GATA6 Activates Wnt Signaling in Pancreatic Cancer by Negatively Regulating the Wnt Antagonist Dickkopf-1

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease characterized by late diagnosis and treatment resistance. Recurrent genetic alterations in defined genes in association with perturbations of developmental cell signaling pathways have been associated with PDAC development and progression. Here, we show that GATA6 contributes to pancreatic carcinogenesis during the temporal progression of pancreatic intraepithelial neoplasia by virtue of Wnt pathway activation. GATA6 is recurrently amplified by both quantitative-PCR and fluorescent in-situ hybridization in human pancreatic intraepithelial neoplasia and in PDAC tissues, and GATA6 copy number is significantly correlated with overall patient survival. Forced overexpression of GATA6 in cancer cell lines enhanced cell proliferation and colony formation in soft agar in vitro and growth in vivo, as well as increased Wnt signaling. By contrast siRNA mediated knockdown of GATA6 led to corresponding decreases in these same parameters. The effects of GATA6 were found to be due to its ability to bind DNA, as forced overexpression of a DNA-binding mutant of GATA6 had no effects on cell growth in vitro or in vivo, nor did they affect Wnt signaling levels in these same cells. A microarray analysis revealed the Wnt antagonist Dickopf-1 (DKK1) as a dysregulated gene in association with GATA6 knockdown, and direct binding of GATA6 to the DKK1 promoter was confirmed by chromatin immunoprecipitation and electrophoretic mobility shift assays. Transient transfection of GATA6, but not mutant GATA6, into cancer cell lines led to decreased DKK1 mRNA expression and secretion of DKK1 protein into culture media. Forced overexpression of DKK1 antagonized the effects of GATA6 on Wnt signaling in pancreatic cancer cells. These findings illustrate that one mechanism by which GATA6 promotes pancreatic carcinogenesis is by virtue of its activation of canonical Wnt signaling via regulation of DKK1

Stability and Change of the Quality of Working Life in Restructuring Municipalities

Local government in Finland has undergone considerable restructuring since 2005 as a number of new larger municipalities (mergers) and partnership areas between social and health sector service producers have been formed. Employees and the quality of their working life have not been among the main issues in this government-driven restructuring process. The article focuses on the observed changes in the quality of working life in Finnish municipalities. The data consist of two comprehensive surveys carried out in 2009 (N=3,710) and 2011 (N=4,618) for employees in the social and health sector and the education sector, and in 2011 also for employees in the administration sector, and of comparison data from the years 1995, 1999 and 2003. Quality of working life (QWL) consists of five sum variables: open ways to solve work conflicts, work influence, supervisory work, social openness at workplace, and intrinsic rewards of work. The measures proved to reflect in context-specific ways situations and conditions of work. The results imply that QWL is quite a slowly changing phenomenon, which is revealed here through a long-term research period and statistical comparisons. On the level of daily work, the widescale reform seemed more incremental than radical. As a positive sign, it is noteworthy that the intrinsic rewards of work have remained on a relatively high level through the years. There are some cases in which QWL has changed more radically. It is obvious that the reform context has increased awareness of human resource issues in these cases, which is visible in the improved QWL. It is also possible that the improvement in the supervisory role as reflected in increased satisfaction with supervisors and the relatively high level of social capital in most of the municipalities have played a buffering role against the confusion and strains related to the reform

Molecular Mechanisms of Barrett’s Esophagus

Barrett’s esophagus (BE) is defined as metaplastic conversion of esophageal squamous epithelium to intestinalized columnar epithelium. As a premalignant lesion of esophageal adenocarcinoma (EAC), it develops as a result of chronic gastroesophageal reflux disease (GERD). Many studies have been conducted to undertand the molecular mechanism of this disease. This review summarizes recent results of involving squamous transcription factors, intestinal transcription factors, signaling pathways, stromal factors, microRNAs, and other factors in the development of BE. A conceptual framework is proposed to guide future studies. We expect elucidation of the molecular mechanism of BE will help us develop proper management of GERD, BE, and EAC