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.

MicroRNA-200c (miR-200c) is increasingly recognized as a crucial small RNA molecule that plays a significant and multifaceted role in the complex processes of tumor development, invasion, and metastasis across various types of cancers. Recent studies have compellingly demonstrated that miR-200c exerts its influence on tumor biology by meticulously regulating a range of critical processes, including cell proliferation, apoptosis, epithelial–mesenchymal transition (EMT), and cell migration, all of which are essential for the progression and aggressiveness of tumors. This comprehensive review aims to summarize the expression characteristics and functional implications of miR-200c across a diverse array of tumor types, delving into its potential utility as both a biomarker for early detection and a therapeutic target in the realm of cancer treatment. By synthesizing current research findings and insights, we aspire to provide valuable information that could significantly enhance early diagnostic capabilities and inform the strategic development of targeted therapy approaches in oncology.

Triple-negative breast cancer (TNBC) contains the highest proportion of cancer stem-like cells (CSC), which display intrinsic resistance to currently available cancer therapies. This therapeutic resistance is partially mediated by an antioxidant defense coordinated by the transcription factor NRF2 and its downstream targets that include NAD(P)H quinone oxidoreductase 1 (NQO1). In this study, we identified the antioxidant enzymes NQO1 and superoxide dismutase 1 (SOD1) as therapeutic vulnerabilities of ALDH+ epithelial-like CSCs and CD24−/loCD44+/hi mesenchymal-like CSCs in TNBC. Effective targeting of these CSC states was achieved by using isobutyl-deoxynyboquinone (IB-DNQ), a potent and specific NQO1-bioactivatable futile redox cycling molecule, which generated large amounts of reactive oxygen species including superoxide and hydrogen peroxide. Furthermore, the CSC killing effect was specifically enhanced by genetic or pharmacologic inhibition of SOD1, a copper-containing superoxide dismutase highly expressed in TNBC. Mechanistically, a significant portion of NQO1 resides in the mitochondrial intermembrane space, catalyzing futile redox cycling from IB-DNQ to generate high levels of mitochondrial superoxide, and SOD1 inhibition markedly potentiated this effect, resulting in mitochondrial oxidative injury, cytochrome c release, and activation of the caspase-3–mediated apoptotic pathway. Treatment with IB-DNQ alone or together with SOD1 inhibition effectively suppressed tumor growth, metastasis, and tumor-initiating potential in xenograft models of TNBC expressing different levels of NQO1. This futile oxidant-generating strategy, which targets CSCs across the epithelial–mesenchymal continuum, could be a promising therapeutic approach for treating patients with TNBC. Significance: Combining NQO1-bioactivatable futile oxidant generators with SOD1 inhibition eliminates breast cancer stem cells, providing a therapeutic strategy that may have wide applicability, as NQO1 and SOD1 are overexpressed in several cancers.

Background: Breast cancer is one of the most common malignant tumors in women. Cell division cycle associated 5 (CDCA5), a master regulator of sister chromatid cohesion, was reported to be upregulated in several types of cancer. Here, the function and regulation mechanism of CDCA5 in breast cancer were explored. Methods: CDCA5 expression was identified through immunohistochemistry staining in breast cancer specimens. The correlation between CDCA5 expression with clinicopathological features and prognosis of breast cancer patients was analyzed using a tissue microarray. CDCA5 function in breast cancer was explored in CDCA5-overexpressed/knockdown cells and mice models. Co-IP, ChIP and dual-luciferase reporter assay assays were performed to clarify underlying molecular mechanisms. Results: We found that CDCA5 was expressed at a higher level in breast cancer tissues and cell lines, and overexpression of CDCA5 was significantly associated with poor prognosis of patients with breast cancer. Moreover, CDCA5 knockdown significantly suppressed the proliferation and migration, while promoted apoptosis in vitro. Mechanistically, we revealed that CDCA5 played an important role in promoting the binding of E2F transcription factor 1 (E2F1) to the forkhead box M1 (FOXM1) promoter. Furthermore, the data of in vitro and in vivo revealed that depletion of FOXM1 alleviated the effect of CDCA5 overexpression on breast cancer. Additionally, we revealed that the Wnt/β-catenin signaling pathway was required for CDCA5 induced progression of breast cancer. Conclusions: We suggested that CDCA5 promoted progression of breast cancer via CDCA5/FOXM1/Wnt axis, CDCA5 might serve as a novel therapeutic target for breast cancer treatment.

Background: Dementia poses a significant global health challenge, characterized by progressive cognitive decline and functional impairment. With the aging global population, dementia prevalence is projected to surge, reaching an estimated 153 million cases by 2050. While the impact of traditional social isolation on dementia risk has been extensively studied, the influence of digital isolation, a phenomenon unique to the digital age, remains underexplored. Objective: This study aimed to investigate the association between digital isolation and dementia risk among older adults, hypothesizing that higher levels of digital isolation significantly increase the risk of developing dementia. Methods: We conducted a longitudinal cohort study using data from the National Health and Aging Trends Study (NHATS), analyzing 8189 participants aged 65 years and older from the 3rd (2013) to the 12th wave (2022). Digital isolation was quantified using a composite digital isolation index, derived from participants’ usage of digital devices, electronic communication, internet access, and engagement in online activities. Participants were stratified into low isolation and moderate to high isolation groups. Dementia incidence was assessed using cognitive tests and proxy reports. Cox proportional hazards models were used to estimate the association between digital isolation and dementia risk, adjusting for potential confounders including sociodemographic factors, baseline health conditions, and lifestyle variables. Results: The moderate to high isolation group demonstrated a significantly elevated risk of dementia compared with the low isolation group. In the discovery cohort, the adjusted hazard ratio (HR) was 1.22 (95% CI 1.01-1.47, P=.04), while the validation cohort showed an HR of 1.62 (95% CI 1.27-2.08, P<.001). The pooled analysis across both cohorts revealed an adjusted HR of 1.36 (95% CI 1.16-1.59, P<.001). Kaplan-Meier curves corroborated a higher incidence of dementia in the moderate to high isolation group. Conclusions: Our findings indicate that digital isolation is a significant risk factor for dementia among older adults. This study underscores the importance of digital engagement in mitigating dementia risk and suggests that promoting digital literacy and access to digital resources should be integral components of public health strategies aimed at dementia prevention.

Familial non-medullary thyroid carcinoma (FNMTC) accounts for 3% to 9% of all thyroid cancer cases, yet its genetic mechanisms remain unknown. Our study aimed to screen and identify novel susceptibility genes for FNMTC. Whole-exome sequencing (WES) was conducted on a confirmed FNMTC pedigree, comprising four affected individuals across two generations. Variants were filtered and analyzed using ExAC and 1000 Genomes Project, with candidate gene pathogenicity predicted using SIFT, PolyPhen, and MutationTaster. Validation was performed through Sanger sequencing in affected pedigree members and sporadic patients (TCGA database) as well as general population data (gnomAD database). Ultimately, we identified the mutant PPP4R3A (NC_000014.8:g.91942196C>T, or NM_001366432.2(NP_001353361.1):p.(Asp409Asn), based on GRCH37) as an FNMTC susceptibility gene. Subsequently, a series of functional experiments were conducted to investigate the impact of PPP4R3A and its Asp409Asn missense variant in thyroid cancer. Our findings demonstrated that wild-type PPP4R3A exerted tumor-suppressive effects via the Akt-mTOR-P70 S6K/4E-BP1 axis. However, overexpression of the PPP4R3A Asp409Asn mutant resulted in loss of tumor-suppressive function, ineffective inhibition of cell invasion, and even promotion of cell proliferation and migration by activating the Akt/mTOR signaling pathway. These results indicated that the missense variant PPP4R3A Asp409Asn is a candidate susceptibility gene for FNMTC, providing new insights into the diagnosis and intervention of FNMTC.