Loss of exosomal miR-200b-3p from hypoxia cancer-associated fibroblasts promotes tumorigenesis and reduces sensitivity to 5-Flourouracil in colorectal cancer via upregulation of ZEB1 and E2F3

• Published in: Cancer gene therapy 2023-06, Vol.30 (6), p.905-916
• Main Authors: Gong, Wenjing, Guo, Yang, Yuan, Hang, Chai, Rui, Wan, Ziang, Zheng, Boan, Hu, Xinye, Chen, Bingchen, Gao, Shan, Dai, Qiaoqiong, Yu, Peng, Tu, Shiliang
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 13/51; 14/28; 14/34; 14/63; 38/91; 5-Fluorouracil; 631/67/1504/1885; 631/67/327; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer-Associated Fibroblasts - pathology; Carcinogenesis - genetics; Cell adhesion & migration; Cell growth; Cell Line, Tumor; Cell migration; Cell proliferation; Cell Proliferation - genetics; Cell Transformation, Neoplastic - genetics; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; E2F3 Transcription Factor; Exosomes; Exosomes - genetics; Exosomes - pathology; Fibroblasts; Fluorouracil - pharmacology; Gene Expression; Gene Expression Regulation, Neoplastic; Gene Therapy; Humans; Hypoxia; MicroRNAs; MicroRNAs - genetics; Targeted cancer therapy; Tumorigenesis; Up-Regulation; Zinc Finger E-box-Binding Homeobox 1 - genetics
• ISSN: 0929-1903; 1476-5500
• DOI: 10.1038/s41417-023-00591-5

Hypoxia-mediated tumor progression is a major clinical challenge in human cancers including colorectal cancer (CRC). In addition, exosome-mediated transfer of miRNAs from cancer-associated fibroblasts (CAFs) to cancer cells could promote tumor progression. However, the mechanisms by which hypoxia CAFs promotes CRC progression remain largely unknown. CAFs and normal fibroblasts (NFs) were isolated from CRC tissues and adjacent normal tissues. Next, exosomes were isolated from the supernatant of CAFs that cultured under normoxia (CAFs-N-Exo) and hypoxia (CAFs-H-Exo). RNA-sequencing was then performed to identify differentially expressed miRNAs (DEMs) between CAFs-N-Exo and CAFs-H-Exo. Compared with exosomes derived from normoxia CAFs, exosomes derived from hypoxic CAFs were able to promote CRC cell proliferation, migration, invasion, stemness and reduce the sensitivity of CRC cells to 5-fluorouracil (5-FU). In addition, miR-200b-3p levels were dramatically decreased in exosomes derived from hypoxic CAFs. Remarkably, increasing exosomal miR-200b-3p in hypoxic CAFs reversed the promoting effects of hypoxic CAFs on CRC cell growth in vitro and in vivo. Furthermore, miR-200b-3p agomir could inhibit CRC cell migration, invasion, stemness and increase the sensitivity of SW480 cells to 5-FU via downregulating ZEB1 and E2F3. Collectively, loss of exosomal miR-200b-3p in hypoxia CAFs could contribute to CRC progression via upregulation of ZEB1 and E2F3. Thus, increasing exosomal miR-200b-3p might serve as an alternative approach for the treatment of CRC.