Normal and cancerous mammary stem cells evade interferon-induced constraint through the miR-199a-LCOR axis.
Normal and cancerous mammary stem cells evade interferon-induced constraint through the miR-199a-LCOR axis.
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DOI：
10.1038/ncb3533
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发表时间：
2017-06
影响因子：
21.3
通讯作者：
Kang Y
中科院分区：
文献类型：
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作者：
Celià-Terrassa T;Liu DD;Choudhury A;Hang X;Wei Y;Zamalloa J;Alfaro-Aco R;Chakrabarti R;Jiang YZ;Koh BI;Smith HA;DeCoste C;Li JJ;Shao ZM;Kang Y
肿瘤起始细胞（TIC）或癌症干细胞（CSC）具有在正常成体组织干细胞中观察到的干细胞样性质。因此，正常干细胞和癌性干细胞可能共享维持自我更新能力和抵抗由细胞内在或微环境线索引起的分化的调节机制。在这里，我们发现miR-199 a通过直接抑制核受体辅阻遏物LCOR促进乳腺干细胞（MaSCs）和乳腺CSC中的干细胞特性，LCOR引发干扰素（IFN）反应。在干细胞富集群体中升高的miR-199 a表达保护正常和恶性干细胞样细胞免于由乳腺中的上皮细胞和免疫细胞产生的IFN诱导的分化和衰老。重要的是，miR-199 a-LCOR-IFN轴在低分化的ER-乳腺肿瘤中被激活，在功能上促进肿瘤的发生和转移，并与不良的临床结局相关。因此，我们的研究揭示了正常和恶性干细胞共享的共同机制，以保护它们免受抑制性免疫细胞因子信号传导的影响。
Tumor-initiating cells (TICs), or cancer stem cells (CSC), possess stem cell-like properties observed in normal adult tissue stem cells. Normal and cancerous stem cells may therefore share regulatory mechanisms for maintaining self-renewing capacity and resisting differentiation elicited by cell-intrinsic or microenvironmental cues. Here, we show that miR-199a promotes stem cell properties in mammary stem cells (MaSCs) and breast CSCs by directly repressing nuclear receptor corepressor LCOR, which primes interferon (IFN) responses. Elevated miR-199a expression in stem cell-enriched populations protects normal and malignant stem-like cells from differentiation and senescence induced by IFNs that are produced by epithelial and immune cells in the mammary gland. Importantly, the miR-199a-LCOR-IFN axis is activated in poorly differentiated ER− breast tumors, functionally promotes tumor initiation and metastasis, and is associated with poor clinical outcome. Our study therefore reveals a common mechanism shared by normal and malignant stem cells to protect them from suppressive immune cytokine signaling.