title: A novel network profiling analysis reveals system changes in epithelial-mesenchymal transition.
abstract: 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.
authors.affiliation: Human Genome Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan. shima@ims.u-tokyo.ac.jp
authors.forename: Teppei
authors.initials: T
authors.lastname: Shimamura
authors.forename: Seiya
authors.initials: S
authors.lastname: Imoto
authors.forename: Yukako
authors.initials: Y
authors.lastname: Shimada
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Hosono
authors.forename: Atsushi
authors.initials: A
authors.lastname: Niida
authors.forename: Masao
authors.initials: M
authors.lastname: Nagasaki
authors.forename: Rui
authors.initials: R
authors.lastname: Yamaguchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods*; D003196:Computer Graphics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D015203:Reproducibility of Results
chemical_list: D015820:Cadherins