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.

Aberrant expression of XIST, a long noncoding RNA (lncRNA) initiating X chromosome inactivation (XCI) in early embryogenesis, is a common feature of breast cancer (BC). However, the roles of post-XCI XIST in breast carcinogenesis remain elusive. Here we identify XIST as a key regulator of breast cancer stem cells (CSCs), which exhibit aldehyde dehydrogenase positive (ALDH⁺) epithelial- (E) and CD24^loCD44^hi mesenchymal-like (M) phenotypes. XIST is variably expressed across the spectrum of BC subtypes, and doxycycline (DOX)-inducible knockdown (KD) of XIST markedly inhibits spheroid/colony forming capacity, tumor growth and tumor-initiating potential. This phenotype is attributed to impaired E-CSC in luminal and E- and M-CSC activities in triple-negative (TN) BC. Gene expression profiling unveils that XIST KD most significantly affects cytokine-cytokine receptor interactions, leading to markedly suppressed expression of proinflammatory cytokines IL-6 and IL-8 in ALDH^- bulk BC cells. Exogenous IL-6, but not IL-8, rescues the reduced sphere-forming capacity and proportion of ALDH⁺ E-CSCs in luminal and TN BC upon XIST KD. XIST functions as a nuclear sponge for microRNA let-7a-2-3p to activate IL-6 production from ALDH^- bulk BC cells, which acts in a paracrine fashion on ALDH⁺ E-CSCs that display elevated cell surface IL-6 receptor (IL6R) expression. This promotes CSC self-renewal via STAT3 activation and expression of key CSC factors including c-MYC, KLF4 and SOX9. Together, this study supports a novel role of XIST by derepressing let-7 controlled paracrine IL-6 proinflammatory signaling to promote CSC self-renewal.

Cancer stem cells (CSCs) are a small group of tumor cells with the capacity to undergo self‐renewal and differentiation. These cells not only initiate and maintain tumor growth, but also confer resistance to current cancer therapies. CSCs display a high degree of plasticity and can be generated under therapeutic stress via dedifferentiation from non‐stem‐like tumor cells, suggesting the necessity simultaneously targeting CSCs and bulk tumor cells to achieve the best therapeutic effect. Despite the findings that therapeutic stress induces CSC plasticity, the mechanisms underpinning CSC formation and therapeutic resistance are not fully defined. Tumor cells display elevated levels of reactive oxygen species (ROS), contributed by rapid proliferation, enhanced metabolic demands and oncogenic signaling. CSCs achieve redox homeostasis partly by regulating redox‐sensitive transcription factors (TFs), including NRF2, HIF‐1α, BACH1, NF‐kB, FOXOs, AP‐1, and others. This review aims to summarize the roles and underlying mechanisms of these TFs in regulation of CSCs and tumor progression from the perspectives of stem cell maintenance, metabolic reprogramming, epithelial–mesenchymal transition (EMT) and angiogenesis. We also discuss the potentials of utilizing specific inhibitors for these TFs in suppressing drug resistance and metastasis by repressing CSC activity, an approach that may provide new targeted therapies for advanced cancer and improve patient outcome.