Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Rd, Taipei 100, Taiwan.
Department of Family Medicine, National Taiwan University Hospital, Taipei 100, Taiwan.
Int J Mol Sci. 2021 Oct 28;22(21):11661. doi: 10.3390/ijms222111661.
Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Chronic liver inflammation due to hepatitis virus infection and other major effectors is a major risk factor of HCC. Indoleamine 2,3-dioxygenase 1 (IDO1), a heme enzyme highly expressed upon stimulation with proinflammatory cytokines such as interferon-γ (IFN-γ), is activated to modulate the tumor microenvironment and potentially crucial in the development of certain cancer types. Earlier studies have majorly reported an immunomodulatory function of IDO1. However, the specific role of IDO1 in cancer cells, particularly HCC, remains to be clarified. Analysis of The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA LIHC) dataset in the current study revealed a significant correlation between IDO1 expression and HCC. We further established inducible IDO1-expressing cell models by coupling lentivirus-mediated knockdown and IFN-γ induction of IDO1 in normal and HCC cells. In functional assays, proliferation and motility-related functions of HCC cells were compromised upon suppression of IDO1, which may partially be rescued by its enzymatic product, kynurenine (KYN), while normal hepatocytes were not affected. Aryl hydrocarbon receptor (AhR), a reported endogenous KYN receptor, is suggested to participate in tumorigenesis. In mechanistic studies, IDO1 activation promoted both AhR and β-catenin activity and nuclear translocation. Immunofluorescence staining and co-immunoprecipitation assays further disclosed interactions between AhR and β-catenin. In addition, we identified a Src-PTEN-PI3K/Akt-GSK-3β axis involved in β-catenin stabilization and activation following IDO1-mediated AhR activation. IDO1-induced AhR and β-catenin modulated the expression of proliferation- and EMT-related genes to facilitate growth and metastasis of HCC cells. Our collective findings provide a mechanistic basis for the design of more efficacious IDO1-targeted therapy for HCC.
肝细胞癌（HCC）是全球第四大常见癌症相关死亡原因。慢性肝脏炎症由肝炎病毒感染和其他主要效应因子引起，是 HCC 的主要危险因素。吲哚胺 2,3-双加氧酶 1（IDO1）是一种血红素酶，在受到干扰素-γ（IFN-γ）等促炎细胞因子的刺激时高度表达，其被激活以调节肿瘤微环境，并在某些癌症类型的发展中起着至关重要的作用。早期研究主要报道了 IDO1 的免疫调节功能。然而，IDO1 在癌细胞中的具体作用，特别是在 HCC 中，仍有待阐明。本研究对癌症基因组图谱肝脏肝癌（TCGA LIHC）数据集的分析表明，IDO1 表达与 HCC 之间存在显著相关性。我们通过在正常和 HCC 细胞中耦合慢病毒介导的 IDO1 敲低和 IFN-γ诱导，进一步建立了可诱导表达 IDO1 的细胞模型。在功能测定中，抑制 IDO1 会削弱 HCC 细胞的增殖和运动相关功能，而其酶产物犬尿氨酸（KYN）可能部分挽救了这一功能，而正常肝细胞不受影响。芳香烃受体（AhR）是一种报道的内源性 KYN 受体，被认为参与了肿瘤发生。在机制研究中，IDO1 的激活促进了 AhR 和 β-连环蛋白的活性和核易位。免疫荧光染色和共免疫沉淀实验进一步揭示了 AhR 和 β-连环蛋白之间的相互作用。此外，我们确定了一个Src-PTEN-PI3K/Akt-GSK-3β 轴，该轴涉及 IDO1 介导的 AhR 激活后 β-连环蛋白的稳定和激活。IDO1 诱导的 AhR 和 β-连环蛋白调节了与增殖和 EMT 相关的基因的表达，从而促进了 HCC 细胞的生长和转移。我们的研究结果为设计更有效的 IDO1 靶向 HCC 治疗提供了机制基础。
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