期刊
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
卷 25, 期 8, 页码 3699-3713出版社
WILEY
DOI: 10.1111/jcmm.15765
关键词
cancer‐ associated fibroblasts; caudal‐ related homeobox 2; chemoresistance; colon cancer; hephaestin; methotrexate; microRNA‐ 24‐ 3p
资金
- National Natural Science Foundation of China [81772932, 81472202, 81972214, 81302065, 81201535]
- Shanghai Natural Science Foundation [12ZR1436000]
- Shanghai Municipal Commission of Health and Family Planning [201540228]
- Construction of Clinical Medical Center for Tumor Biological Samples in Nantong [HS2016004]
- Peak of Six Personnel Foundation in Jiangsu Province [WSW-009]
- Jiangsu 333 Program [BRA2017205]
- Nantong Medical Key Talents Training Plan [43]
- Nantong Science and Technology Project [yyz15026]
- Wu Jieping Medical Foundation [320.6750.14326]
In colon cancer, high expression of miR-24-3p and low expression of HEPH and CDX2 were observed in tissues and cells. CDX2, targeted by miR-24-3p, could up-regulate HEPH. Inhibition of CAF-derived exosomal miR-24-3p decreased cell viability and colony formation, and increased apoptosis, indicating a role in promoting chemotherapy resistance in colon cancer.
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据