Estrogen-induced miR-196a elevation promotes tumor growth and metastasis via targeting SPRED1 in breast cancer.
Estrogen-induced miR-196a elevation promotes tumor growth and metastasis via targeting SPRED1 in breast cancer.
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雌激素诱导的 miR-196a 升高通过靶向乳腺癌中的 SPRED1 促进肿瘤生长和转移
DOI：
10.1186/s12943-018-0830-0
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发表时间：
2018-04-23
期刊：
影响因子：
37.3
通讯作者：
Jiang BH
中科院分区：
文献类型：
--
作者：
Jiang CF;Shi ZM;Li DM;Qian YC;Ren Y;Bai XM;Xie YX;Wang L;Ge X;Liu WT;Zhen LL;Liu LZ;Jiang BH
背景：destrogen通过雌激素受体（ER）介导的基因调控在乳腺癌（BC）进展中起关键作用。新的研究表明，BC细胞的恶性进展受microrna （mirna）和ER-α信号传导之间的串扰影响。然而，雌激素与mirna之间的机制和功能联系尚不清楚。方法采用qRT-PCR和GEO数据集检测miR-196a和SPRED1在46对BC及邻近组织中的表达水平。通过裸鼠CCK-8实验、创面愈合实验、Matrigel侵袭实验和致瘤性实验，检测miR-196a在雌激素诱导BC发生中的作用。采用ChIP-seq、ChIP法和荧光素酶报告基因法分析miR-196a启动子区ER-α的结合位点。通过荧光素酶报告基因检测和western blot分析探索miR-196a在BC细胞中的潜在靶点，并通过BC标本和GEO数据集中的Spearman相关分析分析miR-196a与SPRED1的相关性。采用TCGA BRCA数据根据MSigDB基因集对ESR1的特征进行表征。结果miR-196a在ER阳性（ER+）乳腺肿瘤中的表达水平高于ER阴性（ER-）肿瘤组织样本。此外，miR-196a还参与了雌激素诱导的BC细胞增殖、迁移和侵袭。值得注意的是，miR-196a的上调是通过与其启动子区域的雌激素受体α (ER-α)直接相互作用介导的，而不是雌激素受体β (ER-β)， miR-196a的表达水平与ER-α特征评分呈正相关。此外，SPRED1是miR-196a新的直接靶点，参与miR-196a促进BC的发展，并被配体激活的ER-α信号通路抑制。最后，强制表达miR-196a诱导MCF7细胞的肿瘤生长，而抑制miR-196a在体内显著抑制肿瘤进展。总之，雌激素/miR-196a/SPRED1级联的发现将揭示雌激素信号在BC发生和治疗中的新的分子机制。
BackgroundEstrogen plays a critical role in breast cancer (BC) progression through estrogen receptor (ER)-mediated gene regulation. Emerging studies suggest that the malignant progress of BC cells is influenced by the cross talk between microRNAs (miRNAs) and ER-α signaling. However, the mechanism and functional linkage between estrogen and miRNAs remain unclear.MethodsThe expression levels of miR-196a and SPRED1 in BC were tested by qRT-PCR in 46 paired BC and adjacent tissues and by the GEO datasets. The role of miR-196a in estrogen-induced BC development was examined by CCK-8 assay, wound healing assay, Matrigel invasion assay and tumorigenicity assay in nude mice. The binding site of ER-α in miR-196a promoter region was analyzed by ChIP-seq, ChIP assay and luciferase reporter assay. The potential targets of miR-196a in BC cells were explored using the luciferase reporter assay and western blot analysis, and the correlation between miR-196a and SPRED1 was analyzed by Spearman’s correlation analysis in BC specimens and GEO dataset. TCGA BRCA data was used to characterize the ESR1 signatures according to MSigDB gene set.ResultsThe expression levels of miR-196a were higher in ER-positive (ER+) breast tumors compared to ER-negative (ER-) tumor tissue samples. Besides, miR-196a was involved in estrogen-induced BC cell proliferation, migration and invasion. Notably, the up-regulation of miR-196a was mediated by a direct interaction with estrogen receptor α (ER-α) but not estrogen receptor β (ER-β) in its promoter region, and miR-196a expression levels were positively correlated to ER-α signature scores. Furthermore, SPRED1 was a new direct target of miR-196a which participated in miR-196a-promoted BC development and was suppressed by ligand-activated ER-α signal pathway. Finally, forced expression of miR-196a induced tumor growth of MCF7 cells, while inhibition of miR-196a significantly suppressed the tumor progress in vivo.ConclusionsOverall, the identification of estrogen/miR-196a/SPRED1 cascade will shed light on new molecular mechanism of estrogen signaling in BC development and therapy.
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影响因子：
14.9
作者：
Chen C;Ridzon DA;Broomer AJ;Zhou Z;Lee DH;Nguyen JT;Barbisin M;Xu NL;Mahuvakar VR;Andersen MR;Lao KQ;Livak KJ;Guegler KJ
通讯作者：
Guegler KJ
影响因子：
4.5
作者：
Di Leva G;Piovan C;Gasparini P;Ngankeu A;Taccioli C;Briskin D;Cheung DG;Bolon B;Anderlucci L;Alder H;Nuovo G;Li M;Iorio MV;Galasso M;Santhanam R;Marcucci G;Perrotti D;Powell KA;Bratasz A;Garofalo M;Nephew KP;Croce CM
通讯作者：
Croce CM
癌症中的microRNA生物发生途径。
DOI：
10.1038/nrc3932
发表时间：
2015-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Lin S;Gregory RI
通讯作者：
Gregory RI
SPRSED-1负调节过敏原诱导的气道嗜酸性粒细胞和反应性过高。
影响因子：
15.3
作者：
Inoue, H;Kato, R;Fukuyama, S;Nonami, A;Taniguchi, KI;Matsunmoto, K;Nakano, T;Tsuda, M;Matsumura, M;Kubo, M;Ishikawa, F;Moon, BG;Takatsu, K;Nakanishi, Y;Yoshimura, A
通讯作者：
Yoshimura, A
影响因子：
14.9
作者：
Bhat-Nakshatri P;Wang G;Collins NR;Thomson MJ;Geistlinger TR;Carroll JS;Brown M;Hammond S;Srour EF;Liu Y;Nakshatri H
通讯作者：
Nakshatri H