title: Remodelling of microRNAs in colorectal cancer by hypoxia alters metabolism profiles and 5-fluorouracil resistance.
abstract: Solid tumours have oxygen gradients and areas of near and almost total anoxia. Hypoxia reduces sensitivity to 5-fluorouracil (5-FU)-chemotherapy for colorectal cancer (CRC). MicroRNAs (miRNAs) are hypoxia sensors and were altered consistently in six CRC cell lines (colon cancer: DLD-1, HCT116 and HT29; rectal cancer: HT55, SW837 and VACO4S) maintained in hypoxia (1 and 0.2% oxygen) compared with normoxia (20.9%). CRC cell lines also showed altered amino acid metabolism in hypoxia and hypoxia-responsive miRNAs were predicted to target genes in four metabolism pathways: beta-alanine; valine, leucine, iso-leucine; aminoacyl-tRNA; and alanine, aspartate, glutamate. MiR-210 was increased in hypoxic areas of CRC tissues and hypoxia-responsive miR-21 and miR-30d, but not miR-210, were significantly increased in 5-FU resistant CRCs. Treatment with miR-21 and miR-30d antagonists sensitized hypoxic CRC cells to 5-FU. Our data highlight the complexity and tumour heterogeneity caused by hypoxia. MiR-210 as a hypoxic biomarker, and the targeting of miR-21 and miR-30d and/or the amino acid metabolism pathways may offer translational opportunities.
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, London E1 2AT, UK.
authors.forename: Anke
authors.initials: A
authors.lastname: Nijhuis
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, London E1 2AT, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Thompson
authors.affiliation: Radcliffe Department of Medicine, OCDEM, University of Oxford, Oxford OX3 7LJ, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Adam
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, London E1 2AT, UK.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Parker
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, London E1 2AT, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Gammon
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, London E1 2AT, UK.
authors.forename: Amy
authors.initials: A
authors.lastname: Lewis
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Sir Alexander Fleming Building, London SW7 2AZ, UK.
authors.forename: Jacob G
authors.initials: JG
authors.lastname: Bundy
authors.affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan.
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Soga
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, London E1 2AT, UK.
authors.forename: Aisha
authors.initials: A
authors.lastname: Jalaly
authors.affiliation: Department of Medical Oncology, St Bartholomew's Hospital, Gloucester House, Little Britain, London EC1A 7BE, UK.
authors.forename: David
authors.initials: D
authors.lastname: Propper
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, London E1 2AT, UK.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Jeffery
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, London E1 2AT, UK.
authors.forename: Nirosha
authors.initials: N
authors.lastname: Suraweera
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, London E1 2AT, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: McDonald
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, London E1 2AT, UK.|Academic Surgical Unit, The Royal London Hospital, Whitechapel, London E1 1BB, UK.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Thaha
authors.affiliation: Department of Histopathology, Royal London Hospital, Whitechapel, London, UK.
authors.forename: Roger
authors.initials: R
authors.lastname: Feakins
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, London E1 2AT, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Lowe
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, London E1 2AT, UK.
authors.forename: Cleo L
authors.initials: CL
authors.lastname: Bishop
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, London E1 2AT, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Silver
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018740:Genetic Heterogeneity; D045325:HCT116 Cells; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D010100:Oxygen / Q000378:metabolism
chemical_list: D000596:Amino Acids; C524940:MIRN21 microRNA, human; C543800:MIRN210 microRNA, human; C546086:MIRN30b microRNA, human; D035683:MicroRNAs; D010100:Oxygen; D005472:Fluorouracil