Mir-30 reduction maintains self-renewal and inhibits apoptosis in breast tumor-initiating cells.
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 beta3), 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.
Yu
F
F
Department of Breast Surgery, Sun-Yat-Sen Memorial Hospital, Sun-Yat-Sen University, Guangzhou, PR China.
Deng
H
H
Yao
H
H
Liu
Q
Q
Su
F
F
Song
E
E
D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology*; D051927:CD24 Antigen / Q000032:analysis; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D039661:Integrin beta3 / Q000235:genetics / Q000502:physiology; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000502:physiology; D000098843:Ubiquitin-Conjugating Enzyme UBC9
D051927:CD24 Antigen; C497889:CD24 protein, human; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; C061248:ITGB3 protein, human; D039661:Integrin beta3; C546086:MIRN30b microRNA, human; D035683:MicroRNAs; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9