Genomic Instability-Related LncRNA Signature Predicts the Prognosis and Highlights LINC01614 Is a Tumor Microenvironment-Related Oncogenic lncRNA of Papillary Thyroid Carcinoma.
Genomic Instability-Related LncRNA Signature Predicts the Prognosis and Highlights LINC01614 Is a Tumor Microenvironment-Related Oncogenic lncRNA of Papillary Thyroid Carcinoma.
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基因组不稳定性相关的 LncRNA 特征预测预后并强调 LINC01614 是一种与肿瘤微环境相关的甲状腺乳头状癌的致癌 lncRNA。
DOI：
10.3389/fonc.2021.737867
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发表时间：
2021
影响因子：
4.7
通讯作者：
Gu DN
中科院分区：
文献类型：
--
作者：
Dong X;Jin C;Chen D;Chen Y;Ye ZQ;Zhang X;Huang X;Zhang W;Gu DN
基因组不稳定性(GI)是恶性肿瘤的十大特征之一。长非编码RNA(LncRNAs)是一种很有前景的癌症生物标记物，据报道与胃肠道疾病有关。到目前为止，GI相关LncRNAs(GIlncs)在乳头状甲状腺癌(PTC)中的临床价值尚不清楚。对LncRNA表达和体细胞突变谱进行综合分析以鉴定GILncs。对具有高和低累积体细胞突变数组的差异表达的lncRNAs的分析表明，在PTC中存在显著的GILncs。进行单变量和多变量Cox比例风险回归分析，以确定Hub-GILncs。基于四个lncRNA(FOXD2-AS1、LINC01614、AC073257.2和AC005082.1)的计算模型被确定为使用硅内发现队列的定量指标。GILS评分与预后不良显著相关，这在TCGA数据集中得到了验证，并在我们当地的RNA-Seq队列中得到了进一步的测试。此外，结合临床特征和GILS-临床预后诺模图显示出令人满意的辨别和校正。此外，GILS评分和FOXD2-AS1、LINC01614、AC073257.2和AC005082.1分别与DIVER突变和多个临床病理变量相关。此外，RNA-Seq证实FOXD2-AS1、LINC01614、AC073257.2和AC005082.1在PTC和正常甲状腺组织中的表达模式。生物学实验表明，LINC01614表达下调或过表达会影响PTC细胞的体外增殖、迁移和侵袭。在PTC微环境中，LINC01614高剂量组的间质和免疫细胞也被激活。综上所述，我们确定了PTC临床结果预测的特征，包括与GI相关的四个LncRNA。更好地了解GI，提供PTC进展风险的替代评估。我们的研究还证实了LINC01614是一个新的致癌的lncRNA，并证实了它在PTC中的表型。
Genomic instability (GI) is among the top ten characteristics of malignancy. Long non-coding RNAs (lncRNAs) are promising cancer biomarkers that are reportedly involved in GI. So far, the clinical value of GI-related lncRNAs (GIlncs) in papillary thyroid cancer (PTC) has not been clarified. Integrative analysis of lncRNA expression and somatic mutation profiles was performed to identify GIlncs. Analysis of differentially expressed lncRNAs in the group with high- and low- cumulative number of somatic mutations revealed significant GIlncs in PTC. Univariate and multivariate Cox proportional hazard regression analyses were performed to identify hub-GIlncs. A computational model based on four lncRNAs (FOXD2-AS1, LINC01614, AC073257.2, and AC005082.1) was identified as a quantitative index using an in-silicon discovery cohort. GILS score was significantly associated with poor prognosis, as validated in the TCGA dataset and further tested in our local RNA-Seq cohort. Moreover, a combination of clinical characteristics and the composite GILS-clinical prognostic nomogram demonstrates satisfactory discrimination and calibration. Furthermore, the GILS score and FOXD2-AS1, LINC01614, AC073257.2, and AC005082.1 were also associated with driver mutations and multiple clinical-pathological variables, respectively. Moreover, RNA-Seq confirmed the expression patterns of FOXD2-AS1, LINC01614, AC073257.2, and AC005082.1 in PTC and normal thyroid tissues. Biological experiments demonstrated that downregulated or overexpressed LINC01614 affect PTC cell proliferation, migration, and invasion in vitro. Activation of the stromal and immune cell infiltration was also observed in the high LINC01614 group in the PTC microenvironment. In summary, we identified a signature for clinical outcome prediction in PTC comprising four lncRNAs associated with GI. A better understanding of the GI providing an alternative evaluation of the progression risk of PTC. Our study also demonstrated LINC01614 as a novel oncogenic lncRNA and verified its phenotype in PTC.
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