Remodelling of microRNAs in colorectal cancer by hypoxia alters metabolism profiles and 5-fluorouracil resistance

Anke Nijhuis, Hannah Thompson, Julie Adam, Alexandra Parker, Luke Gammon, Amy Lewis, Jacob G. Bundy, Tomoyoshi Soga, Aisha Jalaly, David Propper, Rosemary Jeffery, Nirosha Suraweera, Sarah McDonald, Mohamed A. Thaha, Roger Feakins, Robert Lowe, Cleo L. Bishop, Andrew Silver

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish
Article numberddx059
Pages (from-to)1552-1564
Number of pages13
JournalHuman molecular genetics
Volume26
Issue number8
DOIs
Publication statusPublished - 2017 Apr 15

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Nijhuis, A., Thompson, H., Adam, J., Parker, A., Gammon, L., Lewis, A., Bundy, J. G., Soga, T., Jalaly, A., Propper, D., Jeffery, R., Suraweera, N., McDonald, S., Thaha, M. A., Feakins, R., Lowe, R., Bishop, C. L., & Silver, A. (2017). Remodelling of microRNAs in colorectal cancer by hypoxia alters metabolism profiles and 5-fluorouracil resistance. Human molecular genetics, 26(8), 1552-1564. [ddx059]. https://doi.org/10.1093/hmg/ddx059