Silencing of the interferon-inducible gene Ifi204/p204 induces resistance to interferon-γ-mediated cell growth arrest of tumor cells
Silencing of the interferon-inducible gene Ifi204/p204 induces resistance to interferon-γ-mediated cell growth arrest of tumor cells
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干扰素诱导基因 Ifi204/p204 的沉默诱导对干扰素 γ 介导的肿瘤细胞生长停滞的抵抗
DOI：
10.1016/j.cyto.2018.06.029
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发表时间：
2018
期刊：
影响因子：
3.8
通讯作者：
Yoshihiro Ohmori
中科院分区：
文献类型：
--
作者：
Hana Yamaguchi;Miki Hiroi;Yoshihiro Ohmori
许多肿瘤细胞逃避癌症免疫监视，并抵抗干扰素(IFN)治疗。虽然干扰素耐药的机制主要归因于干扰素信号通路成分的缺乏，但某些类型的肿瘤细胞抵抗干扰素介导的细胞生长停滞，尽管存在完整的JAK/STAT信号通路。然而，与JAK/STAT通路缺陷无关的对IFN无反应的分子机制仍有待阐明。为了阐明干扰素γ耐药的机制，我们检测了干扰素γ对小鼠肿瘤细胞株的抗增殖作用。尽管存在干扰素γ诱导的STAT1依赖的信号通路，但小鼠鳞状细胞癌细胞仍能抵抗干扰素γ介导的细胞生长停滞，而干扰素γ则将B16/F1细胞(一种众所周知的干扰素γ敏感的小鼠黑色素瘤细胞系)的细胞生长抑制在细胞周期的G1期。干扰素γ处理SCCVII细胞后，既没有下调细胞周期蛋白D1、细胞周期蛋白A2和细胞周期蛋白E1的表达，也没有诱导视网膜母细胞瘤蛋白的低磷酸化、活性形式。有趣的是，高度磷酸化的非活性形式的pRB仅定位于SCCVII细胞的细胞质中。干扰素诱导的204基因(Ifi204)在SCCVII细胞中被抑制，其基因产物p204与pRb结合并发挥抗增殖作用。P204过表达显著抑制细胞生长，pRb结合的LXCXE基序突变降低了抗增殖作用。这些结果表明，沉默IFI204/p204可诱导SCCVII细胞抵抗干扰素γ介导的细胞生长停滞。
Many tumor cells escape from cancer immunosurveillance and resist treatment with interferons (IFNs). Although the mechanism underlying IFN resistance is mostly attributed to a deficiency of components of the IFN-signaling pathway, some types of tumor cells resist IFN-mediated cell growth arrest despite the presence of an intact JAK/STAT signaling pathway. However, the molecular mechanisms underlying the unresponsiveness to IFNs independent of the defective JAK/STAT pathway remain to be clarified. To elucidate the mechanisms underlying IFNγ resistance, we examined the anti-proliferative effect of IFNγ on mouse tumor cell lines. Mouse squamous cell carcinoma (SCCVII) cells were resistant to IFNγ-mediated cell growth arrest despite the presence of the IFNγ-induced STAT1-dependent signaling pathway, whereas IFNγ inhibited cell growth of B16/F1 cells, a well-known IFNγ-sensitive mouse melanoma cell line, at the G1 phase of the cell cycle. Treatment of SCCVII cells with IFNγ neither downregulated the expression of cyclin D1, cyclin A2, and cyclin E1 nor induced a hypo-phosphorylated, active form of retinoblastoma protein (pRb). Interestingly, the hyper-phosphorylated, inactive form of pRb was exclusively localized in the cytoplasm in SCCVII cells. The IFN-inducible 204 gene (Ifi204), whose gene product, p204, binds to pRb and exerts an anti-proliferative effect, was repressed in SCCVII cells. p204 overexpression in SCCVII significantly inhibited cell growth, and mutation of a pRb-binding LXCXE motif decreased the anti-proliferative effect. These results suggest that silencing ofIfi204/p204 induces resistance to IFNγ-mediated cell growth arrest in SCCVII cells.