Isocitrate Dehydrogenase 2 Suppresses the Invasion of Hepatocellular Carcinoma Cells via Matrix Metalloproteinase 9

Abstract

Background/Aims: Isocitrate dehydrogenase 2 (IDH2) is a mitochondrial NADP-dependent isocitrate dehydrogenase, and has been found to be a tumor suppressor in several types of tumors. However, the roles of IDH2 in hepatocellular carcinoma (HCC) as well as underlying mechanisms remain unknown. Methods: The IDH2 and matrix metalloproteinase 9 (MMP9) levels in the specimens from 24 HCC patients were investigated by Western blot and ELISA, respectively. Their relationship was examined by correlation analyses. Patient survival with high IDH2 levels and low IDH2 levels was compared. IDH2 levels and MMP9 levels were modified in a human HCC cell line. The effects of IDH2 or MMP9 modulation on the expression of the other were analyzed. The effects of IDH2 on cell invasion were analyzed in a transwell cell invasion assay. The dependence of nuclear factor κB (NF-κB) signaling was examined using a specific inhibitor. Results: The IDH2 levels significantly decreased in HCC, and were lower in HCC with metastases, compared to those without metastases. IDH2 levels inversely correlated with MMP9 levels in HCC. HCC patients with Low IDH2 had lower 5-year survival. MMP9 levels did not regulate IDH2 levels, while IDH2 inhibited MMP9 levels in HCC cells, in a NF-κB signaling dependent manner, possibly through iκB, to suppress HCC cell invasion. Conclusions: Down regulation of IDH2 may promote HCC cell invasion via NF-κB-dependent increases in MMP9 activity. IDH2 may be a potential therapeutic target for HCC.

Keywords

• Isocitrate dehydrogenase 2 (IDH2)
• NF-κB
• IκB
• Hepatocellular carcinoma (HCC)
• Matrix metalloproteinase 9 (MMP9)
• Metastases