南方医科大学南方医院:外泌体参与结直肠癌转移及化疗耐药
创作:爱的抉择 审核:szx 2019年05月27日
  • 肿瘤相关成纤维细胞(CAF)调控结直肠癌(CRC)的转移及化疗耐药,促进肿瘤进展;
  • CAF直接将外泌体转移到CRC细胞,导致后者中miR-92a-3p的表达增加;
  • miR-92a-3p直接抑制CRC细胞的FBXW7和MOAP1,进而激活Wnt/β-catenin通路,抑制线粒体凋亡,促进CRC细胞干性、上皮间充质转化、转移和化疗耐药;
  • CRC病人的肿瘤组织中miR-92a-3p显著升高,且与FBXW7和MOAP1表达负相关,血清中外泌体的miR-92a-3p升高,且与癌症转移及化疗耐药相关。
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szx
来自南方医科大学南方医院的团队在Molecular Cancer上发表的一项最新研究,发现肿瘤相关成纤维细胞可通过将外泌体分泌至结直肠癌细胞中,增加miR-92a-3p的表达,进而促进结直肠癌细胞的干性、上皮间充质转化、转移和化疗耐药。靶向外泌体中的miR-92a-3p或是对抗结直肠癌转移及化疗耐药的潜在新策略。
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Molecular Cancer [IF:15.302]

CAFs secreted exosomes promote metastasis and chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition in colorectal cancer

肿瘤相关成纤维细胞分泌的外泌体通过增强细胞干性及上皮间充质转化促进结直肠癌转移及化疗耐药性

10.1186/s12943-019-1019-x

2019-05-07, Article

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BACKGROUND: Cancer associated fibroblasts (CAFs) are key stroma cells that play dominant roles in tumor progression. However, the CAFs-derived molecular determinants that regulate colorectal cancer (CRC) metastasis and chemoresistance have not been fully characterized.
METHODS: CAFs and NFs were obtained from fresh CRC and adjacent normal tissues. Exosomes were isolated from conditioned medium and serum of CRC patients using ultracentrifugation method and ExoQuick Exosome Precipitation Solution kit, and characterized by transmission electronic microscopy, nanosight and western blot. MicroRNA microarray was employed to identify differentially expressed miRNAs in exosomes secreted by CAFs or NFs. The internalization of exosomes, transfer of miR-92a-3p was observed by immunofluorescence. Boyden chamber migration and invasion, cell counting kit-8, flow cytometry, plate colony formation, sphere formation assays, tail vein injection and primary colon cancer liver metastasis assays were employed to explore the effect of NFs, CAFs and exosomes secreted by them on epithelial-mesenchymal transition, stemness, metastasis and chemotherapy resistance of CRC. Luciferase report assay, real-time qPCR, western blot, immunofluorescence, and immunohistochemistry staining were employed to explore the regulation of CRC metastasis and chemotherapy resistance by miR-92a-3p, FBXW7 and MOAP1.
RESULTS: CAFs promote the stemness, epithelial-mesenchymal transition (EMT), metastasis and chemotherapy resistance of CRC cells. Importantly, CAFs exert their roles by directly transferring exosomes to CRC cells, leading to a significant increase of miR-92a-3p level in CRC cells. Mechanically, increased expression of miR-92a-3p activates Wnt/β-catenin pathway and inhibits mitochondrial apoptosis by directly inhibiting FBXW7 and MOAP1, contributing to cell stemness, EMT, metastasis and 5-FU/L-OHP resistance in CRC. Clinically, miR-92a-3p expression is significantly increased in CRC tissues and negatively correlated with the levels of FBXW7 and MOAP1 in CRC specimens, and high expression of exosomal miR-92a-3p in serum was highly linked with metastasis and chemotherapy resistance in CRC patients.
CONCLUSIONS: CAFs secreted exosomes promote metastasis and chemotherapy resistance of CRC. Inhibiting exosomal miR-92a-3p provides an alternative modality for the prediction and treatment of metastasis and chemotherapy resistance in CRC.

First Authors:
J L Hu,W Wang,X L Lan

Correspondence Authors:
L Liang

All Authors:
J L Hu,W Wang,X L Lan,Z C Zeng,Y S Liang,Y R Yan,F Y Song,F F Wang,X H Zhu,W J Liao,W T Liao,Y Q Ding,L Liang

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