关键词: 肝内胆管细胞癌, 异柠檬酸脱氢酶1, 炎症, 极化

Abstract: Objective To investigate the correlation between isocitrate dehydrogenase 1 （IDH1） R132H mutation and the inflammation reaction in intrahepatic cholangiocarcinoma (ICC) and to explore the effect of IDH1 mutation on ICC. Methods The clinicopathological characteristics of 131 ICCs were summarized and Sanger sequencing was used to detect IDH1 (R132) mutation in these cases. The inflammation reaction was analyzed in these samples by HE staining. The Cre-LoxP system was performed to construct IDH1 R132H intestinal tissue-specific mutant mice. The hepatic bile duct in the mutant mice was isolated and determined by HE staining if there is inflammation reaction. The supernatant was collected after the intervention of the mutant IDH1 metabolite 2-hydroxyglutarate (2-HG) on THP-1 macrophage cell line. ELISA assay was used to detect tumor necrosis factor-alpha (TNF-α) and interleukin-10 (IL-10) in the supernatant, which are markers of M1 and M2 subtypes of macrophage, respectively. Results Sequencing revealed that 15.3% (20/131) tumors had R132H IDH1 mutation. HE staining showed that inflammatory cell infiltration increase in the IDH1 mutant group compared with the IDH1 wild-type group（P<0.01）and there was similar result in IDH1 (R132H) intestinal tissue-specific mutant mice（P<0.05）. Dihydroxyglutaric acid (2-HG), the metabolite of the mutant IDH1 (R132H), can induce interleukin10 (IL-10) to increase significantly（P<0.01）, which was the marker of M2 subtypes of macrophage. In contrast, there was no obvious difference for TNF-α, which was the marker of M1 subtypes of macrophage. Conclusions The mutation of IDH1 can induce the inflammation reaction in ICC and promote THP-1 polarization toward M2, which may provide a basis for understanding the correlation between IDH1(R132) mutation and ICC and supply a promising therapeutic strategy for ICC patients.

Key words: Intrahepatic Cholangiocarcinoma, Isocitrate dehydrogenase 1, inflammation, polarization