Abstract
Abstract Introduction 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/Fbxw7 mouse model of intestinal/colorectal cancer (CRC). Methods We measured glucose consumption and lactate production, and analysed the expression of 373 miRNAs and 12 metabolic genes using qRT-PCR and Western blotting in mPOs and mNPOs. The overexpressed miRNAs systematically target metabolic genes explored by the TargetScan web server. Organoid viability was assessed using MTT and Sulforhodamine-B (SRB) colorimetric assays. Results The tumour and adjacent non-tumour organoids showed differential metabolic activity. mPOs showed elevated lactate and consumption of glucose in the medium. Murine Apc/Fbxw7 duodenal polyp-derived organoids mimicked colorectal cancer patient-derived organoids. 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. Conclusion Combination with miR-135b antisense nucleotides may represent a novel strategy to sensitise CRC to the chemo-reagent based treatment. Take-home message Our data highlight the therapeutic potential of targeting miR-135/SPOCK1 to enhance the treatment of colorectal cancer.