Transfection of chemically synthesized, double-stranded let-7 mimics into the cytoplasm of tumor cells has emerged as a potential strategy for cancer gene therapy. 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. (the second miRNA gene identified after lin-14), where its expression determines adult cell fate in the worm [4].The let-7 family of miRNAs, which is comprised of multiple paralog genes located in different chromosomes, has been defined as one of the largest and most conserved family of miRNAs across different species, ranging from worms to humans [5,6,7]. In humans, there are 10 mature let-7 miRNAs, including let-7a, let-7b, let-7c, let-7d, let-7e, let-7f, let-7g, let-7i, miR-98 and miR-202, which are derived from 13 precursor genes [8]. During mammalian embryonic development, let-7 expression is silent in embryonic stem cells (ESCs) but reactivated at later development stages [5]. Elbasvir (MK-8742) This role of let-7 in ESC differentiation is further validated by the findings that exogenous expression of let-7 Elbasvir (MK-8742) in miRNA-deficient ESCs rescues their defective differentiation [9]. In cancer cells, the let-7 family of miRNAs generally function as tumor suppressor miRNAs to inhibit tumor growth and metastasis [8,10,11]. Let-7 miRNAs are also involved in suppressing CSC characteristics, including sphere/colony formation, tumor growth, differentiation and regenerative potential [8,10,11]. Malignancy stem cells (CSCs), or tumor-initiating cells (TICs), symbolize a small subset of cells in the tumor that preserve or acquire the capacity to indefinitely self-renew as well as to differentiate into numerous tumor cell progenies constituting the bulk of a tumor mass [12,13]. As CSCs are endowed Elbasvir (MK-8742) with the intrinsic capacity for restorative resistance, they contribute not only to tumorigenesis but also to disease progression and metastatic relapse. As a result of these properties, CSCs Elbasvir (MK-8742) play a major part in the resistance of tumors to the conventional chemotherapy and radiation therapy [13]. miRNAs, especially the let-7 family of miRNAs and their regulatory proteins, are frequently deregulated in a wide variety of malignancy types and influence CSC maintenance, metabolism, tumorigenesis and metastasis. This IL1R1 antibody review summarizes the current state of knowledge on the functions of let-7 miRNAs and their regulatory proteins in regulating CSCs during tumor development and malignancy progression, the signaling pathways and network through which let-7 miRNAs are involved in the rules of CSCs. We also emphasize existing strategies that have been recorded in the literature to harness this family of miRNAs for restorative benefit in preclinical models. 2. Let-7 as Important Tumor Suppressor miRNAs and Bad Regulators of CSCs The CSC model posits that malignancy arises from a rare populace of tumor-initiating cells (TICs) or CSCs that possess dysregulated self-renewal capacity. Yu et al. offered the first evidence that let-7 miRNAs are markedly reduced in TICs but improved in differentiated tumor cells in breast malignancy [14]. This improved let-7 manifestation in differentiated tumor cells (or non-TICs) inhibits the manifestation of H-Ras and HMGA2, known let-7 target genes that promote tumor self-renewal and proliferative capacity. In contrast, antagonizing let-7 by antisense oligonucleotides enhances self-renewal capacity of non-TICs, indicating a critical.