let-7 regulates self renewal and tumorigenicity of breast cancer cells.

By F. Yu, H. Yao, Pengcheng Zhu, Xiaoqin Zhang, Qiuhui Pan, C. Gong, Yijun Huang, Xiaoqu Hu, F. Su, J. Lieberman and 1 more. Cell, 2007

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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.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/05c03b0eea3c1ff75386b79cdf220d739b51a88f

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Citations in the corpus

MicroRNA control of signal transduction (2010, background): “Clearly, this explains only part of the complexity of let-7 biology: in the breast cancer example, epithelial de-differentiation occurs through let-7-mediated downregulation of a different target, high mobility group box A2 (HMGA2; also known as HMGIC”
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MicroRNAs in human cancer. (2013, background): “In a fi nal example of miRNA regulated cancer pathways, isolation of a subset of highly tumorigenic breast cancer cells that were thought to have stemness properties showed that these cells do not express let-7 family members and that expression of let-7 or its known target RAS leads to loss of self”
miR-21: a small multi-faceted RNA (2008, background): “It is also induced in adherent mammosphere cultures differentiating on collagen [26].”
Epithelial–mesenchymal plasticity in carcinoma metastasis (2013, background): “For example, mammospheres isolated from chemotherapytreated breast tumors showed similar mammosphere-initiating capacity after eight passages in culture, whereas cells from untreated tumors vanished within three passages, suggesting again an increase in CSCs after chemotherapy (Yu et al. 2007).”
MicroRNAs in development and disease. (2011, background): “In breast cancer, let-7 suppresses proliferation, tumorgenicity, and metastasic potential of breast cancer stem cell (695).”
The therapeutic promise of the cancer stem cell concept. (2010, background): “For example, CSC chemoresistance has been reported in human leukemias (27, 80, 88–92), in malignant melanoma (13, 93), and in brain (94), breast (95, 96), pancreatic (37), and colorectal (97) cancers.”
MicroRNAs: New Biomarkers for Diagnosis, Prognosis, Therapy Prediction and Therapeutic Tools for Breast Cancer (2015, background): “These TICs have downregulated let-7 expression and, having tumor stem cell properties, can also undergo asymmetric division, thereby sustaining differentiated tumor proliferation [130].”
MicroRNA function in cancer: oncogene or a tumor suppressor? (2009, background): “In addition, let-7 inhibits the expression of HMGA2, a high-mobility group protein, in lung cancer cells [52].”
Hmga2 promotes neural stem cell self-renewal in young, but not old, mice by reducing p16Ink4a and p19Arf expression (2008, background): “Recent studies have demonstrated that let-7 family microRNAs are important negative regulators of Hmga2 expression: loss of the let-7 binding sites in Hmga2 increases Hmga2 expression and promotes tumorigenesis (Lee and Dutta, 2007; Mayr et al., 2007; Yu et al., 2007).”
MicroRNA control in the immune system: basic principles. (2009, background): “…9, 2009 ©2009 Elsevier Inc. 33 process, including tumor metastasis and cancer stem cell maintenance (Huang et al., 2008; Kent and Mendell, 2006; Ma et al., 2007; Tavazoie et al., 2008; Yu et al., 2007). miRNAs appear also to be heavily involved in the pathogenesis of leukemias and lymphomas.”