHA induced micro RNA 34a expression in human pancreatic cancer cells putatively directly inhibited Sirt1 expression by binding within the 3UTR of Sirt1. On cellular level, restoration of miR34a ex pression led to growth inhibition as well as decreased epithelial to mesenchymal transition and inva sion. Although miR34a does not exclusively target Sirt1, this recent study further argues for an oncogenic role of Sirt1 in PDAC development.<br><br> Recent results obtained by Pramanik et al. corroborate this view, Functional studies indicate that the subcellular localization of Sirt1 might have functional implica tions in carcinogenesis. Wauters et al. recently provided Alisertib 臨床試験 evidence that there is nuclear to cytoplasmic shuttling of Sirt1 in rat and mouse acinar cells with potential tumorigenic implications in the acinar to ductal metaplasia carcinogenesis model of PDAC. They also reported on cytoplasmic localization of Sirt1 in exocrine cells of the human pancreas. However, in vestigating human tissue samples of fully developed pancreatic ductal adenocarcinoma, we only detected nuclear localized Sirt1. This may have several reasons. One potential explanation might be that endogenous cytoplasmic Sirt1 levels in comparison to nuclear ex pression levels are too low to be detected by our anti body.<br><br> Another explanation would be that cytoplasmic Sirt1 plays a major role in the development of carcino genic precursors and nuclear Sirt1 has its place in the fully developed cancer. However, this has to be inves tigated in future functional studies. Interestingly, following up the seminal work by Luo et al. and Vasiri et al, a very recent study by Li and co workers explored the Sirt1 p53 axis in chronic mye loid leukemia and found that targeting of Sirt1 by either shRNA or the small molecule inhibitor tenovin 6 resulted in increased levels of acetylated p53 in CML CD34 cells accompanied by increased transcriptional ac tivity of p53. Abrogation of Sirt1 led to growth inhibition and reduced engraftment of the tumor cells.