Exosomal transfer of miR-223-3p from carcinoma-associated fibroblasts promotes the malignant properties and chemoresistance of colon cancer cells by targeting NF2/Hippo signaling.
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Abstract
Cancer-associated fibroblasts (CAFs) play a key role in malignant progression and chemoresistance of cancer. Accumulating studies indicate that exosomal transfer of microRNAs from CAFs to cancer cells is responsible for the effects of CAFs in cancer (Wang et al. in Cancers, 2021, https://doi.org/10.3390/cancers13133160 ). In the present study, we explored the impact of CAFs-derived exosomes on tumorigenesis and chemoresistance of colon cancer, and potential microRNAs involved in this process. CAFs were isolated form colon cancer samples. CAFs-derived exosomes were separated by ultracentrifugation. Differentially expressed microRNAs were identified by microRNA expression array. The function of CAFs-derived exsomes and exosomal microRNAs were evaluated by cell viability assay, soft agar assay, transwell invasion assay, sphere formation assay, qRT-PCR, tumor xenograft model, flow cytometry, western blot, luciferase reporter assay, biotin microRNA pull-down assay. In our study, CAFs-derived exosomes promoted proliferation, anchorage-independent growth, invasion, stemness, tumor xenograft growth and 5-FU resistance of colon cancer cells. MiR-223-3p was significantly upregulated in CAFs-derived exosomes and serum or tissue samples of colon cancer patients. Exosomal transfer of miR-223-3p facilitated malignant properties and 5-FU resistance of colon cancer cells. Moreover, NF2 was identified as a downstream target for miR-223-3p. Restored NF2 expression partially abrogated the effects caused by exosomal transfer of miR-223-3p in colon cancer cells. In addition, exosomal miR-223-3 regulated Hippo pathway in colon cancer cells by targeting NF2. Our results indicated that exosomal transfer of miR-223-3p from CAFs to colon cancer cells promoted malignant properties and chemoresistance through NF2/Hippo pathway.
癌症相关成纤维细胞（CAFs）在癌症的恶性进展和化疗耐药中起着关键作用。越来越多的研究表明，microrna从CAFs向癌细胞的外泌体转移是CAFs在癌症中的作用的原因（Wang et al. in cancer, 2021, https://doi.org/10.3390/cancers13133160）。在本研究中，我们探讨了cafs来源的外泌体对结肠癌肿瘤发生和化疗耐药的影响，以及参与这一过程的潜在microrna。从结肠癌样本中分离出CAFs。通过超离心分离cafs衍生的外泌体。差异表达的microRNA通过microRNA表达阵列进行鉴定。采用细胞活力法、软琼脂法、transwell侵袭法、成球法、qRT-PCR、肿瘤异种移植模型、流式细胞术、western blot、荧光素酶报告基因法、生物素microRNA拉下法评价cafs衍生外泌体和外泌体microRNA的功能。在我们的研究中，cafs衍生的外泌体促进了结肠癌细胞的增殖、非锚定生长、侵袭、干性、肿瘤异种移植物生长和5-FU耐药性。MiR-223-3p在结肠癌患者的cafs来源的外泌体和血清或组织样本中显著上调。miR-223-3p的外泌体转移促进了结肠癌细胞的恶性特性和5-FU耐药性。此外，NF2被确定为miR-223-3p的下游靶点。恢复的NF2表达部分消除了miR-223-3p在结肠癌细胞中外泌体转移引起的影响。此外，外泌体miR-223-3通过靶向NF2调控结肠癌细胞中的Hippo通路。我们的研究结果表明，miR-223-3p从CAFs转移到结肠癌细胞的外泌体通过NF2/Hippo途径促进了恶性特性和化疗耐药。
期刊介绍：
Medical Oncology (MO) communicates the results of clinical and experimental research in oncology and hematology, particularly experimental therapeutics within the fields of immunotherapy and chemotherapy. It also provides state-of-the-art reviews on clinical and experimental therapies. Topics covered include immunobiology, pathogenesis, and treatment of malignant tumors.
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