Exosome circCMTM3 promotes angiogenesis and tumorigenesis of hepatocellular carcinoma through miR-3619-5p/SOX9.

Abstract

As one of the most common and lethal carcinomas, hepatocellular carcinoma (HCC) is a global health concern and affects millions of people worldwide. Current treatments for HCC are very limited due to its unclear pathogenesis. Here, we aim to further investigate the role of circCMTM3/microRNA (miR)-3619-5p in HCC. Human blood samples were collected from HCC patients and healthy people. Quantitative reverse transcription-polymerase chain reaction and western blot analysis were undertaken to measure levels of circCMTM3, miR-3619-5p, SOX9, and exosome markers. The MTT, colony formation, and Transwell assays were used to examine the viability, migration, and invasion of human umbilical vein endothelial cells (HUVECs), respectively. Tube formation assay was used to assess angiogenesis. Dual luciferase assay was used to validate circCMTM3/miR-3619-5p and miR-3619-5p/SOX9 interactions. A nude mouse xenograft model was used to test the role of circCMTM3 in HCC in vivo. Levels of circCMTM3 in exosomes from HCC patients and cells were elevated. Knockdown of circCMTM3 greatly decreased viability, migration, and invasion of HUVECs, as well as angiogenesis. CircCMTM3 acted as a miR-3619-5p sponge and miR-3619-5p inhibitor reversed the effects of si-circCMTM3 on angiogenesis. MiR-3619-5p directly targeted SOX9 and modulated angiogenesis through SOX9. Furthermore, knockdown of circCMTM3 suppressed angiogenesis and HCC tumor growth in vivo. The exosome circCMTM3/miR-3619-5p/SOX9 axis from HCC cells promotes angiogenesis and thus contributes to HCC tumorigenesis.