Int J Biol Sci 2014; 10(4):415-425. doi:10.7150/ijbs.8002
Cantharidin Exerts Anti-Hepatocellular Carcinoma by Mir-214 Modulating Macrophage Polarization
Center of Liver Transplantation, The First Affiliated Hospital of Nanjing Medical University, The Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, China.
Lu S, Gao Y, Huang X, Wang X. Cantharidin Exerts Anti-Hepatocellular Carcinoma by Mir-214 Modulating Macrophage Polarization. Int J Biol Sci 2014; 10(4):415-425. doi:10.7150/ijbs.8002. Available from http://www.ijbs.com/v10p0415.htm
Norcantharidin (NCTD), a demethylated form of cantharidin, has been used as a routine anticancer drug in China. In this study, the effect and mechanism of NCTD on anti-hepatocellular carcinoma (HCC) was examined. In vivo antitumor activity was investigated in hepatoma-bearing mice by intraperitoneal injection of different concentration of NCTD. The levels of MicroRNAs (miRNAs) and mRNA were detected by real-time PCR. The concentrations of IL-10 and IL-12 in BMDMs, Raw 264.7 cells or tumor-associated macrophages (TAMs) were measured with ELISA kit. The effects of TAMs on H22 cell survival and invasion were assayed via the CCK-8 and tumor invasion assay, respectively. Anti-miR-214 or pre-miR-214 was used to down-regulate or up-regulated miR-214 expression. The results showed that NCTD drastically impaired tumor growth in hepatoma-bearing mice, correlating with increased anti-tumor activity of TAMs. Moreover, NCTD stimulation led to an alteration of HCC microenvironment, reflected by a decrease in a shift from M2 to M1 polarization and the populations of CD4+/CD25+Foxp3 T cells. The activation of STAT3 was inhibited in TAMs from hepatoma-bearing mice injected with NCTD. Addition of NCTD to treat RAW264.7 or TAMs enhanced M1 polarization through increase of miR-214 expression. NCTD significantly inhibited β-catenin expression, which could be reversed by miR-214 inhibitor. Conditioned media from TAMs in hepatoma-bearing mice treated with NCTD or TAMs transfected with pre-miR-214 inhibited survival and invasion of H22 cells. This finding reveals a novel role for NCTD on inhibition of HCC through miR-214 modulating macrophage polarization.
Keywords: Norcantharidin, hepatocellular carcinoma, microenvironment, macrophage polarization, miR-214.