DICER1 regulated let‐7 expression levels in p53‐induced cancer repression requires cyclin D1

Abstract

Let-7 miRNAs act as tumour suppressors by directly binding to the 3′UTRs of downstream gene products. The regulatory role of let-7 in downstream gene expression has gained much interest in the cancer research community, as it controls multiple biological functions and determines cell fates. For example, one target of the let-7 family is cyclin D1, which promotes G0/S cell cycle progression and oncogenesis, was correlated with endoribonuclease DICER1, another target of let-7. Down-regulated let-7 has been identified in many types of tumours, suggesting a feedback loop may exist between let-7 and cyclin D1. A potential player in the proposed feedback relationship is Dicer, a central regulator of miRNA expression through sequence-specific silencing. We first identified that DICER1 is the key downstream gene for cyclin D1-induced let-7 expression. In addition, we found that let-7 miRNAs expression decreased because of the p53-induced cell death response, with deregulated cyclin D1. Our results also showed that cyclin D1 is required for Nutlin-3 and TAX-induced let-7 expression in cancer repression and the cell death response. For the first time, we provide evidence that let-7 and cyclin D1 form a feedback loop in regulating therapy response of cancer cells and cancer stem cells, and importantly, that alteration of let-7 expression, mainly caused by cyclin D1, is a sensitive indicator for better chemotherapies response.

MYC and DNMT3A‐mediated DNA methylation represses microRNA‐200b in triple negative breast cancer

“…The immunofluorescence results showed the transfection of the lentivirus vectors into MDA‐MB‐231 and BT549 cells was successful and led to DNMT3A repression (Figure D and E and Figure A). The number of mammospheres represents the self‐renewal ability of the cells, and the diameter of mammospheres indicates the self‐renewal ability of each sphere‐generating cell . The cells overexpressing miR‐200b formed fewer and smaller mammospheres than the scramble groups.…”

“…The number of mammospheres represents the self-renewal ability of the cells, and the diameter of mammospheres indicates the self-renewal ability of each sphere-generating cell. 33,34 The cells overexpressing miR-200b formed fewer and smaller mammospheres than the scramble groups. Notably, DNMT3A silencing also resulted in lower mammosphere-forming efficiency ( Figure 5F and G).…”

Let-7 miRNAs sensitize breast cancer stem cells to radiation-induced repression through inhibition of the cyclin D1/Akt1/Wnt1 signaling pathway

“…Cells of different groups were plated in ultra-low attachment (non-adherent condition) 6-well plates (Corning Incorporated) to test their ability of forming primary mammospheres. The mammosphere numbers were counted on day 10 and the mammosphere formation efficiency (MFE) was calculated as the percentage ratio between obtained spheres and plated cells (10,(15)(16)(17). Obtained mammospheres from the different groups were disaggregated then re-suspended to test their ability of self-renewal in the next generation.…”

Let-7 inhibits self-renewal of hepatocellular cancer stem-like cells through regulating the epithelial-mesenchymal transition and the Wnt signaling pathway

“…Functioning as tumor suppressors, let-7 miRNAs were found to repress Ras, Bcl-xl, MAPK, c-Myc, cyclin D1 and other oncogenes in HCC [8, 9]. Wnt1 stimulates the Wnt/β-catenin/TCF pathway, leading to different cell fates, and then regulating the transcription of many downstream genes which contain the TCF/LEF1 motif, affecting biological functions and the maintenance of self-renewal of cancer stem cells (CSCs) [10–12].…”