Coptisine Blocks Secretion of Exosomal circCCT3 from Cancer-Associated Fibroblasts to Reprogram Glucose Metabolism in Hepatocellular Carcinoma

Coptisine, extracted from rhizoma coptidis, has been shown to inhibit a variety of cancers. However, the underlying mechanism by which coptisine regulates hepatocellular carcinoma (HCC) progression remains unknown. MTT assay, transwell invasion assay, and TUNEL assay were employed to examine cell viability, invasion, and Apoptosis. In vivo tumor growth was determined by xenograft experiment. Reverse transcription-quantitative PCR was used to detect circCCT3 and HK2 gene expression. We utilized glucose consumption and lactate production assay to examine glucose metabolism state. Conditioned medium of coptisine-treated cancer-associated fibroblast (CAF) suppressed cell viability and invasion of HepG2 and Huh-7, whereas increased cell Apoptosis. Coptisine significantly inhibited tumor growth of HepG2 cells in immunodeficient mice. Mechanistically, coptisine blocked secretion of exosomal circCCT3 from CAF. More notably, circCCT3 was upregulated in clinical HCC tumors. Moreover, circCCT3 was confirmed to affect glucose metabolism of HCC cells. We identified HK2 as a key downstream effector for circCCT3-modulated HCC tumorigenesis. In summary, our research revealed novel molecular mechanism of coptisine-blocked HCC progression, thereby providing solid rationale for using coptisine to treat HCC.