ESR1-Stabilizing Long Noncoding RNA TMPO-AS1 Promotes Hormone-Refractory Breast Cancer Progression
ESR1-Stabilizing Long Noncoding RNA TMPO-AS1 Promotes Hormone-Refractory Breast Cancer Progression
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DOI：
10.1128/mcb.00261-19
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发表时间：
2019-12-01
影响因子：
5.3
通讯作者：
Inoue, Satoshi
中科院分区：
文献类型：
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作者：
Mitobe, Yuichi;Ikeda, Kazuhiro;Inoue, Satoshi
获得性内分泌治疗耐药是乳腺癌患者的一个重要临床问题。近年来，长链非编码RNA（lncRNA）作为肿瘤进展的重要调控因子受到越来越多的关注。基于癌症基因组图谱数据库中乳腺浸润性癌的RNA测序数据，我们将胸腺生成素反义转录物1（TMPO-AS 1）鉴定为与增殖生物标志物显著相关的功能性lncRNA。原位杂交分析TMPO-AS 1阳性与乳腺癌患者预后不良显著相关。与亲代细胞相比，内分泌治疗耐药的MCF-7细胞中TMPO-AS 1表达上调，并且是雌激素诱导的。TMPO-AS 1的获得和丧失实验表明，TMPO-AS 1在体外和体内促进雌激素受体（ER）阳性乳腺癌细胞的增殖和活力。使用微阵列的全球表达分析表明，TMPO-AS 1与雌激素信号通路密切相关。TMPO-AS 1通过与雌激素受体1（ESR 1）mRNA相互作用，稳定ESR 1 mRNA的表达，从而正向调节ESR 1 mRNA的表达。TMPO-AS 1增强ESR 1 mRNA的表达可能在ER阳性乳腺癌的增殖中起重要作用。我们的研究结果为理解乳腺癌进展和内分泌抵抗的分子机制提供了新的见解。
Acquired endocrine therapy resistance is a significant clinical problem for breast cancer patients. In recent years, increasing attention has been paid to long noncoding RNA (lncRNA) as a critical modulator for cancer progression. Based on RNA-sequencing data of breast invasive carcinomas in The Cancer Genome Atlas database, we identified thymopoietin antisense transcript 1 (TMPO-AS1) as a functional lncRNA that significantly correlates with proliferative biomarkers. TMPO-AS1 positivity analyzed by in situ hybridization significantly correlates with poor prognosis of breast cancer patients. TMPO-AS1 expression was upregulated in endocrine therapy-resistant MCF-7 cells compared with levels in parental cells and was estrogen inducible. Gain and loss of TMPO-AS1 experiments showed that TMPO-AS1 promotes the proliferation and viability of estrogen receptor (ER)-positive breast cancer cells in vitro and in vivo. Global expression analysis using a microarray demonstrated that TMPO-AS1 is closely associated with the estrogen signaling pathway. TMPO-AS1 could positively regulate estrogen receptor 1 (ESR1) mRNA expression by stabilizing ESR1 mRNA through interaction with ESR1 mRNA. Enhanced expression of ESR1 mRNA by TMPO-AS1 could play a critical role in the proliferation of ER-positive breast cancer. Our findings provide a new insight into the understanding of molecular mechanisms underlying hormone-dependent breast cancer progression and endocrine resistance.