Oncogenic Properties of the Antisense lncRNA COMET in BRAF- and RET-Driven Papillary Thyroid Carcinomas

被引:22
作者
Esposito, Roberta [1 ,5 ,6 ]
Esposito, Daniela [1 ]
Pallante, Pierlorenzo [2 ]
Fusco, Alfredo [2 ,3 ]
Ciccodicola, Alfredo [1 ,4 ]
Costa, Valerio [1 ]
机构
[1] CNR, Inst Genet & Biophys Adriano Buzzati Traverso, Naples, Italy
[2] CNR, Inst Expt Endocrinol & Oncol IEOS, Naples, Italy
[3] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, Naples, Italy
[4] Univ Naples Parthenope, Dept Sci & Technol, Naples, Italy
[5] Univ Bern, Bern Univ Hosp, Inselspital, Dept Med Oncol, Bern, Switzerland
[6] Univ Bern, Bern Univ Hosp, Inselspital, Dept Biomed Res, Bern, Switzerland
关键词
CANCER; TRANSCRIPTION; GENE; INHIBITION; EXPRESSION; LANDSCAPE; IDENTIFICATION;
D O I
10.1158/0008-5472.CAN-18-2520
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
RET rearrangements as well as BRAF and RAS mutations drive differential pathway activation in papillary thyroid carcinomas, leading to different tumor phenotypes and prognoses. Although The Cancer Genome Atlas Consortium has identified tumor subgroups based on protein-coding gene signatures, neither expression of long noncoding RNAs (lncRNA) nor their correlation with specific tumor-driving mutations and rearrangements have been systematically assessed. Here, we reanalyzed our RNA-sequencing data using a de novo discovery approach to identify lncRNAs and define tumor subtype-specific signatures of annotated lncRNAs. Among them, we identified COMET (Correlated-to-MET), a natural antisense transcript that was highly expressed in carcinomas harboring BRAF(V600E) mutation or RET gene rearrangements (i.e., BRAF-like tumors) and induced the downstream MAPK pathway. In papillary thyroid carcinomas, COMET was part of a coexpression network including different oncogenes belonging to the MAPK pathway, and its expression highly correlated with MET expression. Depletion of COMET resulted in reduced expression of genes within this network, including the MET oncogene. COMET repression inhibited viability and proliferation of tumor cells harboring BRAF(V600E) somatic mutation or RET oncogene rearrangement and dramatically reduced motility and invasiveness of tumor cells. Moreover, silencing COMET markedly increased sensitivity to vemurafenib, a common inhibitor of mutated B-raf. Collectively, our results suggest COMET as a new target to improve drug-based cancer therapies, especially in BRAF-mutated and MET addicted papillary thyroid carcinomas.
引用
收藏
页码:2124 / 2135
页数:12
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