AUTHOR=Dong Xubin , Jin Cong , Chen Danxiang , Chen Yizuo , Ye Zhi-qiang , Zhang Xiaohua , Huang Xiaoli , Zhang Wei , Gu Dian-na 

TITLE=Genomic Instability-Related LncRNA Signature Predicts the Prognosis and Highlights LINC01614 Is a Tumor Microenvironment-Related Oncogenic lncRNA of Papillary Thyroid Carcinoma

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.737867

DOI=10.3389/fonc.2021.737867

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>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.</p></sec><sec><title>Methods</title><p>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.</p></sec><sec><title>Results</title><p>A computational model based on four lncRNAs (<italic>FOXD2-AS1</italic>, <italic>LINC01614</italic>, <italic>AC073257.2</italic>, and <italic>AC005082.1</italic>) was identified as a quantitative index using an <italic>in-silicon</italic> 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 <italic>FOXD2-AS1</italic>, <italic>LINC01614</italic>, <italic>AC073257.2</italic>, and <italic>AC005082.1</italic> were also associated with driver mutations and multiple clinical-pathological variables, respectively. Moreover, RNA-Seq confirmed the expression patterns of <italic>FOXD2-AS1</italic>, <italic>LINC01614</italic>, <italic>AC073257.2</italic>, and <italic>AC005082.1</italic> in PTC and normal thyroid tissues. Biological experiments demonstrated that downregulated or overexpressed <italic>LINC01614</italic> affect PTC cell proliferation, migration, and invasion <italic>in vitro</italic>. Activation of the stromal and immune cell infiltration was also observed in the high <italic>LINC01614</italic> group in the PTC microenvironment.</p></sec><sec><title>Conclusion</title><p>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 <italic>LINC01614</italic> as a novel oncogenic lncRNA and verified its phenotype in PTC.</p></sec>