Cancer-associated fibroblasts-derived exosomal miR-17-5p promotes colorectal cancer aggressive phenotype by initiating a RUNX3/MYC/TGF-β1 positive feedback loop
| Autor: | Yuxin Fang, Changjie Wu, Aimin Li, Xinke Wang, Yue Zhang, Shanci Wang, Qiuhua Lai, Yongfeng Liu, Side Liu, Qingyuan Li, Chuncai Gu, Junsheng Chen, Jianqun Cai |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Adult Male Cancer Research Stromal cell Colorectal cancer Biology Exosomes Proto-Oncogene Mas Metastasis Proto-Oncogene Proteins c-myc Transforming Growth Factor beta1 03 medical and health sciences Mice 0302 clinical medicine Cancer-Associated Fibroblasts Cell Line Tumor medicine Tumor Microenvironment Animals Humans Autocrine signalling Transcription factor Aged Feedback Physiological Mice Inbred BALB C Middle Aged medicine.disease digestive system diseases Hedgehog signaling pathway MicroRNAs 030104 developmental biology Core Binding Factor Alpha 3 Subunit Phenotype Oncology 030220 oncology & carcinogenesis Cancer research Female Colorectal Neoplasms Transforming growth factor Signal Transduction |
| Zdroj: | Cancer letters. 491 |
| ISSN: | 1872-7980 |
| Popis: | Cancer-associated fibroblasts (CAFs) are the main stromal cells in the tumour microenvironment (TME). We found that the distribution of CAFs was significantly increased with tumour progression and led to a poor prognosis. In vitro and in vivo assays revealed that CAFs enhanced colorectal cancer (CRC) metastasis. Based on extraction and identification of exosomes of CAFs and normal fibroblasts (NFs), CAFs-exo showed higher expression of miR-17-5p than NFs-exo and could deliver exosomal miR-17-5p from parental CAFs to CRC cells. Further exploration verified that miR-17-5p influenced CRC metastasis capacity and directly targeted 3'-untranslated regions (UTRs) of RUNX family transcription factor 3(RUNX3). Our findings further revealed that RUNX3 interacted with MYC proto-oncogene(MYC) and that both RUNX3 and MYC bound to the promoter of transforming growth factor beta1(TGF-β1) at base pairs 1005-1296, thereby activating the TGF-β signalling pathway and contributing to tumour progression. In addition, RUNX3/MYC/TGF-β1 signalling sustained autocrine TGF-β1 to activate CAFs, and activated CAFs released more exosomal miR-17-5p to CRC cells, forming a positive feedback loop for CRC progression. Taken together, these data provide a new understanding of the potential diagnostic value of exosomal miR-17-5p in CRC. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect