Exosomes derived from Fusobacterium nucleatum-infected colorectal cancer cells facilitate tumour metastasis by selectively carrying miR-1246/92b-3p/27a-3p and CXCL16

Abstract

ObjectiveExosomes released from tumour cells are packed with unique RNA and protein cargo, and they are emerging as an important mediator in the communication network that promotes tumour progression. The facultative intracellular bacterium Fusobacterium nucleatum (Fn) is an important colorectal cancer (CRC)-associated bacterium. To date, the function of exosomes from Fn-infected CRC cells has not been explored.DesignExosomes were isolated by sequential differential centrifugation and verified by transmission electron microscopy, NanoSight analysis and Western blotting. Given that exosomes have been shown to transport miRNAs and proteins to alter cellular functions, we performed miRNA sequencing and proteome analysis of exosomes from Fn-infected and non-infected cells. The biological role and mechanism of exosomes from Fn-infected cells in CRC tumour growth and liver metastasis were determined in vitro and in vivo.ResultsWe demonstrated that exosomes delivered miR-1246/92b-3p/27a-3p and CXCL16/RhoA/IL-8 from Fn-infected cells into non-infected cells to increase cell migration ability in vitro and promote tumour metastasis in vivo. Finally, both circulating exosomal miR-1246/92b-3p/27a-3p and CXCL16 levels were closely associated with Fn abundance and tumour stage in patients with CRC.ConclusionThis study suggests that Fn infection may stimulate tumour cells to generate miR-1246/92b-3p/27a-3p-rich and CXCL16/RhoA/IL-8 exosomes that are delivered to uninfected cells to promote prometastatic behaviours.

The complex, bidirectional role of extracellular vesicles in infection

“…In humans, EVs have been reported in all body fluids [68][69][70][71][72] and are produced by many different cell types [71,[73][74][75][76]. EVs play an important role in extending the functional range of the bioactive molecules released by cells, increasing their stability, and targeting their delivery to achieve higher localised concentrations [77,78]. It is now clear that EVs have a role in both the co-ordination and the delivery of antimicrobial immune responses.…”

“…Epithelial [ 77 , 89 ] and immune [ 79–81 , 90 ] cells and platelets [ 91 , 92 ] that come into contact with bacterial pathogens [ 77 , 79 , 80 , 89 , 90 ] or the toxins pathogens secrete [ 91 , 92 ], release EVs that contain signals, including regulatory RNAs [ 77 , 93 ] cytokines [ 91 , 92 ], pathogen-associated molecular patterns (PAMPs) [ 79 , 80 , 89 , 90 ] and even toxins [ 46 , 94 ] that may activate endothelial cells [ 81 , 92 ], amplify the release of proinflammatory signals from immune cells [ 79 , 90 ], recruit macrophages/neutrophils [ 91 , 95 ] or promote B-cell/T-cell interactions that lead to antibody production [ 71 , 96 , 97 ].…”

MiR-1539 and Its Potential Role as a Novel Biomarker for Colorectal Cancer

“…Derived from endosomes, exosomes carry unique cargo such as RNA (typically miRNA), proteins, and lipids. Exosomes travel to adjacent and distant target cells, inducing intercellular communications and gene regulation ( 23 , 25 , 26 ). With an inherent ability to actively select and enrich for miRNAs, tumor-derived exosomes transfer specific cell-independent mature miRNAs to recipient cells, to change their biological function, to silence mRNAs and promote oncogenesis ( 27 , 28 ).…”

MiR-1246 regulates the PI3K/AKT signaling pathway by targeting PIK3AP1 and inhibits thyroid cancer cell proliferation and tumor growth

“…miR-1246 expression was considerably diminished in the samples of thyroid cancer, suggesting that miR-1246 could be correlated with the onset of thyroid cancer and that it could be a promising predictive biomarker for thyroid cancer diagnosis and prognosis. Importantly, miR-1246 is considered to be involved in the occurrence and advancement of many cancer [9,10]. However, its role in thyroid cancer and its potential molecular mechanism have not been determined.…”

“…The development of many cancers has been shown to be inhibited by miRNA overexpression or inhibition [7,8]. miR-1246 performs an essential task in the oncogenesis of certain cancers, such as colorectal [9], breast cancer [10], and oral carcinomas [11].…”