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Updated: Apr 17, 2026
Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
Published on: March 30, 2019
DICER1 regulated let-7 expression levels in p53-induced cancer repression requires cyclin D1
Xin Sun1, Shou-Ching Tang2,3, Chongwen Xu1
1Oncology Department of the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
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.
Insights
Let-7 microRNAs (miRNAs) are tumor suppressors. This study reveals a feedback loop between let-7 and cyclin D1, crucial for regulating cancer therapy response and cell death.
Area of Science:
- Oncology
- Molecular Biology
- Gene Regulation
Background:
- Let-7 microRNAs (miRNAs) function as tumor suppressors by targeting 3' untranslated regions of genes.
- Dysregulation of let-7 miRNAs is observed in various cancers, indicating potential roles in oncogenesis and cell fate determination.
- Cyclin D1, a target of let-7, promotes cell cycle progression and oncogenesis.
Purpose of the Study:
- To investigate the regulatory relationship between let-7 miRNAs and cyclin D1 in cancer.
- To elucidate the role of this feedback loop in cancer cell response to therapy and cell death pathways.
- To determine if alterations in let-7 expression can predict chemotherapy response.
Main Methods:
- Analysis of gene expression patterns.
- Investigating the interaction between let-7, cyclin D1, and DICER1 (a miRNA regulator).
- Utilizing cancer cell models treated with chemotherapeutic agents (Nutlin-3, TAX).
Main Results:
- DICER1 was identified as a key downstream gene regulated by cyclin D1-induced let-7 expression.
- Let-7 miRNA levels decreased during p53-induced cell death, associated with deregulated cyclin D1.
- Cyclin D1 is essential for Nutlin-3 and TAX-induced let-7 expression, impacting cancer repression and cell death.
Conclusions:
- A feedback loop between let-7 and cyclin D1 is established, influencing cancer therapy response in cancer and cancer stem cells.
- Altered let-7 expression, primarily driven by cyclin D1, serves as a sensitive biomarker for predicting chemotherapy efficacy.
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