title: Lung adenocarcinoma subtypes definable by lung development-related miRNA expression profiles in association with clinicopathologic features.
abstract: Accumulation of genetic and epigenetic changes alters regulation of a web of interconnected genes including microRNAs (miRNAs), which confer hallmark capabilities and characteristic cancer features. In this study, the miRNA and messenger RNA expression profiles of 126 non-small cell lung cancer specimens were analyzed, with special attention given to the diversity of lung adenocarcinomas. Of those, 76 adenocarcinomas were classified into two major subtypes, developing lung-like and adult lung-like, based on their distinctive miRNA expression profiles resembling those of either developing or adult lungs, respectively. A systems biology-based approach using a Bayesian network and non-parametric regression was employed to estimate the gene regulatory circuitry functioning in patient tumors in order to identify subnetworks enriched for genes with differential expression between the two major subtypes. miR-30d and miR-195, identified as hub genes in such subnetworks, had lower levels of expression in the developing lung-like subtype, whereas introduction of miR-30d or miR-195 into the lung cancer cell lines evoked shifts of messenger RNA expression profiles toward the adult lung-like subtype. Conversely, the influence of miR-30d and miR-195 was significantly different between the developing lung-like and adult lung-like subtypes in our analysis of the patient data set. In addition, RRM2, a child gene of the miR-30d-centered subnetwork, was found to be a direct target of miR-30d. Together, our findings reveal the existence of two miRNA expression profile-defined lung adenocarcinoma subtypes with distinctive clinicopathologic features and also suggest the usefulness of a systems biology-based approach to gain insight into the altered regulatory circuitry involved in cancer development.
authors.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan, Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya 466-8550, Japan and Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan.
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Arima
authors.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan, Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya 466-8550, Japan and Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Kajino
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tamada
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Seiya
authors.initials: S
authors.lastname: Imoto
authors.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan, Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya 466-8550, Japan and Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan.
authors.forename: Yukako
authors.initials: Y
authors.lastname: Shimada
authors.affiliation: Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya 466-8550, Japan and.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakatochi
authors.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan, Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya 466-8550, Japan and Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan.
authors.forename: Motoshi
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan, Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya 466-8550, Japan and Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan.
authors.forename: Hisanori
authors.initials: H
authors.lastname: Isomura
authors.affiliation: Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
authors.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan, Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya 466-8550, Japan and Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan, Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya 466-8550, Japan and Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yanagisawa
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan, Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya 466-8550, Japan and Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan tak@med.nagoya-u.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D001499:Bayes Theorem; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D008168:Lung / Q000254:growth & development*; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*
chemical_list: C552722:MIRN195 microRNA, human; C546086:MIRN30b microRNA, human; D035683:MicroRNAs