Ma Ben, Luo Yi, Xu Weibo, Han Litao, Liu Wanlin, Liao Tian, Yang Yichen, Wang Yu
Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, People's Republic of China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China.
Endocrinology. 2023 Feb 11;164(4). doi: 10.1210/endocr/bqac204.
Anaplastic thyroid cancer (ATC) is the most aggressive type of thyroid cancer. This study aimed to identify specific long noncoding RNAs (lncRNAs) associated with ATC, and further investigated their biological functions and molecular mechanism underlying regulation of malignancy in ATC. We searched for lncRNAs associated with dedifferentiation and screened out specific lncRNAs significantly deregulated in ATC by using transcriptome data of dedifferentiation cancers from Fudan University Shanghai Cancer Center (FUSCC) and the Gene Expression Omnibus (GEO) database. The above lncRNAs were analyzed to identify a potential biomarker in thyroid cancer patients from the FUSCC, GEO, and The Cancer Genome Atlas, which was then investigated for its functional roles and molecular mechanism in ATC in vitro. The clinicopathological association analyses revealed that LINC00886 expression was significantly correlated with dedifferentiation and suppressed in ATC. In vitro, LINC00886 was confirmed to negatively regulate cell proliferation, and cell migration and invasion of ATC. LINC00886 physically interacted with protein kinase R (PKR) and affected its stability through the ubiquitin/proteasome-dependent degradation pathway in the ATC cell. Decreased PKR caused by downregulation of LINC00886 enhanced the activity of eukaryotic initiation factor 2α (eIF2α) via reducing phosphorylation of eIF2α and thus promoted protein synthesis to maintain ATC malignancy. Our findings identify LINC00886 as a novel biomarker of thyroid cancer and suggest that LINC00886/PKR/eIF2α signaling is a potential therapeutic target in ATC.
间变性甲状腺癌（ATC）是最具侵袭性的甲状腺癌类型。本研究旨在鉴定与ATC相关的特定长链非编码RNA（lncRNA），并进一步研究其生物学功能以及ATC恶性肿瘤调控的分子机制。我们利用复旦大学附属肿瘤医院（FUSCC）的去分化癌症转录组数据和基因表达综合数据库（GEO），搜索与去分化相关的lncRNA，并筛选出在ATC中显著失调的特定lncRNA。对上述lncRNA进行分析，以鉴定FUSCC、GEO和癌症基因组图谱中甲状腺癌患者的潜在生物标志物，然后在体外研究其在ATC中的功能作用和分子机制。临床病理关联分析显示，LINC00886表达与去分化显著相关，且在ATC中受到抑制。在体外，LINC00886被证实对ATC的细胞增殖、迁移和侵袭具有负调控作用。LINC00886与蛋白激酶R（PKR）发生物理相互作用，并通过泛素/蛋白酶体依赖性降解途径影响其稳定性。LINC00886下调导致PKR减少，通过降低真核起始因子2α（eIF2α）的磷酸化增强其活性，从而促进蛋白质合成以维持ATC的恶性程度。我们的研究结果确定LINC00886为甲状腺癌的一种新型生物标志物，并表明LINC00886/PKR/eIF2α信号通路是ATC的一个潜在治疗靶点。
