CAFs-derived small extracellular vesicles circN4BP2L2 promotes proliferation and metastasis of colorectal cancer via miR-664b-3p/HMGB3 pathway

Abstract

Our previous research has demonstrated that colorectal cancer (CRC) progression was promoted by circN4BP2L2. This study aimed to further explore the mechanism of circN4BP2L2 in the development of CRC from the perspective of small extracellular vesicles (sEVs). Cancer-associated fibroblasts cell (CAFs) and normal fibroblasts cell (NFs) were isolated from CRC tissues and adjacent tissues, respectively. The ultra-centrifugation was used for extraction of their related sEVs. Cell proliferation and apoptosis were analyzed using CCK-8 and flow cytometry, respectively. Transwell assay was conducted to measure cell migration. The tube formation ability was assessed by tube formation assay. The target relationships between circN4BP2L2 and miR-664b-3p, and miR-664b-3p and HMGB3 were validated by dual-luciferase reporter detection. The effect of CAFs-derived sEV (CAFs-sEVs) circN4BP2L2 on CRC was further studied in nude mice. CAFs-exo promoted cell proliferation, migration, tube formation ability, and inhibited apoptosis of CRC cells. CAFs-sEV circN4BP2L2 knockdown reversed the above results. CircN4BP2L2 directly targeted miR-664b-3p, and HMGB3 was targeted by miR-664b-3p. Moreover, subcutaneous tumorigenesis and liver metastasis of nude mice with CRC were repressed by CAFs-sEV circN4BP2L2 knockdown. CAFs-sEV circN4BP2L2 knockdown restrained CRC cell proliferation and migration by regulating miR-664b-3p/HMGB3 pathway.

Extracellular vesicles in neuroblastoma: role in progression, resistance to therapy and diagnostics

“…EVs derived from adipocytes and adipose-endothelial cells were found to induce proliferation, migration and invasion of the recipient prostate cancer cells, thereby promoting metastasis in prostate cancer ( 64 , 65 ). While CAFs were found to support the surrounding tumor cells by transferring tumor-supportive signals via EVs, thereby contributing to tumor growth and metastasis in several cancer types ( 62 , 66 – 68 ). In addition, endothelial cell derived-EVs were shown to affect macrophages, by converting them to a M2-like phenotype thereby inducing an immunosuppressive environment and aiding in cancer progression ( 69 ).…”

Crosstalk between cancer-associated fibroblasts and regulated cell death in tumors: insights into apoptosis, autophagy, ferroptosis, and pyroptosis

“…Currently, a substantial body of research has illuminated the role of CAFs in the initiation and progression of cancers through the regulation of apoptosis. In colorectal cancer (CRC), the exosomes transport miRNAs (miR-224-5p [ 80 ], miR-181b-3p [ 81 ], and miR-135b-5p [ 82 ]) and circRNAs (circN4BP2L2 [ 83 ] and circSLC7A6 [ 84 ]) from CAFs into cancer cells to act as inhibitors of apoptosis and promote the pathogenesis of CRC. Moreover, the secretion of IL-6 by CAFs leads to the upregulation of BCL-XL and MCL-1 in CRC cells via the IL-6/STAT3 signaling pathway, which simultaneously promotes apoptosis resistance [ 85 ]; however, the dynamic interactions between pro-apoptotic and anti-apoptotic BCL‑2 protein families (BCL-2, BCL-XL, BCL-w, MCL-1 and BCL-2A1) balance the commitment of cells to apoptosis [ 86 , 87 ].…”

Crosstalk between colorectal cancer cells and cancer-associated fibroblasts in the tumor microenvironment mediated by exosomal noncoding RNAs

“…Prior study has shown that treatment of CRC cells with exosomes derived from CAFs promotes cell proliferation, migration, tube-forming ability and inhibits apoptosis of CRC cells. The results of mechanistic experiments showed that CAFs could deliver circN4BP2L2 to CRC cells through secreted exosomes and inhibit CRC cell proliferation and migration by regulating the miR-664b-3p/HMGB3 pathway ( 121 ). There’s a significant increase in SNHG3 expression in CRC cells and CAFs-derived exosomes, while incubation of CRC cells using CAFs-EVs facilitated cell proliferation.…”