Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530007, China; Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, 15260, USA.
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, 15260, USA; Department of Rheumatology and Immunology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China.
Cancer Lett. 2021 May 28;506:95-106. doi: 10.1016/j.canlet.2021.03.002. Epub 2021 Mar 6.
Interferon regulatory factor 1 (IRF-1) is a tumor suppressor gene in cancer biology with anti-proliferative and pro-apoptotic effect on cancer cells, however mechanisms of IRF-1 regulating tumor microenvironment (TME) in hepatocellular carcinoma (HCC) remain only partially characterized. Here, we investigated that IRF-1 regulates C-X-C motif chemokine 10 (CXCL10) and chemokine receptor 3 (CXCR3) to activate anti-tumor immunity in HCC. We found that IRF-1 mRNA expression was positively correlated with CXCL10 and CXCR3 through qRT-PCR assay in HCC tumors and in analysis of the TCGA database. IRF-1 response elements were identified in the CXCL10 promoter region, and ChIP-qPCR confirmed IRF-1 binding to promote CXCL10 transcription. IRF-2 is a competitive antagonist for IRF-1 mediated transcriptional effects, and overexpression of IRF-2 decreased basal and IFN-γ induced CXCL10 expression. Although IRF-1 upregulated CXCR3 expression in HCC cells, it inhibited proliferation and exerted pro-apoptotic effects, which overcome proliferation partly mediated by activating the CXCL10/CXCR3 autocrine axis. In vitro and in vivo studies showed that IRF-1 increased CD8 T cells, NK and NKT cells migration, and activated IFN-γ secretion in NK and NKT cells to induce tumor apoptosis through the CXCL10/CXCR3 paracrine axis. Conversely, this effect was markedly abrogated in HCC tumor bearing mice deficient in CXCR3. Therefore, the IRF-1/CXCL10/CXCR3 axis contributes to the anti-tumor microenvironment in HCC.
干扰素调节因子 1（IRF-1）在癌症生物学中是一种肿瘤抑制基因，对癌细胞具有抗增殖和促凋亡作用，然而，IRF-1 调节肝癌（HCC）肿瘤微环境（TME）的机制仍部分特征不明。在这里，我们研究了 IRF-1 通过调节 C-X-C 基序趋化因子 10（CXCL10）和趋化因子受体 3（CXCR3）来激活 HCC 中的抗肿瘤免疫。我们发现，通过 qRT-PCR 分析 HCC 肿瘤和 TCGA 数据库分析，IRF-1mRNA 表达与 CXCL10 和 CXCR3 呈正相关。在 CXCL10 启动子区域鉴定出 IRF-1 反应元件，ChIP-qPCR 证实 IRF-1 结合以促进 CXCL10 转录。IRF-2 是 IRF-1 介导的转录效应的竞争性拮抗剂，IRF-2 的过表达降低了基础和 IFN-γ 诱导的 CXCL10 表达。尽管 IRF-1 上调 HCC 细胞中 CXCR3 的表达，但它抑制增殖并发挥促凋亡作用，通过激活 CXCL10/CXCR3 自分泌轴部分克服增殖。体外和体内研究表明，IRF-1 增加 CD8 T 细胞、NK 和 NKT 细胞迁移，并激活 NK 和 NKT 细胞中的 IFN-γ 分泌，通过 CXCL10/CXCR3 旁分泌轴诱导肿瘤凋亡。相反，在缺乏 CXCR3 的 HCC 肿瘤荷瘤小鼠中，这种作用明显减弱。因此，IRF-1/CXCL10/CXCR3 轴有助于 HCC 的抗肿瘤微环境。
