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Cancer-associated fibroblast-derived exosomal microRNA-24-3p enhances colon cancer cell resistance to MTX by down-regulating CDX2/HEPH axis |
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| Authors: | Hong-Wei Zhang Yi Shi Ji-Bin Liu Hui-Min Wang Pei-Yao Wang Zhi-Jun Wu Liu Li Li-Peng Gu Ping-Sheng Cao Gao-Ren Wang Yu-Shui Ma Da Fu |
| Affiliation: | 1. Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China Cancer Institute, Nantong Tumor Hospital, Nantong, China Institute of Interdisciplinary Integrative Biomedical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China Contribution: Project administration (equal), Validation (equal), Writing - review & editing (equal);2. Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China Cancer Institute, Nantong Tumor Hospital, Nantong, China Contribution: Project administration (equal), Validation (equal), Writing - review & editing (equal);3. Cancer Institute, Nantong Tumor Hospital, Nantong, China Contribution: Conceptualization (equal), Investigation (equal), Writing - original draft (equal);4. Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China Cancer Institute, Nantong Tumor Hospital, Nantong, China Contribution: Visualization (equal), Writing - review & editing (equal);5. Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China Contribution: Visualization (equal), Writing - review & editing (equal);6. Department of Oncology, Nantong Second People's Hospital, Nantong, China Department of Radiotherapy, Nantong Tumor Hospital, Nantong, China Contribution: Data curation (equal), Formal analysis (equal);7. Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China Contribution: Data curation (equal), Formal analysis (equal);8. Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China Contribution: Methodology (equal), Resources (equal);9. Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China Contribution: Resources (equal), Software (equal);10. Department of Radiotherapy, Nantong Tumor Hospital, Nantong, China;11. Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China |
| Abstract: | MicroRNA-24-3p (miR-24-3p) has been implicated as a key promoter of chemotherapy resistance in numerous cancers. Meanwhile, cancer-associated fibroblasts (CAFs) can secret exosomes to transfer miRNAs, which mediate tumour development. However, little is known regarding the molecular mechanism of CAF-derived exosomal miR-24-3p in colon cancer (CC). Hence, this study intended to characterize the functional relevance of CAF-derived exosomal miR-24-3p in CC cell resistance to methotrexate (MTX). We identified differentially expressed HEPH, CDX2 and miR-24-3p in CC through bioinformatics analyses, and validated their expression in CC tissues and cells. The relationship among HEPH, CDX2 and miR-24-3p was verified using ChIP and dual-luciferase reporter gene assays. Exosomes were isolated from miR-24-3p inhibitor–treated CAFs (CAFs-exo/miR-24-3p inhibitor), which were used in combination with gain-of-function and loss-of-function experiments and MTX treatment. CCK-8, flow cytometry and colony formation assays were conducted to determine cell viability, apoptosis and colony formation, respectively. Based on the findings, CC tissues and cells presented with high expression of miR-24-3p and low expression of HEPH and CDX2. CDX2 was a target gene of miR-24-3p and could up-regulate HEPH. Under MTX treatment, overexpressed CDX2 or HEPH and down-regulated miR-24-3p reduced cell viability and colony formation and elevated cell apoptosis. Furthermore, miR-24-3p was transferred into CC cells via CAF-derived exosomes. CAF-derived exosomal miR-24-3p inhibitor diminished cell viability and colony formation and increased cell apoptosis in vitro and inhibited tumour growth in vivo under MTX treatment. Altogether, CAF-derived exosomal miR-24-3p accelerated resistance of CC cells to MTX by down-regulating CDX2/HEPH axis. |
| Keywords: | cancer-associated fibroblasts caudal-related homeobox 2 chemoresistance colon cancer hephaestin methotrexate microRNA-24-3p |