miRNA-1246 induces pro-inflammatory responses in mesenchymal stem/stromal cells by regulating PKA and PP2A.
miRNA-1246 induces pro-inflammatory responses in mesenchymal stem/stromal cells by regulating PKA and PP2A.
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DOI：
10.18632/oncotarget.14915
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发表时间：
2017-07-04
期刊：
影响因子：
--
通讯作者：
Wiemann S
中科院分区：
文献类型：
--
作者：
Bott A;Erdem N;Lerrer S;Hotz-Wagenblatt A;Breunig C;Abnaof K;Wörner A;Wilhelm H;Münstermann E;Ben-Baruch A;Wiemann S
肿瘤微环境（TME）通过在肿瘤内创造促炎环境对乳腺癌的进展有影响。然而，在这一过程中，关于mirna在TME细胞中的作用知之甚少。我们在乳腺癌数据集中确定了6个假定的肿瘤，它们都与较差的总体患者生存率密切相关。在六个候选物中，miR-1246在侵袭性乳腺癌亚型中上调，并在间充质干细胞/基质细胞（MSCs）中表达最高水平。在功能上，miR-1246导致MSCs中促炎介质IL-6、CCL2和CCL5的转录和释放的p65依赖性增加，并增加NF-κB活性。MSCs中miR-1246的促炎表型独立于TNFα刺激，并通过直接靶向肿瘤抑制因子PRKAR1A和PPP2CB介导。体外重现的TME显示，在条件培养基（CM）中培养过表达miR-1246的MSCs后，乳腺上皮细胞（MCF10A）和癌细胞（SK-BR-3, MCF7, T47D）中Stat3磷酸化增加。此外，这种刺激增强了MCF10A细胞的增殖，增加了MDA-MB-231细胞的迁移，并诱导了THP-1单核细胞的吸引力。我们的数据显示，miR-1246在乳腺癌中既是MSCs中促炎反应的关键增强子，也是假定的oncomiR，这表明它对癌症相关炎症和乳腺癌进展有影响。
The tumor microenvironment (TME) has an impact on breast cancer progression by creating a pro-inflammatory milieu within the tumor. However, little is known about the roles of miRNAs in cells of the TME during this process. We identified six putative oncomiRs in a breast cancer dataset, all strongly correlating with poor overall patient survival. Out of the six candidates, miR-1246 was upregulated in aggressive breast cancer subtypes and expressed at highest levels in mesenchymal stem/stroma cells (MSCs). Functionally, miR-1246 led to a p65-dependent increase in transcription and release of pro-inflammatory mediators IL-6, CCL2 and CCL5 in MSCs, and increased NF-κB activity. The pro-inflammatory phenotype of miR-1246 in MSCs was independent of TNFα stimulations and mediated by direct targeting of the tumor-suppressors PRKAR1A and PPP2CB. In vitro recapitulation of the TME revealed increased Stat3 phosphorylation in breast epithelial (MCF10A) and cancer cells (SK-BR-3, MCF7, T47D) upon incubation with conditioned medium (CM) of MSCs overexpressing miR-1246. Additionally, this stimulation enhanced proliferation of MCF10A cells, increased migration of MDA-MB-231 cells and induced attraction of THP-1 monocytic cells. Our data shows that miR-1246 acts as both key-enhancer of pro-inflammatory responses in MSCs and putative oncomiR in breast cancer, suggesting its influence on cancer-related inflammation and breast cancer progression.
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DOI：
10.1186/bcr1680
发表时间：
2007
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Berishaj M;Gao SP;Ahmed S;Leslie K;Al-Ahmadie H;Gerald WL;Bornmann W;Bromberg JF
通讯作者：
Bromberg JF
影响因子：
16
作者：
Firulli, BA;Howard, MJ;Firulli, AB
通讯作者：
Firulli, AB
DOI：
10.1016/j.bbrc.2013.05.129
发表时间：
2013-07-05
影响因子：
3.1
作者：
Choi, Hyo-Kyung;Park, Soo-Yeon;Yoon, Ho-Geun
通讯作者：
Yoon, Ho-Geun
影响因子：
5.2
作者：
Clark, Elizabeth A.;Kalomoiris, Stefanos;Nolta, Jan A.;Fierro, Fernando A.
通讯作者：
Fierro, Fernando A.
MiR-1246通过抑制靶基因血小板反应蛋白2促进SiHa宫颈癌细胞增殖、侵袭和迁移
影响因子：
2.6
作者：
Chen, Junying;Yao, Desheng;Long, Fengyi
通讯作者：
Long, Fengyi