Search Results (5,193)

The Hippo–Yorkie (Yki) signaling pathway is a conserved regulator of tissue growth, and its dysregulation leads to excessive growth and tumorigenesis. Although several microRNAs (miRNAs) have been implicated in Hippo pathway regulation, how they modulate Yki activity in vivo remains incompletely understood. Here, we identify miR-137 as a suppressor of Yki-driven overgrowth in a Drosophila model. A functional miRNA screen revealed that miR-137 overexpression markedly suppresses Yki-induced eye overgrowth, whereas inhibition of miR-137 enhances eye overgrowth phenotypes. Through bioinformatic prediction and genetic screening, we identified Drep1 as a candidate downstream factor associated with miR-137 function. RNAi-mediated depletion of Drep1 phenocopies the suppressive effects of miR-137, whereas Drep1 overexpression enhances Yki-driven tissue overgrowth and proliferation. Consistent with these phenotypes, miR-137 overexpression or Drep1 depletion reduces the expression of canonical Yki target genes, including Diap1 and Expanded, indicating decreased Yki transcriptional output. Importantly, Drep1 knockdown was associated with reduced Yki immunostaining in a complementary wing-disk context, suggesting a potential link between Drep1 and Yki-associated signaling. Consistent with this, miR-137 also reduced the expression of ICAD, the mammalian homolog of Drep1, providing preliminary evidence that miR-137 may regulate ICAD expression in mammalian cells. Together, these findings support a potential regulatory relationship between miR-137 and Drep1 that modulates Yki-driven eye overgrowth and reveal an additional layer of Hippo pathway regulation in vivo. Full article

Current 3D tumor models for aggressive breast cancers inadequately recapitulate the native tumor microenvironment (TME), leading to poor translational potential. There is a critical need for models capable of mimicking the unique biochemical signals present in the TME. To address this gap, breast tissue and a patient-derived xenograft tumor were decellularized and processed to produce breast tissue- and tumor-specific decellularized extracellular matrices (dECM). Histology confirmed complete cellular removal while maintaining the ECM. Further, DNA content was significantly reduced while ECM composition (POSTN, COLI, FN1) was retained. Breast dECM was incorporated (0, 5, 10, 20, and 50 µg/mL) with triple-negative breast cancer cell lines to generate spheroids. Imaging and histology demonstrated that cells in low dECM (5 and 10 µg/mL) formed compact singular spheres, while higher dECM concentrations (20 and 50 µg/mL) resulted in cells concentrated on the outer edge of the sphere and irregular sphere circularity. RNA-sequencing of MDA-MB-231 dECM spheres demonstrated that gene changes were mediated by both the inclusion of dECM and its composition. High-density tumor dECM upregulated genes associated with metastasis, while high-density breast dECM enhanced tumor suppressors and anti-metastasis genes. These findings indicate that dECM provides physiological cues in 3D tumor models by incorporating TME. Full article

Oncogenic viruses are responsible for between 12% and 20% of human cancers worldwide. They trigger tumorigenesis by integrating into host-cell genomes, altering cell cycle pathways, and evading immune detection. Oncoviral cancers exhibit low rates of mutation, implicating alternative splicing as an underappreciated alternative mechanism for oncogene and oncogenic pathway activation in oncoviral pathogenesis and progression. In order to create alternatively spliced viral proteins for replication and viral genome maintenance, oncoviruses take advantage of host-cell splicing machinery. Some of these proteins inhibit major host-cell tumor suppressors to promote the proliferation of DNA-damaged host-cells in order to facilitate persistent infection, whilst others interact with and de-regulate the expression and activity of host-cell splicing factors to alter host transcript splice site selection. The latter reprograms host-cell transcriptomes to express aberrant, sometimes oncogenic protein isoforms, which interact with oncoviral proteins to promote host-cell transformation and subsequent tumor progression to metastatic disease. In this article, we review oncovirus-induced alternative splicing as a fundamental, underappreciated, oncogenic and tumor-promoting mechanism. We present detailed descriptions of individual human oncoviruses. We compare how these oncoviruses hijack host-cell splicing mechanisms, how specific aberrant alternatively spliced host-cell protein isoforms, induced by oncoviruses, influence tumor pathogenesis and progression, organized with respect to the hallmarks of cancer, and provide a section on therapeutic perspectives. This approach not only crystallizes the complexity of how oncovirus-induced host-cell alternative splicing can influence cancer pathogenesis and progression but also reveals novel potential therapeutic opportunities. Full article

Protein arginine methyltransferase 5 (PRMT5) mediates arginine methylation of a wide range of proteins and plays context-dependent oncogenic or tumor-suppressive roles. In cancer, PRMT5 represses several tumor suppressor genes, including E-cadherin, TP53BP1, ST7, PTEN, and RB (retinoblastoma). Elevated PRMT5 expression has been reported across multiple cancer types, notably triple-negative breast cancer (TNBC). In TNBC, high PRMT5 levels are associated with enhanced cancer stem cell self-renewal, increased tumor growth and metastasis, and reduced patient survival. Mechanistically, PRMT5 promotes breast cancer stem cell maintenance and proliferation through stabilization of the transcription factors KLF4 and KLF5. Disruption of the PRMT5–KLF4 axis results in significant tumor reduction in TNBC models. Moreover, increased PRMT5 expression has been linked to resistance to chemotherapy and immunotherapy in TNBC. Notably, PRMT5 inhibitors demonstrate synergistic anticancer activity when combined with inhibitors of key oncogenic signaling pathways, including EGFR, PARP, and AKT. While several PRMT5 inhibitors are currently being evaluated in clinical trials for other malignancies, no clinical trials have yet been initiated specifically for TNBC. Full article

The continuous expression of HPV oncogenes E6 and E7 contributes to the maintenance of the cervical cancer (CC) phenotype by altering gene expression programs involved in tumor progression and aggressiveness. MicroRNAs (miRNAs) have emerged as critical regulators of gene expression in CC, including miR-218-5p, which has been described as a tumor suppressor. In this study, we investigated the impact of HPV-16 oncoproteins E6 and E7 on the regulation of miR-218-5p expression and its target gene PIK3C2A, as well as their functional and clinical relevance in CC. We found that miR-218-5p expression is significantly reduced in HPV-16-positive CC cell lines, while PIK3C2A expression is increased. Silencing the expression of the E6/E7 oncogenes in Ca Ski cells restored miR-218-5p levels and reduced PIK3C2A expression. Conversely, overexpression of the E6 and E7 oncogenes in C-33 A cells significantly decreased miR-218-5p expression and increased PIK3C2A expression. Functional assays performed on C-33 A cells expressing E6 and E7 revealed that ectopic expression of miR-218-5p suppresses cell proliferation and migration, effects that are partially mediated by PIK3C2A. Bioinformatics analysis showed that low miR-218-5p expression and high PIK3C2A expression are associated with reduced overall survival in patients with cervical cancer. Our findings identify the miR-218-5p/PIK3C2A axis as a novel regulatory pathway modulated by HPV-16 oncoproteins E6 and E7 that contributes to CC cell proliferation and migration. Furthermore, miR-218-5p and PIK3C2A emerge as potential prognostic biomarkers in CC. Full article

Background/Objectives. Oral epithelial dysplasia exhibits unpredictable behavior, prompting research to identify biomarkers that may help predict its progression to malignancy. This study aimed to ascertain the prognostic value of biomarkers indicative of the epithelial–mesenchymal transition (EMT) process using immunohistochemistry. Methods. A systematic review was conducted using PubMed data from 1978 to June 2026. Articles that employed immunohistochemistry to identify cells exhibiting epithelial–mesenchymal transition changes in oral epithelial dysplasia were included. Exclusion criteria included in vivo studies, book chapters, reviews, conference abstracts, and studies lacking population descriptions. The risk of bias was assessed using the “JBI Checklist for Critical Appraisal of Case Series”. Results. A total of 21 articles were included, analyzing 57 biomarkers: 34 epithelial, 19 mesenchymal, two cell-proliferation biomarkers, and two tumor-suppressor biomarkers. The sample sizes varied significantly between the studies. Most articles employed semiquantitative assessment, cell percentage, and immunostaining intensity, with 12 demonstrating low risk of bias. Conclusions. Studies with conclusive results and a low risk of bias suggest that E-cadherin and Vimentin are valuable biomarkers for identifying early EMT in OED. However, the lack of statistical support means that this assertion should be viewed with caution. Full article

Myeloid-derived suppressor cells (MDSCs) are a class of immature, heterogenous, and functionally immunosuppressive myeloid progenitors that are expanded in malignant disease including glioblastoma (GBM). Extensive preclinical evaluation of GBM has revealed that MDSCs express multiple different chemokine and cytokine receptors that facilitate their entry, infiltration, expansion and immunosuppression of antitumor immunity in the tumor microenvironment. Additionally, translational investigation of approaches that target MDSCs directly or indirectly through immune remodeling has yielded promising effects that are under clinical trial investigation. Given the immunosuppressive phenotype of high-grade gliomas like GBM, the removal of MDSCs represents a clinically relevant strategy to enhance immune responses against neoplastic cells. In this review, we provide a comprehensive summary of MDSCs in GBM, emphasizing clinical observations and large-scale multi-omics studies that position MDSCs at the nexus of GBM immunosuppression. Next, we provide detailed coverage of multiple chemokines, cytokines, and growth factors that are relevant to MDSC migration, survival and expansion in GBM along with commentary on the associated receptors. Lastly, we discuss therapeutic approaches that directly target MDSCs as a strategy to improve immune responses against malignant brains and observations on the changes to MDSCs in the tumor microenvironment after immunotherapy. Our review serves as a valuable resource for the neuro-oncology research space, updating scientists and clinicians on a cell central to the biology and therapeutic targeting of GBM. Full article

Human papillomavirus (HPV) has become a leading cause of oropharyngeal cancers, alongside well-known risk factors such as tobacco and alcohol use. Currently, HPV-positive oropharyngeal squamous cell carcinoma (HPV+ OPSCC) has increased significantly in developed countries, with HPV-16 being the most common high-risk subtype. Clinically, HPV+ OPSCC shows clear differences in prognosis compared to HPV-negative tumors, particularly regarding survival rates and treatment responses. Patients with HPV+ OPSCC tend to have notably better survival outcomes and a more favorable outlook. Strong evidence indicates that HPV-related oropharyngeal cancers represent a distinct epidemiological, clinical, and molecular group, setting them apart from non-HPV-related cancers. As a result, treatment strategies for these subtypes should follow specific clinical protocols to optimize outcomes. Additionally, the viral oncoproteins E6 and E7, which systematically disrupt host tumor-suppressor networks, provide strong reasons for targeted phytotherapeutic interventions. Therefore, there is increasing interest in exploring plant bioactive compounds with promising anti-HPV and anticancer effects that target key oncogenic pathways. This review aims to compile the latest data on bioactive phytochemicals with mechanistic evidence in HPV+ OPSCC, highlight their molecular interactions across oncogenic signaling pathways, and discuss evidence-based findings focusing on research published from 2000 to 2025. Full article

Osteosarcoma (OS) is the most common primary bone cancer in adolescents and young adults. Despite tremendous preclinical and clinical efforts to advance therapy for OS, the standard of care, consisting of surgical resection and pre- and postoperative chemotherapy, has remained unchanged for over 40 years. Growing molecular understanding of OS highlights tumor heterogeneity as a major obstacle to therapeutic advances. In this narrative review, we comprehensively discuss current evidence of OS heterogeneity and strategies to overcome the barrier. Evidence shows that OS heterogeneity is multifactorial: it retains complex and dynamic somatic genomics, including genomic instability, alterations in tumor suppressors, and amplification/overexpression of oncogenes such as MYC. The tumor is associated with various germline vulnerabilities. OS’s tumor microenvironment has intense cellular and spatial diversity, which significantly shapes its heterogeneity. The effects of lineage plasticity, as well as epigenetic and metabolomic mechanisms, on OS heterogeneity are under study. To overcome this extreme heterogeneity, the therapeutic strategies for OS must be comprehensive and diversified. While surgical resection remains a mainstay of treatment, efforts to identify actionable biomarkers that guide risk stratification and therapy are ongoing. Diverse preclinical models offer insights into OS biology and novel therapeutics. To enhance combinational therapy for OS, various agents, including multi-targeted receptor tyrosine kinase inhibitors, immunotherapies, and epigenetic and metabolic modifiers, are being investigated. Distinctive efforts are continuing to establish maintenance therapy for OS. In summary, elucidating the complex drivers of OS heterogeneity, together with the development of multifaceted strategies to address them, is critical to accelerating therapeutic progress in OS. Full article

Immune checkpoint inhibitors targeting the PD-1 (Programmed Cell Death Protein 1)/PD-L1 (Programmed Death-Ligand 1) axis have transformed cancer therapeutics, yet their efficacy in gynecologic malignancies particularly high-grade serous ovarian carcinoma remains disappointingly limited. This therapeutic resistance stems from a highly orchestrated, multidimensional immunosuppressive tumor microenvironment (TME) characterized by the convergent actions of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and an inhibitory cytokine network (IL-10, TGF-β, VEGF). Emerging evidence positions TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domain) as a master checkpoint integrator that coordinately regulates CD8+ T-cell exhaustion, NK-cell dysfunction, and Treg-mediated suppression. Dual blockade of PD-1 and TIGIT represents a mechanistically rational strategy to dismantle this immunosuppressive fortress. This review synthesizes current understanding of the gynecologic TME architecture, delineates the molecular and cellular basis for TIGIT/PD-1 synergy, critically evaluates ongoing clinical translation efforts, and proposes an integrative framework leveraging spatial transcriptomics, single-cell resolution immunoprofiling, and patient-derived experimental models to accelerate biomarker-driven therapeutic development. Full article

Cancer progression is closely associated with dysregulation of apoptosis, enabling malignant cells to evade programmed cell death and develop resistance to therapy. Among the key regulators of this process, the tumor suppressor protein p53 and the Bcl-2 family of proteins play central and interconnected roles in controlling cell survival and mitochondrial integrity. In recent years, naturally occurring flavonoids have attracted considerable attention as potential modulators of these pathways due to their diverse biological activities and relatively low toxicity. This review provides a focused and integrative overview of how different subclasses of flavonoids modulate the p53–Bcl-2 signaling axis to regulate apoptosis in cancer cells. Particular emphasis is placed on the mechanistic interplay between p53 stabilization, transcriptional regulation of apoptotic targets, mitochondrial outer membrane permeabilization, and caspase activation. In contrast to previous general reviews on flavonoids and cancer, this work provides an integrated overview of evidence across multiple flavonoid subclasses and experimental cancer models, highlighting both shared and pathway-specific apoptotic responses. Experimental findings from in vitro and in vivo studies are discussed, including the effects of quercetin, kaempferol, myricetin, epigallocatechin gallate, and related compounds on cell-cycle arrest, oxidative stress, mitochondrial dysfunction, and intrinsic apoptotic signaling. Furthermore, the review examines the relationship between flavonoid chemical structure and biological activity, with particular attention to bioavailability, metabolic transformation, and strategies aimed at improving therapeutic efficacy, including structural modification and nanocarrier-based delivery systems. Despite promising preclinical findings, significant translational challenges remain, including poor pharmacokinetic properties, variability among experimental models, and limited clinical validation. Overall, flavonoids represent a promising class of bioactive compounds capable of targeting apoptosis through modulation of the p53–Bcl-2 network, and a deeper mechanistic understanding of their activity may support the development of novel targeted and combination anticancer therapies. Full article

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immature myeloid cell populations with potent immunosuppressive activity. MDSCs accumulate during states of chronic inflammation in response to inflammatory cytokine signaling that triggers emergency myelopoiesis in the bone marrow. In rheumatoid arthritis and experimental models of inflammatory arthritis, MDSCs were initially thought to serve as a regulatory checkpoint that limits excessive inflammation. However, subsequent studies have shown that these cells can either alleviate or worsen arthritis depending on immunophenotype, disease timing, microenvironment, cytokines/chemokines, and transcriptional states. Taken together, the seemingly paradoxical roles of MDSCs in inflammatory arthritis likely reflect a highly plastic and context-dependent myeloid continuum. This review examines current knowledge of MDSCs in inflammatory arthritis, highlighting the conditions that direct their functional diversity and the factors that determine whether they alleviate or exacerbate disease. We also discuss emerging therapeutic strategies and emerging concepts to better understand these immune cell populations in the context of inflammatory arthritis. Full article

In vertebrates, SWI/SNF complexes, also known as BRG1/BRM-associated factor (BAF) complexes, come in three major subtypes, canonical BAF (cBAF or BAF), polybromo-associated BAF (PBAF) and non-canonical BAF (ncBAF), that are targeted to different types of chromosomal cis-regulatory gene expression control elements. Approximately 20% of malignancies exhibit mutations in genes coding for subunits of the SWI/SNF family of ATP-dependent chromatin remodelling complexes. SMARCD is an essential evolutionarily conserved subunit of these complexes in all eukaryotes. Whilst the integral role of SMARCD in targeting and stabilising the SWI/SNF complexes is conserved from yeast to plants to humans, the three human SMARCD paralogs display specific expression patterns underlying their functional divergence. Although, all three SMARCD paralogs exhibit context-dependent roles in cancer, acting as both tumour suppressors and oncogenes, it is SMARCD1 that appears to show the broadest oncogenic footprint across malignancies, driving proliferation, invasion and metastasis in diverse cancer types. Here we review the recent literature pertaining to the molecular and cellular roles of the mammalian SMARCD paralogs and discuss their roles in oncogenesis from those perspectives. Full article

Neuroblastoma (NB), the most common extracranial solid tumor of childhood, exemplifies one of the most formidable paradigms of tumor immune evasion (TIME) in pediatric oncology. Despite significant advances in multimodal therapy and the clinical integration of immunotherapeutic strategies, high-risk NB (HR-NB) remains largely refractory to durable immune control. This failure reflects not an absence of immune engagement, but the presence of a highly evolved and developmentally wired immune escape architecture. In this review, we synthesize emerging insights from single-cell, multi-omics, and functional studies to define how developmental lineage, cellular plasticity, metabolic rewiring, epigenetic regulation, and therapy-induced adaptation converge to engineer immune blindness in NB. We discuss how NB’s neural crest origin establishes a baseline of low immunogenicity, which is subsequently reinforced through coordinated suppression of antigen presentation, dominance of immune checkpoint signaling, and profound dysfunction of cytotoxic T and natural killer cells within an immunosuppressive tumor microenvironment. Central to this process is tumor-intrinsic plasticity, whereby lineage instability and dedifferentiation, exacerbated by therapeutic pressure, embed immune silence as a stable tumor state. We highlight evidence positioning RD3 as a master upstream regulator linking cellular identity to immune visibility, governing antigen presentation, innate immune sensing, checkpoint expression, and cytotoxic lymphocyte engagement. Beyond tumor-intrinsic mechanisms, we examine the roles of immunosuppressive myeloid populations, tumor-derived exosomes, metabolic stress, hypoxia, and ferroptosis-associated pathways in reinforcing immune paralysis. Finally, we outline emerging therapeutic strategies aimed at dismantling this architecture, including combinatorial checkpoint blockade, metabolic and epigenetic reprogramming, exosome-targeted interventions, and next-generation immune engineering platforms. Together, this review reframes TIME in NB as a programmable, developmentally rooted process and provides a mechanistic roadmap for restoring immune competence and therapeutic susceptibility in HR disease. Full article

Background/Objectives: Tumors are induced by overactivation of oncogenes and loss of tumor suppressor genes. Recently, a family of proteins containing CID (C-terminal domain (CTD)-interacting domain) domains, named CREPT/RPRD1B and p15RS/RPRD1A, has been identified to be involved in tumorigenesis through the regulation of the cell cycle. Interestingly, while p15RS was shown to inhibit cell proliferation, CREPT was demonstrated to promote tumorigenesis by accelerating tumor cell cycle progression. Methods: To decipher why these two proteins function oppositely, we aimed to reveal the disparities in their clinical outcomes and protein properties. Results: We observed that CREPT and p15RS are both highly expressed in tumors, but with opposite prognostic implications. We confirmed that CREPT promotes, but p15RS inhibits cell proliferation via regulation of Wnt/β-catenin signaling activation. The CID domain of CREPT differs from that of p15RS in conformation and charge distribution. CREPT exhibits a significantly stronger oligomerization capacity than p15RS, which is mediated by the CCT (coiled-coil terminus) domain. We demonstrated that the differences in both CID and CCT domains between CREPT and p15RS contribute to their opposite physiological functions. Conclusions: In conclusion, our results demonstrate that despite high primary sequence similarity, CREPT and p15RS exhibit distinctive biochemical properties. These differences ultimately explain their functional divergence in tumorigenesis and offer novel insights into CREPT-targeted drug design. Full article