Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
Sci Rep. 2017 Jan 6;7:39692. doi: 10.1038/srep39692.
Non-small-cell lung carcinoma (NSCLC) accounts for 85% of malignant lung tumors and is the leading cause of cancer deaths. Our group previously identified Tripartite Motif 14 (TRIM14) as a component of a prognostic multigene expression signature for NSCLC. Little is known about the function of TRIM14 protein in normal or disease states. We investigated the functional and prognostic role of TRIM14 in NSCLC using in vitro and in vivo perturbation model systems. Firstly, a pooled RNAi screen identified TRIM14 to effect cell proliferation/survival in NSCLC cells. Secondly, silencing of TRIM14 expression significantly enhanced tumor growth in NSCLC xenograft mouse models, while exogenous TRIM14 expression attenuated tumorigenesis. In addition, differences in apoptotic activity between TRIM14-deficient and control tumors suggests that TRIM14 tumor suppressor activity may depend on cell death signaling pathways. TRIM14-deficient cell lines showed both resistance to hypoxia-induced cell death and attenuation of interferon response via STAT1 signaling. Consistent with these phenotypes, multivariate analyses on published mRNA expression datasets of over 600 primary NSCLCs demonstrated that low TRIM14 mRNA levels are significantly associated with poorer prognosis in early stage NSCLC patients. Our functional data therefore establish a novel tumor suppressive role for TRIM14 in NSCLC progression.
非小细胞肺癌（NSCLC）占恶性肺肿瘤的 85%，是癌症死亡的主要原因。我们的研究小组先前发现三结构域蛋白 14（TRIM14）是 NSCLC 预后多基因表达特征的一个组成部分。关于 TRIM14 蛋白在正常或疾病状态下的功能知之甚少。我们使用体外和体内扰动模型系统研究了 TRIM14 在 NSCLC 中的功能和预后作用。首先， pooled RNAi 筛选发现 TRIM14 影响 NSCLC 细胞的增殖/存活。其次，沉默 TRIM14 表达显著增强 NSCLC 异种移植小鼠模型中的肿瘤生长，而外源性 TRIM14 表达则减弱了肿瘤发生。此外，TRIM14 缺陷和对照肿瘤之间的凋亡活性差异表明，TRIM14 肿瘤抑制活性可能依赖于细胞死亡信号通路。TRIM14 缺陷细胞系表现出对缺氧诱导的细胞死亡的抗性和通过 STAT1 信号减弱干扰素反应。与这些表型一致，对超过 600 例 NSCLC 原发性患者的 mRNA 表达数据集的多变量分析表明，低 TRIM14 mRNA 水平与早期 NSCLC 患者的预后不良显著相关。因此，我们的功能数据确立了 TRIM14 在 NSCLC 进展中的新型肿瘤抑制作用。
