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- Title
Remodelling of microRNAs in colorectal cancer by hypoxia alters metabolism profiles and 5-fluorouracil resistance.
- Authors
Nijhuis, Anke; Thompson, Hannah; Adam, Julie; Parker, Alexandra; Gammon, Luke; Lewis, Amy; Bundy, Jacob G.; Soga, Tomoyoshi; Jalaly, Aisha; Propper, David; Jeffery, Rosemary; Suraweera, Nirosha; McDonald, Sarah; Thaha, Mohamed A.; Feakins, Roger; Lowe, Robert; Bishop, Cleo L.; Silver, Andrew
- 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 metabolismin hypoxia and hypoxia-responsive miRNAs were predicted to target genes in four metabolismpathways: beta-alanine; valine, leucine, isoleucine; 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 metabolismpathways may offer translational opportunities.
- Publication
Human Molecular Genetics, 2017, Vol 26, Issue 8, p1552
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddx059