CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom; Department of Oncology, University of Oxford, Oxford, United Kingdom; Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou, China.
CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom; Department of Oncology, University of Oxford, Oxford, United Kingdom.
Int J Radiat Oncol Biol Phys. 2018 May 1;101(1):97-106. doi: 10.1016/j.ijrobp.2018.01.091. Epub 2018 Feb 3.
To investigate the induction of type III interferons (IFNs) in human cancer cells by gamma-rays.
Type III IFN expression in human cancer cell lines after gamma-ray irradiation in vitro was assessed by reverse transcription-quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Signaling pathways mediating type III IFN induction were examined by a variety of means, including immunoblotting, flow cytometry, confocal imaging, and reverse transcription-quantitative polymerase chain reaction. Key mediators in these pathways were further explored and validated using gene CRISPR knockout or short hairpin RNA knockdown.
Exposure to gamma-rays directly induced type III IFNs (mainly IFNL1) in human cancer cell lines in dose- and time-dependent fashions. The induction of IFNL1 was primarily mediated by the cytosolic DNA sensors-STING-TBK1-IRF1 signaling axis, with a lesser contribution from the nuclear factor kappa b signaling in HT29 cells. In addition, type III IFN signaling through its receptors serves as a positive feedback loop, further enhancing IFN expression via up-regulation of the kinases in the STING-TBK1 signaling axis.
Our results suggest that IFNL1 can be up-regulated in human cancer cell lines after gamma-ray treatment. In HT29 cells this induction occurs via the STING pathway, adding another layer of complexity to the understanding of radiation-induced antitumor immunity, and may provide novel insights into IFN-based cancer treatment.
研究γ射线诱导人类癌细胞产生 III 型干扰素（IFNs）。
通过逆转录定量聚合酶链反应和酶联免疫吸附试验评估γ射线体外辐照后人癌细胞系中 III 型 IFN 的表达。通过多种方法（包括免疫印迹、流式细胞术、共聚焦成像和逆转录定量聚合酶链反应）研究介导 III 型 IFN 诱导的信号通路。使用基因 CRISPR 敲除或短发夹 RNA 敲低进一步探索和验证这些途径中的关键介质。
γ射线以剂量和时间依赖的方式直接诱导人癌细胞系中 III 型 IFNs（主要是 IFNL1）。IFNL1 的诱导主要由细胞质 DNA 传感器-STING-TBK1-IRF1 信号轴介导，在 HT29 细胞中核因子 kappa b 信号的贡献较小。此外，III 型 IFN 通过其受体的信号转导作为正反馈回路，通过上调 STING-TBK1 信号轴中的激酶进一步增强 IFN 的表达。
我们的结果表明，IFNL1 可以在人癌细胞系接受γ射线治疗后上调。在 HT29 细胞中，这种诱导是通过 STING 途径发生的，这为理解辐射诱导的抗肿瘤免疫增加了另一层复杂性，并可能为基于 IFN 的癌症治疗提供新的见解。
