DICER1 RNase IIIb domain mutations trigger widespread miRNA dysregulation and MAPK activation in pediatric thyroid cancer.
DICER1 RNase IIIb domain mutations trigger widespread miRNA dysregulation and MAPK activation in pediatric thyroid cancer.
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DOI：
10.3389/fendo.2023.1083382
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发表时间：
2023
影响因子：
5.2
通讯作者：
中科院分区：
文献类型：
--
作者：
DICER1是一种高度保守的RNase III内切核酸酶，对于从茎环前体miRNAs生成单链成熟microRNAs(MiRNAs)是必不可少的。DICER1的RNase IIIb结构域的体细胞突变削弱了其产生成熟5P miRNAs的能力，并被认为是导致DICER1综合征相关和散发性甲状腺肿瘤的肿瘤发生的原因。然而，在甲状腺组织中，DICER1驱动的miRNAs的特异性变化和由此导致的基因表达的变化却知之甚少。在这项研究中，我们分析了20例非肿瘤性甲状腺癌、8例腺瘤性甲状腺癌和60例儿童甲状腺癌(13例滤泡性甲状腺癌和47例乳头状甲状腺癌)的miRNA(n=2,083)和m RNA(n=2,559)转录本，其中8例有DICER1 RNase IIIb突变。所有DICER1突变的分化型甲状腺癌(DTC)均为滤泡型，其中6例为滤泡型，2例为滤泡型，无一例发生淋巴结转移。我们证明DICER1致病体细胞突变与5P来源的miRNAs的全球减少有关，包括那些在非肿瘤性甲状腺组织中特别丰富的miRNAs，如let-7和mir-30家族，以其肿瘤抑制功能而闻名。在RNase IIIb突变的肿瘤中，3p miRNAs的表达也意外增加，可能与DICER1的表达增加有关。这些异常表达的3p miRNAs在DICER1-wt DTC和非肿瘤性甲状腺组织中低表达或缺失，构成了携带DICER1 RNase IIIb突变的甲状腺恶性肿瘤的特殊标记。MiRNA转录组的广泛紊乱导致了基因表达的变化，这表明细胞周期的正向调节。此外，差异表达的基因表明MAPK信号输出增加，甲状腺分化丧失，与PTC的RAS样亚组(由癌症基因组图谱创造)相当，这反映了这些肿瘤更懒惰的临床行为。
DICER1 is a highly conserved RNase III endoribonuclease essential for the biogenesis of single-stranded mature microRNAs (miRNAs) from stem-loop precursor miRNAs. Somatic mutations in the RNase IIIb domain of DICER1 impair its ability to generate mature 5p miRNAs and are believed to drive tumorigenesis in DICER1 syndrome-associated and sporadic thyroid tumors. However, the DICER1-driven specific changes in miRNAs and resulting changes in gene expression are poorly understood in thyroid tissue. In this study, we profiled the miRNA (n=2,083) and mRNA (n=2,559) transcriptomes of 20 non-neoplastic, 8 adenomatous and 60 pediatric thyroid cancers (13 follicular thyroid cancers [FTC] and 47 papillary thyroid cancers [PTC]) of which 8 had DICER1 RNase IIIb mutations. All DICER1-mutant differentiated thyroid cancers (DTC) were follicular patterned (six follicular variant PTC and two FTC), none had lymph node metastasis. We demonstrate that DICER1 pathogenic somatic mutations were associated with a global reduction of 5p-derived miRNAs, including those particularly abundant in the non-neoplastic thyroid tissue such as let-7 and mir-30 families, known for their tumor suppressor function. There was also an unexpected increase of 3p miRNAs, possibly associated with DICER1 mRNA expression increase in tumors harboring RNase IIIb mutations. These abnormally expressed 3p miRNAs, which are otherwise low or absent in DICER1-wt DTC and non-neoplastic thyroid tissues, make up exceptional markers for malignant thyroid tumors harboring DICER1 RNase IIIb mutations. The extensive disarray in the miRNA transcriptome results in gene expression changes, which were indicative of positive regulation of cell-cycle. Moreover, differentially expressed genes point to increased MAPK signaling output and loss of thyroid differentiation comparable to the RAS-like subgroup of PTC (as coined by The Cancer Genome Atlas), which is reflective of the more indolent clinical behavior of these tumors.
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影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
捕获microRNA结合的mRNA将肿瘤抑制器miR-34a识别为生长因子信号传导的调节剂。
影响因子：
4.5
作者：
Lal A;Thomas MP;Altschuler G;Navarro F;O'Day E;Li XL;Concepcion C;Han YC;Thiery J;Rajani DK;Deutsch A;Hofmann O;Ventura A;Hide W;Lieberman J
通讯作者：
Lieberman J
DOI：
10.1200/jco.21.01861
发表时间：
2022-04-01
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Franco AT;Ricarte-Filho JC;Isaza A;Jones Z;Jain N;Mostoufi-Moab S;Surrey L;Laetsch TW;Li MM;DeHart JC;Reichenberger E;Taylor D;Kazahaya K;Adzick NS;Bauer AJ
通讯作者：
Bauer AJ
影响因子：
7.3
作者：
Chen, Jiamin;Wang, Yemin;Huntsman, David G.
通讯作者：
Huntsman, David G.
影响因子：
64.8
作者：
Ghandi, Mahmoud;Huang, Franklin W.;Sellers, William R.
通讯作者：
Sellers, William R.