Abstract
Accumulating evidence indicates that a sub-population of cancer cells with stem-like properties, termed tumor-initiating cells (T-ICs), exist in many different kinds of malignancies, which have a pivotal role in tumorigenesis, tumor progression, metastasis and post-treatment relapse. However, how the stem-like properties of T-ICs are regulated remains obscure. Our previous study showed that reduction of let-7 microRNA (miRNA) in breast tumor-initiating cells (BT-ICs) contributes to the maintenance of their self-renewal capacity and undifferentiated status. In this study we show the effect of mir-30 reduction on the stem-like features of BT-ICs. Similar to let-7, mir-30 is reduced in BT-ICs, and the protein level of Ubc9 (ubiquitin-conjugating enzyme 9) and ITGB3 (integrin β3), the target genes of mir-30, is markedly upregulated. Enforced constitutive expression of mir-30 in BT-ICs inhibits their self-renewal capacity by reducing Ubc9, and induces apoptosis through silencing ITGB3. On the contrary, blocking the miRNA with a specific antisense oligonucleotide (ASO) in differentiated breast cancer cells revived their self-renewal capacity. Furthermore, ectopic expression of mir-30 in BT-IC xenografts reduces tumorigenesis and lung metastasis in nonobese diabetic/severe combined immunodeficient mice, whereas blocking mir-30 expression enhances tumorigenesis and metastasis. Together, our data suggest mir-30 as one of the important miRNAs in regulating the stem-like features of T-ICs.
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Acknowledgements
This work was supported by the Natural Science Foundation of China Grant (30921140312, 30830110, 30772550, 30973396, 30525022, 30671930, 30973505), 973 (2010CB912800, 2009CB521706, 2005CB724605) Projects from the Ministry of Science and Technology of China, and Natural Science Foundation of Guangdong Province (8251008901000011).
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Yu, F., Deng, H., Yao, H. et al. Mir-30 reduction maintains self-renewal and inhibits apoptosis in breast tumor-initiating cells. Oncogene 29, 4194–4204 (2010). https://doi.org/10.1038/onc.2010.167
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DOI: https://doi.org/10.1038/onc.2010.167
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