let-7 Regulates Self Renewal and Tumorigenicity of Breast Cancer Cells

Abstract

Cancers may arise from rare self-renewing tumor-initiating cells (T-IC). However, how T-IC self renewal, multipotent differentiation, and tumorigenicity are maintained remains obscure. Because miRNAs can regulate cell-fate decisions, we compared miRNA expression in self-renewing and differentiated cells from breast cancer lines and in breast T-IC (BT-IC) and non-BT-IC from 1 degrees breast cancers. let-7 miRNAs were markedly reduced in BT-IC and increased with differentiation. Infecting BT-IC with let-7-lentivirus reduced proliferation, mammosphere formation, and the proportion of undifferentiated cells in vitro and tumor formation and metastasis in NOD/SCID mice, while antagonizing let-7 by antisense oligonucleotides enhanced in vitro self renewal of non-T-IC. Increased let-7 paralleled reduced H-RAS and HMGA2, known let-7 targets. Silencing H-RAS in a BT-IC-enriched cell line reduced self renewal but had no effect on differentiation, while silencing HMGA2 enhanced differentiation but did not affect self renewal. Therefore let-7 regulates multiple BT-IC stem cell-like properties by silencing more than one target.

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

“…Of the four most effective miRNAs identified, let-7c and miR200b belong to the let-7 and miRNA-200s families, respectively, of which the tumour-suppressor roles in TICs have been well appreciated 8,23,46 , while miR-222 and miR-424 were first identified as TIC-suppressing miRNAs despite a tumoursuppressor role of both miRNAs has been identified in a number of cancers other than HCC [47][48][49][50] . Paradoxically, miR-222 was previously regarded as oncogene in some reports because it could enhance some tumour cell growth by targeting CDK inhibitor p27 in vitro, and was found to be upregulated in HCC and some other types of cancers 42,51,52 ; however, its tumourpromoting role was rarely validated in vivo.…”

“…In fact, aberrant expression of miRNAs such as let-7, miR-34a, miR-181a, miRNA-130b in TICs has been found in a variety of tumour types. These aberrantly expressed miRNAs play essential roles in the regulation of TIC properties as either TIC suppressors or promoters [20][21][22][23][24] . Moreover, a series of critical signalling pathways involved in the regulation of TIC properties have been uncovered with the identification of the targets of these miRNAs 19,[25][26][27][28] .…”

Rod‐Shaped Active Drug Particles Enable Efficient and Safe Gene Delivery

“…For example, lethal‐7a (let‐7a), one of the founding members in the miRNA family,3 is poorly expressed in human cancers including prostate, breast, and brain cancers, which is decreased by more than threefold in contrast to other healthy tissues. [[qv: 2b,4]] Accordingly, upregulation of let‐7a results in a marked promotion of apoptosis and inhibition of the proliferation and metastasis of cancer cell by silencing KRAS and high‐mobility group AT‐hook 2 (HMGA2) 5. Therefore, miRNA replacement therapies can be employed as a promising treatment strategy if the miRNA can be delivered to cancer cells with high efficiency.…”

MicroRNAs as potential cancer therapeutics

“…Since in both studies let-7 miRNA was delivered at the same time as tumorigenesis was initiated, these two studies showed that let-7 can be used as a preventive therapy against lung cancer in the LSL-Kras G12D mice. In a similar experiment using let-7 treatment, Yu et al (2007a) showed that in a xenograft model of breast cancer, tumor-initiating cells, SK-3rd cells infected with lentivirus expressing let-7, developed significantly fewer tumors than cells given the control virus.…”