Anti-miR-135/SPOCK1 axis antagonizes the influence of metabolism on drug response in intestinal/colon tumour organoids

Roya Babaei-Jadidi; Hossein Kashfi; Walla Alelwani; Ashkan Karimi Bakhtiari; Shahad W Kattan; Omniah A Mansouri; Abhik Mukherjee; Dileep N Lobo; Abdolrahman S Nateri

doi:10.1038/s41389-021-00376-1

Anti-miR-135/SPOCK1 axis antagonizes the influence of metabolism on drug response in intestinal/colon tumour organoids

Oncogenesis. 2022 Jan 19;11(1):4. doi: 10.1038/s41389-021-00376-1.

Authors

Roya Babaei-Jadidi^{1

2}, Hossein Kashfi^{1

3}, Walla Alelwani⁴, Ashkan Karimi Bakhtiari¹, Shahad W Kattan^{1

5}, Omniah A Mansouri⁶, Abhik Mukherjee⁷, Dileep N Lobo^{8

9}, Abdolrahman S Nateri¹⁰

Affiliations

¹ Cancer Genetics & Stem Cell Group, BioDiscovery Institute, Translational Medical Sciences Unit, School of Medicine, University of Nottingham, Nottingham, NG7 2UH, UK.
² Respiratory Medicine, School of Medicine, University of Nottingham, Nottingham, NG7 2UH, UK.
³ Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
⁴ Department of Biochemistry, College of Science, University of Jeddah, Jeddah, Saudi Arabia.
⁵ Medical Laboratory Department, College of Applied Medical Sciences, Taibah University, Yanbu, Saudi Arabia.
⁶ Department of Biology, University of Jeddah, College of Science, Jeddah, 21959, Saudi Arabia.
⁷ Histopathology, BioDiscovery Institute, School of Medicine, University of Nottingham, NG7 2UH, Nottingham, UK.
⁸ Nottingham Digestive Diseases Centre, National Nottingham Digestive Diseases Centre, National Institute for Health Research Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.
⁹ MRC Versus Arthritis Centre for Musculoskeletal Ageing Research, School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
¹⁰ Cancer Genetics & Stem Cell Group, BioDiscovery Institute, Translational Medical Sciences Unit, School of Medicine, University of Nottingham, Nottingham, NG7 2UH, UK. a.nateri@nottingham.ac.uk.

Abstract

Little is known about the role of microRNAs (miRNAs) in rewiring the metabolism within tumours and adjacent non-tumour bearing normal tissue and their potential in cancer therapy. This study aimed to investigate the relationship between deregulated miRNAs and metabolic components in murine duodenal polyps and non-polyp-derived organoids (mPOs and mNPOs) from a double-mutant Apc^MinFbxw7^∆G mouse model of intestinal/colorectal cancer (CRC). We analysed the expression of 373 miRNAs and 12 deregulated metabolic genes in mPOs and mNPOs. Our findings revealed miR-135b might target Spock1. Upregulation of SPOCK1 correlated with advanced stages of CRCs. Knockdown of miR-135b decreased the expression level of SPOCK1, glucose consumption and lactic secretion in CRC patient-derived tumours organoids (CRC tPDOs). Increased SPOCK1 induced by miR-135b overexpression promoted the Warburg effect and consequently antitumour effect of 5-fluorouracil. Thus, combination with miR-135b antisense nucleotides may represent a novel strategy to sensitise CRC to the chemo-reagent based treatment.

Abstract

Grants and funding