›› 2019, Vol. 39 ›› Issue (11): 1556-1560.

• 研究论文 • 上一篇    下一篇



  1. 1. 空军军医大学空军军医大学西京医院病理科暨基础医学院病理学教研室, 肿瘤生物学国家重点实验室
    2. 空军军医大学基础医学院病理学教研室
    3. 空军军医大学基础医学院五大队十八队
    4. 空军军医大学空军军医大学西京医院病理科暨基础医学院病理学教研室
    5. 第四军医大学
  • 收稿日期:2019-04-28 修回日期:2019-09-19 出版日期:2019-11-05 发布日期:2019-11-05
  • 通讯作者: 袁媛 E-mail:yy12103034@163.com
  • 基金资助:

Effect of isocitrate dehydrogenase 1 on the inflammation in intrahepatic cholangiocarcinoma

  • Received:2019-04-28 Revised:2019-09-19 Online:2019-11-05 Published:2019-11-05

摘要: 目的 研究肝内胆管细胞癌(ICC)中异柠檬酸脱氢酶1(IDH1)132位点核苷酸突变与炎性反应的关系,探讨IDH1突变对ICC发生的影响。 方法 收集ICC标本131例。采用Sanger法分析IDH1突变率;HE观察ICC炎性反应发生情况。用Cre-LoxP系统,构建IDH1 R132H肠道组织特异性基因突变小鼠;分离小鼠肝脏内胆管,HE观察小鼠肝内胆管及胆道炎性反应情况。用突变型IDH1代谢产物2-羟基戊二酸(2-HG)对THP-1巨噬细胞系进行干预;收集培养液上清,ELISA检测上清中M1型巨噬细胞标志物肿瘤坏死因子(TNF-α)和M2型标志物白介素(IL-10)的浓度。结果 131例ICC标本中IDH1(R132H)突变率为15.3%(20/131)。与IDH1野生型组相比,IDH1(R132H)突变组标本中炎细胞浸润明显增多(P<0.01);在肠道组织特异性突变小鼠模型中也得到一致结果(P<0.05)。2-HG能够诱导M2型巨噬细胞标志物IL-10表达明显增多(P<0.01),而M1型标志物TNF-α没有统计学意义。结论 IDH1突变能够诱发胆管发生炎性反应,并促进THP-1巨噬细胞系向M2型极化,为进一步明确IDH1突变与肝内胆管细胞癌发生的关系以及靶向治疗提供依据。

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