TGF-β upregulates miR-181a expression to promote breast cancer metastasis
TGF-β upregulates miR-181a expression to promote breast cancer metastasis
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DOI：
10.1172/jci64946
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发表时间：
2013-01-01
影响因子：
15.9
通讯作者：
Schiemann, William P.
中科院分区：
文献类型：
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作者：
Taylor, Molly A.;Sossey-Alaoui, Khalid;Schiemann, William P.
晚期乳腺癌转移是由TGF-β信号失调驱动的，但其潜在的分子机制尚未完全阐明。我们试图通过使用生物力学顺应性或刚性3D器官型培养物来概括肿瘤和转移性微环境，并将其与全局microRNA（miR）谱分析相结合，以鉴定TGF-β在转移性乳腺癌细胞中上调的miR。在此，我们将miR-18 Ia确定为TGF-β调节的“转移因子”，其通过促进上皮-间充质转化、迁移和侵袭表型来增强乳腺癌的转移潜力。从机制上讲，miR-181 a的失活提高了促凋亡分子Bim的表达，Bim使转移性细胞对失巢凋亡敏感。沿着这些路线，miR-181 a表达在驱动小鼠肺微转移生长和增强晚期乳腺肿瘤的致死率方面是必不可少的。最后，miR-181 a表达在转移性乳腺肿瘤中显著且选择性地上调，特别是三阴性乳腺癌，并且高度预测人类乳腺癌患者的总生存期降低。总的来说，我们的研究结果强烈暗示miR-181 a是乳腺癌转移和患者生存的预测生物标志物，因此，作为转移性乳腺癌的潜在治疗靶点。
Late-stage breast cancer metastasis is driven by dysregulated TGF-beta signaling, but the underlying molecular mechanisms have not been fully elucidated. We attempted to recapitulate tumor and metastatic micro-environments via the use of biomechanically compliant or rigid 3D organotypic cultures and combined them with global microRNA (miR) profiling analyses to identify miRs that were upregulated in metastatic breast cancer cells by TGF-beta. Here we establish miR-18 la as a TGF-beta-regulated "metastamir" that enhanced the metastatic potential of breast cancers by promoting epithelial-mesenchymal transition, migratory, and invasive phenotypes. Mechanistically, inactivation of miR-181a elevated the expression of the proapoptotic molecule Bim, which sensitized metastatic cells to anoikis. Along these lines, miR-181a expression was essential in driving pulmonary micrometastatic outgrowth and enhancing the lethality of late-stage mammary tumors in mice. Finally, miR-181a expression was dramatically and selectively upregulated in metastatic breast tumors, particularly triple-negative breast cancers, and was highly predictive for decreased overall survival in human breast cancer patients. Collectively, our findings strongly implicate miR-181a as a predictive biomarker for breast cancer metastasis and patient survival, and consequently, as a potential therapeutic target in metastatic breast cancer.