JAK2-binding long noncoding RNA promotes breast cancer brain metastasis
JAK2-binding long noncoding RNA promotes breast cancer brain metastasis
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JAK2结合长非编码RNA促进乳腺癌脑转移
DOI：
10.1172/jci91553
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发表时间：
2017-12-01
影响因子：
15.9
通讯作者：
Lin, Chunru
中科院分区：
文献类型：
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作者：
Wang, Shouyu;Liang, Ke;Lin, Chunru
乳腺癌脑转移瘤（BCBMs）的常规治疗由于化疗耐药性和血脑屏障的不可渗透性而在很大程度上无效。全面了解乳腺癌细胞浸润大脑的潜在机制对于规避BCBM的治疗抗性是必要的。在这里，我们确定了一个长的非编码RNA（lncRNA），我们已经命名为lncRNA与BCBM（lnc-BM）的表达是乳腺癌患者脑转移进展的预后。在临床前小鼠模型中，Lnc-BM表达升高驱动了BCBM，而用纳米颗粒包裹的SiRNA消除Lnc-BM有效地治疗了BCBM。Lnc-BM增加JAK 2激酶活性以介导制瘤素M和IL-6触发的STAT 3磷酸化。在乳腺癌细胞中，Lnc-BM促进ICAM 1和CCL 2的STAT 3依赖性表达，其分别介导脑中巨噬细胞的血管共选择和募集。募集的巨噬细胞反过来产生制瘤素M和IL-6，从而进一步激活Lnc-BM/JAK 2/STAT 3途径并增强BCBM。总的来说，我们的研究结果表明，Lnc-BM和JAK 2通过介导乳腺癌细胞和大脑微环境之间的通信来促进BCBMs。此外，这些结果表明靶向Lnc-BM是对抗这种困难疾病的潜在策略。
Conventional therapies for breast cancer brain metastases (BCBMs) have been largely ineffective because of chemoresistance and impermeability of the blood-brain barrier. A comprehensive understanding of the underlying mechanism that allows breast cancer cells to infiltrate the brain is necessary to circumvent treatment resistance of BCBMs. Here, we determined that expression of a long noncoding RNA (lncRNA) that we have named lncRNA associated with BCBM (Lnc-BM) is prognostic of the progression of brain metastasis in breast cancer patients. In preclinical murine models, elevated Lnc-BM expression drove BCBM, while depletion of Lnc-BM with nanoparticle-encapsulated siRNAs effectively treated BCBM. Lnc-BM increased JAK2 kinase activity to mediate oncostatin M– and IL-6–triggered STAT3 phosphorylation. In breast cancer cells, Lnc-BM promoted STAT3-dependent expression of ICAM1 and CCL2, which mediated vascular co-option and recruitment of macrophages in the brain, respectively. Recruited macrophages in turn produced oncostatin M and IL-6, thereby further activating the Lnc-BM/JAK2/STAT3 pathway and enhancing BCBM. Collectively, our results show that Lnc-BM and JAK2 promote BCBMs by mediating communication between breast cancer cells and the brain microenvironment. Moreover, these results suggest targeting Lnc-BM as a potential strategy for fighting this difficult disease.