A Novel Network Profiling Analysis Reveals System Changes in Epithelial-Mesenchymal Transition

Patient-specific analysis of molecular networks is a promising strategy for making individual risk predictions and treatment decisions in cancer therapy. Although systems biology allows the gene network of a cell to be reconstructed from clinical gene expression data, traditional methods, such as Bayesian networks, only provide an averaged network for all samples. Therefore, these methods cannot reveal patient-specific differences in molecular networks during cancer progression. In this study, we developed a novel statistical method called NetworkProfiler, which infers patient-specific gene regulatory networks for a specific clinical characteristic, such as cancer progression, from gene expression data of cancer patients. We applied NetworkProfiler to microarray gene expression data from 762 cancer cell lines and extracted the system changes that were related to the epithelial-mesenchymal transition (EMT). Out of 1732 possible regulators of E-cadherin, a cell adhesion molecule that modulates the EMT, NetworkProfiler, identified 25 candidate regulators, of which about half have been experimentally verified in the literature. In addition, we used NetworkProfiler to predict EMT-dependent master regulators that enhanced cell adhesion, migration, invasion, and metastasis. In order to further evaluate the performance of NetworkProfiler, we selected Krueppel-like factor 5 (KLF5) from a list of the remaining candidate regulators of E-cadherin and conducted in vitro validation experiments. As a result, we found that knockdown of KLF5 by siRNA significantly decreased E-cadherin expression and induced morphological changes characteristic of EMT. In addition, in vitro experiments of a novel candidate EMT-related microRNA, miR-100, confirmed the involvement of miR-100 in several EMT-related aspects, which was consistent with the predictions obtained by NetworkProfiler

Visceral obesity and the risk of Barrett's esophagus in Japanese patients with non-alcoholic fatty liver disease

<p>Abstract</p> <p>Background</p> <p>The association between obesity and the risk of Barrett's esophagus (BE) is unclear. Furthermore, the association between visceral obesity and the risk of BE is entirely unknown.</p> <p>Methods</p> <p>We conducted a retrospective study in 163 patients with non-alcoholic fatty liver disease (NAFLD) who underwent both endoscopy and abdominal CT at an interval of less than a year at our institution. BE was endoscopically diagnosed based on the Prague C & M Criteria. The surface areas of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were calculated from CT images at the level of the umbilicus. The correlations between the BMI, VAT, and SAT and the risk of BE were examined by univariate and multivariate analyses.</p> <p>Results</p> <p>Sixty-nine of the 163 study participants (42.3%) were diagnosed to have endoscopic BE, which was classified as short-segment BE (SSBE) in almost all of the cases. There were no significant differences in the age or gender distribution between the groups with and without BE. According to the results of the univariate analysis, VAT was significantly associated with the risk of BE; the BMI tended to be higher in the group with BE than in the group without BE, but this relation did not reach statistical significance. VAT was independently associated with the risk of BE even after adjustment for the BMI.</p> <p>Conclusion</p> <p>In Japanese patients with NAFLD, obesity tended to be associated with the risk of BE, and this risk appeared to be mediated for the most part by abdominal visceral adiposity.</p