Semi-synthetic product dihydroartemisinin inhibited fibronectin-1 and integrin-β1 and interfered with the migration of HCCLM6 cells via PI3K-AKT pathway.

Objective: Dihydroartemisinin (DHA), a predominant phytoconstituent in Artemisia annua L. (a plant widely used as a traditional medicine in China), inhibits lung tumorigenesis and metastasis. However, its anticancer effect against hepatocellular carcinoma has not yet been investigated. In this study, the anti-tumor potential of DHA was evaluated in vitro against the hepatocellular carcinoma HCCLM6 cell line.

Results: DHA (1-100 μM) treatment suppressed the cell proliferation in dose-dependently. In addition, expression of all genes, involved in cellular proliferation (e.g. E2F1, BCL2, PCNA, MKI67 and CCNE2) and cellular motility (e.g. DOCK1, ITGA2, VCL, MMP2, FN1), was significantly downregulated by DHA (50 and 100 μM). Global gene expression profile identified 1731 differentially expressed genes (DEGs); among them, 211 were up-regulated and 1520 were down-regulated. Besides, the extracellular matrix (ECM)-receptor interaction, focal adhesion, regulation of actin cytoskeleton and TNF pathways were enriched by DEGs. Based on the KEGG signal pathway enrichment, the FN1 and integrin-β1 could be a potential target for DHA for inhibiting proliferation. The expression of FN1 and integrin-β1 was further analyzed by the qPCR, immunohistochemistry and Western blot assay in vitro and in vivo. The results indicated that DHA decreased the FN1 and integrin-β1 protein levels and interfered with PI3K-AKT signal transduction pathway.

Conclusions: Our findings revealed that DHA could inhibit proliferation and migration of human hepatocellular carcinoma cells targeting FN1 and ITGB1 via the PI3K-AKT pathway. Therefore, DHA might be a novel drug with a potential effect against liver tumorigenesis and metastasis.