Abstract
Cancer has long been viewed as a disease of normal development gone awry. Cancer stem-like cells (CSCs), also termed as tumor-initiating cells (TICs), are increasingly recognized as a critical tumor cell population that drives not only tumorigenesis but also cancer progression, treatment resistance and metastatic relapse. The let-7 family of microRNAs (miRNAs), first identified in C. elegans but functionally conserved from worms to human, constitutes an important class of regulators for diverse cellular functions ranging from cell proliferation, differentiation and pluripotency to cancer development and progression. Here, we review the current state of knowledge regarding the roles of let-7 miRNAs in regulating cancer stemness. We outline several key RNA-binding proteins, long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) involved in the regulation of let-7 biogenesis, maturation and function. We then highlight key gene targets and signaling pathways that are regulated or mutually regulated by the let-7 family of miRNAs to modulate CSC characteristics in various types of cancer. We also summarize the existing evidence indicating distinct metabolic pathways regulated by the let-7 miRNAs to impact CSC self-renewal, differentiation and treatment resistance. Lastly, we review current preclinical studies and discuss the clinical implications for developing let-7-based replacement strategies as potential cancer therapeutics that can be delivered through different platforms to target CSCs and reduce/overcome treatment resistance when applied alone or in combination with current chemo/radiation or molecularly targeted therapies. By specifically targeting CSCs, these strategies have the potential to significantly improve the efficacy of cancer therapies.
Highlights
MicroRNAs are a small class of non-coding RNAs identified as evolutionary conserved, single-strand RNAs with the size of 18–25 nucleotides
This review summarizes the current state of knowledge on the roles of let-7 miRNAs and their regulatory proteins in regulating Cancer stemlike cells (CSCs) during tumor development and cancer progression, the signaling pathways and network through which let-7 miRNAs are involved in the regulation of CSCs
Epithelial-mesenchymal transition or epithelial-to-mesenchymal transition (EMT), a cellular process facilitating tumor cell invasion, migration and dissemination has been shown to associate with the acquisition of mesenchymal CSC-like properties [20]
Summary
MicroRNAs (miRNAs) are a small class of non-coding RNAs identified as evolutionary conserved, single-strand RNAs with the size of 18–25 nucleotides. Since the initial discovery of C. elegans miRNA gene (lin-14) in the early 1990s [1], over 2000 miRNAs have been identified, which regulate diverse cellular processes, including proliferation, differentiation, survival, stem cell maintenance and tumorigenesis [2,3]. MiRNAs, especially the let-7 family of miRNAs and their regulatory proteins, are frequently deregulated in a wide variety of cancer types and influence CSC maintenance, metabolism, tumorigenesis and metastasis. This review summarizes the current state of knowledge on the roles of let-7 miRNAs and their regulatory proteins in regulating CSCs during tumor development and cancer progression, the signaling pathways and network through which let-7 miRNAs are involved in the regulation of CSCs. We emphasize existing strategies that have been documented in the literature to harness this family of miRNAs for therapeutic benefit in preclinical models
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