Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14470-5. doi: 10.1073/pnas.1212811109. Epub 2012 Aug 20.
Cancer stem-like cells (CSCs) are a highly tumorigenic cell type present as a minority population in developmentally diverse tumors and cell lines. Using a genetic screen in an inducible model of CSC formation in a breast cell line, we identify microRNAs (miRNAs) that inhibit CSC growth and are down-regulated in CSCs. Aside from the previously identified miR-200 family, these include the miR-15/16 (miR-16, miR-15b) and miR-103/107 (miR-103, miR-107) families as well as miR-145, miR-335, and miR-128b. Interestingly, these miRNAs affect common target genes that encode the Bmi1 and Suz12 components of the polycomb repressor complexes as well as the DNA-binding transcription factors Zeb1, Zeb2, and Klf4. Conversely, expression of the CSC-modulating miRNAs is inhibited by Zeb1 and Zeb2. There is an inverse relationship between the levels of CSC-regulating miRNAs and their respective targets in samples from triple-negative breast cancer patients, providing evidence for the relevance of these interactions in human cancer. In addition, combinatorial overexpression of these miRNAs progressively attenuates the growth of CSCs derived from triple-negative breast cancers. These observations suggest that CSC formation and function are reinforced by an integrated regulatory circuit of miRNAs, transcription factors, and chromatin-modifying activities that can act as a bistable switch to drive cells into either the CSC or the nonstem state within the population of cancer cells.
癌症干细胞样细胞 (CSCs) 是一种高度致瘤性的细胞类型，作为少数群体存在于发育多样化的肿瘤和细胞系中。我们在诱导型乳腺癌细胞系 CSC 形成模型中使用遗传筛选，鉴定了抑制 CSC 生长且在 CSCs 中下调的 microRNAs (miRNAs)。除了先前鉴定的 miR-200 家族外，这些 miRNA 还包括 miR-15/16 (miR-16、miR-15b) 和 miR-103/107 (miR-103、miR-107) 家族以及 miR-145、miR-335 和 miR-128b。有趣的是，这些 miRNAs 影响常见的靶基因，这些靶基因编码多梳抑制复合物的 Bmi1 和 Suz12 成分以及 DNA 结合转录因子 Zeb1、Zeb2 和 Klf4。相反，CSC 调节 miRNA 的表达受 Zeb1 和 Zeb2 的抑制。三阴性乳腺癌患者样本中 CSC 调节 miRNA 的水平与其各自靶基因之间存在负相关关系，为这些相互作用在人类癌症中的相关性提供了证据。此外，这些 miRNA 的组合过表达逐渐减弱了源自三阴性乳腺癌的 CSCs 的生长。这些观察结果表明，CSC 的形成和功能是由 miRNA、转录因子和染色质修饰活性的综合调控回路加强的，该回路可以作为双稳态开关，将细胞驱动到癌细胞群体中的 CSC 或非干细胞状态。
