Transcription start site-level expression of thyroid transcription factor 1 isoforms in lung adenocarcinoma and its clinicopathological significance.
Transcription start site-level expression of thyroid transcription factor 1 isoforms in lung adenocarcinoma and its clinicopathological significance.
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DOI：
10.1002/cjp2.213
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Saito T
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文献类型：
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作者：
Sano K;Hayashi T;Suehara Y;Hosoya M;Takamochi K;Kohsaka S;Kishikawa S;Kishi M;Saito S;Takahashi F;Kaneko K;Suzuki K;Yao T;Ishijima M;Saito T
有多个转录起始位点（tss）与编码NKX2‐1/TTF‐1（甲状腺转录因子1）不同亚型的多个转录变体一致；然而，NKX2‐1/TTF‐1各转录异构体在肺腺癌（LAD）中的临床病理意义尚不清楚。本文利用基因表达帽分析（CAGE）测序数据的生物信息学分析，评估了71个lad中NKX2‐1/TTF‐1亚型的TSS水平表达，该数据提供了5′‐非翻译区和不同亚型TSS的全基因组表达水平。通过原位杂交进一步验证了CAGE的结果。NKX2‐1/TTF‐1中17个TSSs中的14个（占哺乳动物启动子图谱FANTOM5中已知TSSs的80%）在LADs中被鉴定，包括TSSs 1 - 13和15；NKX2‐1/TTF‐1转录本的四种亚型（NKX2‐1_001、NKX2‐1_002、NKX2‐1_004和NKX2‐1_005）在LADs中表达，尽管NKX2‐1_005不含同源域。其中，6个TSSs调控NKX2‐1_004和NKX2‐1_005，这两个基因都含有外显子1。在CAGE数据集中，TSS 11区调节外显子1的亚型低表达的lad与预后不良显著相关。在验证集中，62例肿瘤（9.3%）未显示NKX2‐1/TTF‐1外显子1的表达；这类肿瘤与年龄、EGFR野生型肿瘤和不良预后显著相关。相比之下，94例肿瘤，包括30例肺浸润性粘液腺癌（IMAs）中的22例，显示外显子1表达，而不表达免疫组织化学TTF‐1蛋白。此外，与EGFR突变的LADs相比，ima通常表现出更高的外显子1表达，而外显子4/5含有同源结构域。这些转录组和临床病理结果表明，LAD使用至少80%的NKX2‐1 tss，并且不含外显子1的NKX2‐1/TTF‐1转录异型（NKX2‐1_004和NKX2‐1_005）的表达定义了LAD的一个独特亚群，其特征是老年患者的攻击行为。此外，调节NKX2‐1_005的替代tss区域可能出现在LADs亚群中。
There are multiple transcription start sites (TSSs) in agreement with multiple transcript variants encoding different isoforms of NKX2‐1/TTF‐1 (thyroid transcription factor 1); however, the clinicopathological significance of each transcript isoform of NKX2‐1/TTF‐1 in lung adenocarcinoma (LAD) is unknown. Herein, TSS‐level expression of NKX2‐1/TTF‐1 isoforms was evaluated in 71 LADs using bioinformatic analysis of cap analysis of gene expression (CAGE)‐sequencing data, which provides genome‐wide expression levels of the 5′‐untranslated regions and the TSSs of different isoforms. Results of CAGE were further validated in 664 LADs using in situ hybridisation. Fourteen of 17 TSSs in NKX2‐1/TTF‐1 (80% of known TSSs in FANTOM5, an atlas of mammalian promoters) were identified in LADs, including TSSs 1–13 and 15; four isoforms of NKX2‐1/TTF‐1 transcripts (NKX2‐1_001, NKX2‐1_002, NKX2‐1_004, and NKX2‐1_005) were expressed in LADs, although NKX2‐1_005 did not contain a homeodomain. Among those, six TSSs regulated NKX2‐1_004 and NKX2‐1_005, both of which contain exon 1. LADs with low expression of isoforms from TSS region 11 regulating exon 1 were significantly associated with poor prognosis in the CAGE data set. In the validation set, 62 tumours (9.3%) showed no expression of NKX2‐1/TTF‐1 exon 1; such tumours were significantly associated with older age, EGFR wild‐type tumours, and poor prognosis. In contrast, 94 tumours, including 22 of 30 pulmonary invasive mucinous adenocarcinomas (IMAs) exhibited exon 1 expression without immunohistochemical TTF‐1 protein expression. Furthermore, IMAs commonly exhibited higher exon 1 expression relative to that of exon 4/5, which contained a homeodomain in comparison with EGFR‐mutated LADs. These transcriptome and clinicopathological results reveal that LAD use at least 80% of NKX2‐1 TSSs and expression of the NKX2‐1/TTF‐1 transcript isoform without exon 1 (NKX2‐1_004 and NKX2‐1_005) defines a distinct subset of LAD characterised by aggressive behaviour in elder patients. Moreover, usage of alternative TSSs regions regulating NKX2‐1_005 may occur in subsets of LADs.
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DOI：
10.1158/1078-0432.ccr-17-2343
发表时间：
2018-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
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作者：
Hayashi T;Desmeules P;Smith RS;Drilon A;Somwar R;Ladanyi M
通讯作者：
Ladanyi M
DOI：
10.1007/978-1-4939-0805-9_7
发表时间：
2014-01-01
期刊：
TRANSCRIPTION FACTOR REGULATORY NETWORKS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Murata, Mitsuyoshi;Nishiyori-Sueki, Hiromi;Itoh, Masayoshi
通讯作者：
Itoh, Masayoshi
影响因子：
20.4
作者：
Hwang, David H.;Sholl, Lynette M.;Dong, Fei
通讯作者：
Dong, Fei
DOI：
10.1038/s41580-020-00315-9
发表时间：
2021-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Statello L;Guo CJ;Chen LL;Huarte M
通讯作者：
Huarte M
影响因子：
4.5
作者：
Mullen DJ;Yan C;Kang DS;Zhou B;Borok Z;Marconett CN;Farnham PJ;Offringa IA;Rhie SK
通讯作者：
Rhie SK