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Exosomal and intracellular miR-320b promotes lymphatic metastasis in esophageal squamous cell carcinoma

Cancer-cell-released exosomal microRNAs (miRNAs) are important mediators of cell-cell communication in the tumor microenvironment. In this study, we sequenced serum exosome miRNAs from esophageal squamous cell carcinoma (ESCC) patients and identified high expression of miR-320b to be closely associa...

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Detalles Bibliográficos
Autores principales: Liu, Tong, Li, Peilong, Li, Juan, Qi, Qiuchen, Sun, Zhaowei, Shi, Shuang, Xie, Yan, Liu, Shibiao, Wang, Yunshan, Du, Lutao, Wang, Chuanxin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8526502/
https://www.ncbi.nlm.nih.gov/pubmed/34729394
http://dx.doi.org/10.1016/j.omto.2021.09.003
Descripción
Sumario:Cancer-cell-released exosomal microRNAs (miRNAs) are important mediators of cell-cell communication in the tumor microenvironment. In this study, we sequenced serum exosome miRNAs from esophageal squamous cell carcinoma (ESCC) patients and identified high expression of miR-320b to be closely associated with peritumoral lymphangiogenesis and lymph node (LN) metastasis. Functionally, miR-320b could be enriched and transferred by ESCC-released exosomes directly to human lymphatic endothelial cells (HLECs), promoting tube formation and migration in vitro and facilitating lymphangiogenesis and LN metastasis in vivo as assessed by gain- and loss-of-function experiments. Furthermore, we found programmed cell death 4 (PDCD4) as a direct target of miR-320b through bioinformatic prediction and luciferase reporter assay. Re-expression of PDCD4 could rescue the effects induced by exosomal miR-320b. Notably, the miR-320b-PDCD4 axis activates the AKT pathway in HLECs independent of vascular endothelial growth factor-C (VEGF-C). Moreover, overexpression of miR-320b promotes the proliferation, migration, invasion, and epithelial-mesenchymal transition progression of ESCC cells. Finally, we demonstrate that METTL3 could interact with DGCR8 protein and positively modulate pri-miR-320b maturation process in an N6-methyladenosine (m6A)-dependent manner. Therefore, our findings uncover a VEGF-C-independent mechanism of exosomal and intracellular miR-320b-mediated LN metastasis and identify miR-320b as a novel predictive marker and therapeutic target for LN metastasis in ESCC.