Cantharidin exerts anti-hepatocellular carcinoma by miR-214 modulating macrophage polarization.

Abstract

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.

• Authors: Sen Lu, Yun Gao, Xinli Huang, Xuehao Wang
• Journal: International journal of biological sciences (Int J Biol Sci) Vol. 10 Issue 4 Pg. 415-25 ( 2014) ISSN: 1449-2288 [Electronic] Australia
• PMID: 24719559 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Bridged Bicyclo Compounds, Heterocyclic
• MicroRNAs
• Mirn214 microRNA, mouse
• beta Catenin
• Interleukin-10
• Interleukin-12
• norcantharidin

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Bridged Bicyclo Compounds, Heterocyclic (therapeutic use)
• Carcinoma, Hepatocellular (drug therapy, genetics, metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Gene Expression Regulation, Neoplastic
• Interleukin-10 (metabolism)
• Interleukin-12 (metabolism)
• Macrophages
• Male
• Mice
• MicroRNAs (genetics, metabolism, physiology)
• Tumor Microenvironment (drug effects)
• beta Catenin (metabolism)