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

doi:10.1093/hmg/ddx059

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

Graduate School of Media and Governance

Research output: Contribution to journal › Article › peer-review

37 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 language	English
Article number	ddx059
Pages (from-to)	1552-1564
Number of pages	13
Journal	Human molecular genetics
Volume	26
Issue number	8
DOIs	https://doi.org/10.1093/hmg/ddx059
Publication status	Published - 2017 Apr 15

ASJC Scopus subject areas

Molecular Biology
Genetics
Genetics(clinical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/hmg/ddx059

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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

Nijhuis, A, Thompson, H, Adam, J, Parker, A, Gammon, L, Lewis, A, Bundy, JG, Soga, T, Jalaly, A, Propper, D, Jeffery, R, Suraweera, N, McDonald, S, Thaha, MA, Feakins, R, Lowe, R, Bishop, CL & Silver, A 2017, 'Remodelling of microRNAs in colorectal cancer by hypoxia alters metabolism profiles and 5-fluorouracil resistance', Human molecular genetics, vol. 26, no. 8, ddx059, pp. 1552-1564. https://doi.org/10.1093/hmg/ddx059

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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.",

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AU - Gammon, Luke

AU - Lewis, Amy

AU - Bundy, Jacob G.

AU - Soga, Tomoyoshi

AU - Jalaly, Aisha

AU - Propper, David

AU - Jeffery, Rosemary

AU - Suraweera, Nirosha

AU - McDonald, Sarah

AU - Thaha, Mohamed A.

AU - Feakins, Roger

AU - Lowe, Robert

AU - Bishop, Cleo L.

AU - Silver, Andrew

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AB - 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.

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

Abstract

ASJC Scopus subject areas

UN SDGs

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