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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 ApcMinFbxw7∆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.
Highlights
The control of nutritional uptake and metabolic pathway activity is required for maintaining intestinal homoeostasis and intestinal stem and progenitor cell behaviours [1,2,3]
This study aimed to investigate the relationship between deregulated miRNAs and metabolic components in murine duodenal polyps and non-polyp-derived organoids from a doublemutant ApcMinFbxw7ΔG mouse model of intestinal/colorectal cancer (CRC)
Duodenal ApcMinFbxw7ΔG double-mutant polyps showed confirmed the induction observed on mRNA levels
Summary
The control of nutritional uptake and metabolic pathway activity is required for maintaining intestinal homoeostasis and intestinal stem and progenitor cell behaviours [1,2,3]. Glucose, and glutamine act as upstream regulators of oxygen and pH, and are considered important onco-metabolites [7, 8], with tumour cells taking up high amounts of glucose and producing large volumes of lactate even in the presence of oxygen. This process is known as the “Warburg effect or aerobic glycolysis” [8, 9]. Elucidating the molecular mechanisms that orchestrate cellular transformation in these diverse cells and tissues may answer critical biological questions about early tumour formation and lead to identifying new therapeutic targets
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