"111" Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing, 400044, China.
Biotechnol Lett. 2020 Jun;42(6):917-926. doi: 10.1007/s10529-020-02839-8. Epub 2020 Feb 18.
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.
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.
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.
二氢青蒿素（DHA）是青蒿（在中国被广泛用作传统药物的植物）中的主要植物成分，可抑制肺癌的发生和转移。然而，其对肝细胞癌的抗癌作用尚未得到研究。本研究评估了 DHA 对肝癌细胞系 HCCLM6 的体外抗肿瘤潜力。
DHA（1-100 μM）处理呈剂量依赖性抑制细胞增殖。此外，DHA（50 和 100 μM）显著下调了所有参与细胞增殖（如 E2F1、BCL2、PCNA、MKI67 和 CCNE2）和细胞迁移（如 DOCK1、ITGA2、VCL、MMP2 和 FN1）的基因的表达。全基因表达谱鉴定出 1731 个差异表达基因（DEGs）；其中 211 个上调，1520 个下调。此外，DEGs 富集了细胞外基质（ECM）-受体相互作用、粘着斑、肌动蛋白细胞骨架调节和 TNF 途径。基于 KEGG 信号通路富集，FN1 和整合素-β1 可能是 DHA 抑制增殖的潜在靶点。通过体外和体内的 qPCR、免疫组织化学和 Western blot 分析进一步研究了 FN1 和整合素-β1 的表达。结果表明，DHA 降低了 FN1 和整合素-β1 的蛋白水平，并干扰了 PI3K-AKT 信号转导通路。
我们的研究结果表明，DHA 通过 PI3K-AKT 通路靶向 FN1 和 ITGB1 抑制人肝癌细胞的增殖和迁移。因此，DHA 可能是一种针对肝肿瘤发生和转移的新型潜在药物。
