Dihydroartemisinin targets ANXA2 to suppress hepatocellular carcinoma angiogenesis through the PI3K/AKT signaling pathway

Background: Annexin A2 (AnxA2), implicated in the progression of multiple cancers, is considered a promising biomarker for anti-cancer therapies. Our research explores the molecular mechanisms of AnxA2 in hepatocellular carcinoma (HCC) and discovers the potential of traditional Chinese medicine compounds to target AnxA2, aiming to improve current HCC therapeutic approaches.

Methods: Our study leveraged TCGA data to investigate AnxA2 expression in HCC, complemented by gene set enrichment analysis to elucidate its potential impact. We quantified AnxA2 expressions in HCC cells using qRT-PCR and western blot. Modulating AnxA2 expression, we used cell counting kit-8 to gauge cell viability and Transwell assays to measure invasiveness. Scratch and tube formation assays were conducted on human umbilical vein endothelial cells (HUVECs), and vascular endothelial growth factor A (VEGFA) levels were detected via enzyme-linked immunosorbent assay. Molecular docking with AutoDock and cell thermal shift assays established the binding affinity and targeting of dihydroartemisinin (DHA) to AnxA2.

Results: AnxA2 was upregulated in HCC tissues and cells and was particularly enriched in the PI3K/Akt signaling pathway. Knockdown of AnxA2 in HCC cells resulted in the inhibition of cell invasion and angiogenesis, while overexpression led to the opposite effects. We discovered a binding relationship between DHA and AnxA2, suggesting that the therapeutic effects of DHA on HCC are mediated through targeting AnxA2.

Conclusion: DHA, by engaging AnxA2, mitigates the PI3K/Akt signaling, thereby inhibiting invasive and angiogenic activities of HCC.

ANXA2; Angiogenesis; Dihydroartemisinin; Hepatocellular carcinoma; PI3K/AKT signaling.