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

Abstract

BackgroundGenomic 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.MethodsIntegrative 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.ResultsA 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.ConclusionIn 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.

Identification of Long Noncoding RNAs Associated With the Clinicopathological Features of Papillary Thyroid Carcinoma Complicated With Hashimoto’s Thyroiditis

“…Some lncRNAs have been identified as important regulators of PTC. For instance, lncRNA LINC01614 affect PTC cell proliferation, migration, and invasion in vitro , this study also demonstrated LINC01614 as a novel oncogenic lncRNA in PTC ( 13 ). The lncRNA PTCSC3-mediated glycolysis suppresses thyroid cancer progression via interfering with PGK1 degradation and may be a potential therapeutic target for PTC treatment ( 14 ).…”

Risk SNP‐mediated LINC01614 upregulation drives head and neck squamous cell carcinoma progression via PI3K/AKT signaling pathway

“…To date, plenty of evidence has corroborated the oncogenic role of LINC01614 in various types of cancers, including lung cancer, breast cancer, glioma, osteosarcoma, bladder cancer, thyroid carcinoma, and gastric cancer 36,37,62–65 . Recently, Wang et al's 39 study revealed that LINC01614 may be an oncogene and a credible diagnostic and prognostic biomarker for many cancers, including HNC.…”

“…Yan et al's 30 study illustrated that rs6695584 in LncSLCC1 changed the protein-binding motif of BATF, altered the enhancer activity, and subsequently activated LncSLCC1 expression. Therefore, the biological function of rs16854802 needs further research.To date, plenty of evidence has corroborated the oncogenic role of LINC01614 in various types of cancers, including lung cancer, breast cancer, glioma, osteosarcoma, bladder cancer, thyroid carcinoma, and gastric cancer 36,37,[62][63][64][65]. Recently, Wang et al's39 study revealed that LINC01614 may be an oncogene and a credible diagnostic and prognostic biomarker for many cancers, including HNC.…”

Papillary Thyroid Cancer Prognosis: An Evolving Field

“…Several experimental and clinical data suggest that other molecules may have a role in the prognostic stratification of TC patients. These include immune checkpoint factors and immune-related signature (IRS), estrogen receptors, Vitamin D, tumor angiogenic microenvironment, circular RNAs, long noncoding RNAs, and the angiotensin converting enzymes ACE and ACE2 [ 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 ]. However, all of them are awaiting validation in large case studies.…”