title: Systematic integration of molecular profiles identifies miR-22 as a regulator of lipid and folate metabolism in breast cancer cells.
abstract: Dysregulated microRNA (miRNA) mediate malignant phenotypes, including metabolic reprogramming. By performing an integrative analysis of miRNA and metabolome data for the NCI-60 cell line panel, we identified an miRNA cluster strongly associated with both c-Myc expression and global metabolic variation. Within this cluster the cancer-associated and cardioprotective miR-22 was shown to repress fatty acid synthesis and elongation in tumour cells by targeting ATP citrate lyase and fatty acid elongase 6, as well as impairing mitochondrial one-carbon metabolism by suppression of methylene tetrahydrofolate dehydrogenase/cyclohydrolase. Across several data sets, expression of these target genes were associated with poorer outcomes in breast cancer patients. Importantly, a beneficial effect of miR-22 on clinical outcomes in breast cancer was shown to depend on the expression levels of the identified target genes, demonstrating the relevance of miRNA/mRNA interactions to disease progression in vivo. Our systematic analysis establishes miR-22 as a novel regulator of tumour cell metabolism, a function that could contribute to the role of this miRNA in cellular differentiation and cancer development. Moreover, we provide a paradigmatic example of effect modification in outcome analysis as a consequence of miRNA-directed gene targeting, a phenomenon that could be exploited to improve patient prognosis and treatment.
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.|Department of Cytogenetics and Genomics, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
authors.forename: C
authors.initials: C
authors.lastname: Koufaris
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: G N
authors.initials: GN
authors.lastname: Valbuena
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.|Translational Research Unit, Chulabhorn Research Institute, Bangkok, Thailand.
authors.forename: Y
authors.initials: Y
authors.lastname: Pomyen
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: G D
authors.initials: GD
authors.lastname: Tredwell
authors.affiliation: Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Nevedomskaya
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: C-He
authors.initials: CH
authors.lastname: Lau
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: T
authors.initials: T
authors.lastname: Yang
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Benito
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: J K
authors.initials: JK
authors.lastname: Ellis
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.|Centre for Systems Oncology and Cancer Innovation, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: H C
authors.initials: HC
authors.lastname: Keun
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*
chemical_list: C548375:MIRN22 microRNA, human; D035683:MicroRNAs; D005492:Folic Acid