Search Results (2,296)

Epigenetic regulation is critical to B cell development, guiding gene expression via DNA methylation, histone modifications, chromatin remodeling, and noncoding RNAs. In mature B cell neoplasms, particularly diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL), these mechanisms are frequently disrupted. Recurrent mutations in key epigenetic regulators such as EZH2, KMT2D, CREBBP, and TET2 lead to altered chromatin states, repression of tumor suppressor genes, and enhanced oncogenic signaling. Dysregulation of specific microRNAs (e.g., miR-155, miR-21) further contributes to pathogenesis and therapeutic resistance. In DLBCL, hypermethylation of SMAD1 and CREBBP mutations are associated with immune evasion and chemoresistance. In FL, EZH2 gain-of-function and KMT2D loss-of-function mutations alter germinal center B cell programming, while in CLL, DNA hypomethylation patterns reflect the cell of origin and correlate with clinical outcome. Targeted therapies such as the EZH2 inhibitor tazemetostat have demonstrated efficacy in EZH2-mutant FL, while HDAC and BET inhibitors show variable responses across B cell malignancies. The limitations of current epigenetic therapies reflect the complexity of targeting epigenetic dysregulation rather than therapeutic futility. These challenges nonetheless highlight the relevance of epigenetic alterations as biomarkers and therapeutic targets, with potential to improve the management of mature B cell neoplasms. Full article

Background/Objectives: Despite advances in diagnosis and treatment, colorectal cancer (CRC) remains one of the most prevalent and challenging malignancies worldwide. The dysregulation of microRNAs (miRNAs) has emerged as a critical factor in CRC onset, progression, and therapeutic resistance. This study aims to provide an overview of global research trends on miRNAs in CRC, (i) identifying the most studied miRNAs, (ii) exploring under-investigated areas, and (iii) highlighting emerging themes and potential future directions. Methods: To assess the evolution of the global miRNA–CRC research trends, we conducted a bibliometric analysis of 828 CRC–miRNA-focused articles published between 2008 and 2024, sourced from the Scopus database. Bibliometric mapping was performed using the R/Bibliometrix package and by leveraging a customized Python-based pipeline, which is useful for extracting and validating miRNA identifiers (miRNA IDs) based on the miRBase database. This miRNA ID-related approach enabled us to systematically identify the most frequently studied miRNAs over time while highlighting underexplored miRNA. Results: The analysis revealed a substantial and accelerating publication growth rate, delineating three major phases in CRC–miRNA research. China emerged as the leading contributor in terms of the publication volume. miR-21, miR-34a, and miR-195-5p were among the most frequently studied miRNAs, underscoring their relevance to CRC biology and therapy. Keyword and citation analyses identified key thematic areas, such as cell proliferation, epithelial–mesenchymal transition, and chemoresistance, especially to oxaliplatin and 5-fluorouracil. Emerging research frontiers included ferroptosis, ceRNA networks, and exosome-mediated miRNA transport. An analysis of the collaborations indicated strong intra-national collaborations, with room for expanding international research networks. Conclusions: This study provides an in-depth bibliometric landscape of the CRC-related miRNA research by highlighting influential studies and journals while identifying gaps and underexplored topics. These insights offer valuable guidance for future translational and clinical research on this topic. Full article

Cisplatin is an effective chemotherapeutic drug, but is limited both by its toxicity and its tendency to induce drug resistance rapidly in some patients. Tissue transglutaminase 2 (TG2), which is overexpressed in various cancers, has two main isoforms: a long (TG2-L) and a short form (TG2-S). While TG2-L supports cell survival, conversely, TG2-S promotes cell death. Evidence increasingly suggests that TG2 may be a suitable target for combating chemoresistance in a variety of human cancers. Here, we show that cisplatin toxicity towards wild-type MCF-7 breast cancer cells is associated with reduced TG2-L and TG2-S expression, whereas approximately doubling the TG2-L expression through the retinoic acid pre-treatment of these cells induces survival in the presence of cisplatin at levels similar to those seen in long-term cisplatin-co-cultured cells, which have reduced sensitivity. The treatment of cisplatin-surviving cells with cisplatin alone did not significantly alter the levels of either TG2 isoform, whereas the cisplatin challenge of cisplatin-surviving MCF-7 cells following 20 µM retinoic acid pre-treatment resulted in increased levels of TG2-L, increased TG2 enzyme activity, and no significant change in TG2-S levels, with increased cell survival. These findings suggest a subtype-specific regulatory effect of RA in cisplatin-surviving MCF-7 cells, with TG2-L upregulated at higher RA concentrations, potentially contributing to altered cisplatin sensitivity. Anti-TG2 siRNA silencing reduced cisplatin IC50 to base levels in both wild-type and cisplatin-surviving MCF-7 cells, supporting the notion that the modulation of TG2 expression could offer a significant benefit to cisplatin efficacy. Preventing excessive retinoic acid exposure may also be a mechanism for maximising cisplatin efficacy, considering TG2 modulation. Full article

Background and Clinical Significance: Acute megakaryoblastic leukemia (AMKL) is a rare and aggressive hematologic malignancy. The presence of genetic abnormalities often increases the complexity of AMKL. Among these, patients with monosomy 7 constitute a high-risk group associated with a poorer prognosis and greater chemoresistance. We report the case of a 10-year-old boy who had AMKL along with monosomy 7 and familial GATA2 deficiency. The case highlights the diagnostic and therapeutic challenges faced, as well as the critical importance of early genetic screening and timely hematopoietic stem cell transplantation (HSCT). Case Presentation: A 10-year-old boy presented with easy bruising and pancytopenia. AMKL was diagnosed with the help of a bone marrow biopsy and immunophenotyping. Genetic testing showed a GATA2 mutation and monosomy 7. Two induction cycles with daunorubicin and cytarabine were administered but failed to eliminate residual disease. The patient also developed pneumonia of a fungal origin. HSCT was delayed due to liver toxicity and elevated minimal residual disease (MRD). Azacitidine and venetoclax stabilized the disease, thereby allowing for successful haploidentical HSCT. The patient achieved complete remission with full donor chimerism. Conclusions: This case emphasizes the importance of early molecular diagnostics in pediatric AMKL. Identifying GATA2 mutations and monosomy 7 early can help guide risk stratification and the timing of HSCT. Multimodal therapy, which includes the use of infection control and targeted agents, is important for improving the outcomes in high-risk patients. Full article

Therapeutic resistance remains a critical barrier in effective cancer treatment, contributing to disease recurrence, progression, and reduced patient survival. In recent years, natural bioactive compounds have emerged as promising adjuncts in oncology due to their ability to modulate multiple biological processes involved in resistance. This review explores current evidence on the role of natural compounds in influencing cancer cell behavior and their interactions with the tumor microenvironment. By organizing these compounds into chemical families, we provide a structured overview of their potential to enhance the efficacy of standard chemotherapy and reduce resistance-related mechanisms. We also highlight innovative strategies, including combination therapies and advanced drug delivery systems, that aim to improve their clinical applicability. Overall, this work underscores the relevance of integrating natural bioactives into modern cancer therapy and calls for further translational research to bridge preclinical findings with clinical implementation. Full article

Glioblastoma (GBM) is the most aggressive primary brain tumor, characterized by rapid proliferation, invasiveness, therapeutic resistance, and an immunosuppressive tumor microenvironment. A subpopulation of glial stem-like cells (GSCs) within GBM tumors contributes significantly to tumor initiation, progression, and relapse, displaying remarkable adaptability to oxidative stress and metabolic reprogramming. Recent evidence implicates the atypical kinases RIOK1 and RIOK2 in promoting GBM growth and proliferation through their interaction with oncogenic pathways such as AKT and c-Myc. Concurrently, the redox-sensitive Nrf2/Keap1 axis regulates antioxidant defenses and supports GSC survival and chemoresistance. Additionally, aberrant activation of the canonical Wnt/β-catenin pathway in GSCs enhances their self-renewal, immune evasion, and resistance to standard therapies, particularly under oxidative stress conditions. This review integrates current knowledge on how redox homeostasis and key signaling pathways converge to sustain GSC maintenance and GBM malignancy. Finally, we discuss emerging redox-based therapeutic strategies designed to target GSC resilience, modulate the tumor immune microenvironment, and surmount treatment resistance. Full article

Background: Pancreatic cancer ranks as the fourth leading cause of cancer-related deaths in the USA. The human aldehyde dehydrogenase (ALDH) family comprises 19 functional members and has been implicated in prognosis and therapy resistance. However, it remains unclear which specific ALDHs are associated with adverse prognoses in pancreatic cancer. Methods: We obtained transcriptomic and clinical data for pancreatic adenocarcinoma (PAAD) from the TCGA, corresponding mutational data, and normal pancreatic tissue transcriptomic data from GTEx. Prognostic analysis was carried out using Kaplan–Meier analysis. KEGG and GO analyses were used for biological signaling pathways, and ESTIMATE algorithms were used for tumor microenvironment (TME) assessment. CIBERSORT algorithm, immune infiltration analysis, and OncoPredict algorithms were employed for predicting chemotherapy sensitivity. Results: Our study identified four of the 19 ALDH genes (ALDH1L1, ALDH3A1, ALDH3B1, ALDH5A1) that were significantly associated with pancreatic cancer prognosis. High expression of ALDH1L1, ALDH3A1, and ALDH3B1 was associated with shorter overall survival, while ALDH5A1 expression was associated with longer overall survival of pancreatic cancer patients. Clinicopathological analysis revealed a significant association with KRAS mutational status and ALDH3A1 expression. Immune correlation analysis indicated that high expression of ALDH3A1 and ALDH3B1 was associated with lower expression of CD8⁺ T cell-associated gene expression. ESTIMATE analyses further revealed that high expression of ALDH3A1 and ALDH3B1 was associated with lower levels of immune cell infiltration. PAAD tumors with low ALDH3A1 expression were more sensitive to paclitaxel. Immunohistochemical analysis demonstrated high expression of ALDH3A1 in pancreatic cancer cells of human tumor tissues compared to normal pancreatic tissues. Conclusions: This study unveils specific ALDH family members relevant for prognosis and chemotherapy response in pancreatic cancer patients. These findings contribute valuable insights into prognostic biomarkers and their potential clinical utility in the treatment of pancreatic adenocarcinoma. Full article

Fusobacterium nucleatum (F. nucleatum), a Gram-negative anaerobe, is increasingly implicated in the pathogenesis of colorectal cancer (CRC) and inflammatory bowel disease (IBD). Its adhesin FadA enables epithelial adherence and invasion, promoting inflammation and tumorigenesis. F. nucleatum has been shown to activate the NLRP3 inflammasome, leading to IL-1β release, and is associated with chemoresistance and poor prognosis in CRC. Additionally, lipid peroxidation markers such as malondialdehyde (MDA) and 4-hydroxy-nonenal (4-HNA) may contribute to inflammation-driven carcinogenesis. This study protocol aims to investigate the role of F. nucleatum in the development and progression of IBD and CRC through integrated clinical, molecular, and imaging approaches. The protocol involves quantifying F. nucleatum in tissue biopsies across disease stages and assessing correlations with inflammatory and oxidative markers. It will explore the bacterium’s involvement in NLRP3 inflammasome activation, IL-1β production, and autophagy, and its potential contribution to chemoresistance. Furthermore, radiomic analysis of computed tomography (CT) images will be performed to identify imaging phenotypes associated with microbial load and inflammatory activity. Although primarily a protocol, the study includes preliminary in vitro data showing that exposure to FadA significantly increases inflammatory markers in Caco-2 cells, supporting the hypothesis that F. nucleatum contributes to a pro-inflammatory, pro-tumorigenic microenvironment relevant to CRC progression. Full article

Multidrug resistance (MDR) remains a formidable barrier to successful cancer treatment, driven by mechanisms such as efflux pump overexpression, enhanced DNA repair, evasion of apoptosis and the protective characteristics of the tumour microenvironment. Nanoparticle-based delivery systems have emerged as promising platforms capable of addressing these challenges by enhancing intracellular drug accumulation, enabling targeted delivery and facilitating stimuli-responsive and controlled release. This review provides a comprehensive overview of the molecular and cellular mechanisms underlying MDR and critically examines recent advances in nanoparticle strategies developed to overcome it. Various nanoparticle designs are analysed in terms of their structural and functional features, including surface modifications, active targeting ligands and responsiveness to tumour-specific cues. Particular emphasis is placed on the co-delivery of chemotherapeutic agents with gene regulators, such as siRNA, and the use of nanoparticles to deliver CRISPR/Cas9 gene editing tools as a means of re-sensitising resistant cancer cells. While significant progress has been made in preclinical settings, challenges such as tumour heterogeneity, limited clinical translation and immune clearance remain. Future directions include the integration of precision nanomedicine, scalable manufacturing and non-viral genome editing platforms. Collectively, nanoparticle-based drug delivery systems offer a multifaceted approach to combat MDR and hold great promise for improving therapeutic outcomes in resistant cancers. Full article

Background and objectives: Chemotherapy is an established treatment modality for breast cancer; however, it is impaired by issues such as highly refractory chemoresistance and significant side effects. Magnesium ions (Mg²⁺), inorganic metal ions with anti-tumor bioactivity, sensitize cancer cells to chemotherapy by depressing P-glycoprotein (P-gp) expression. Moreover, Mg²⁺ functions as an immunoadjuvant to potentiate anti-tumor immune responses, while excessive Mg²⁺ can induce marked tumor cell apoptosis. Methods: To enable Mg²⁺ to serve as a chemotherapeutic adjuvant for enhanced treatment efficacy, a Trojan horse-like chemoamplifier, denoted as MMSN@Dox, endowed with tumor microenvironment (TME) responsiveness and capable of achieving chemotherapy sensitization and anti-tumor immune activation, was constructed to enhance the efficacy of breast cancer treatment. Leveraging Mg²⁺-enabled TME-responsive degradability of the chemoamplifier, density functional theory (DFT) simulations were conducted to elucidate carrier structural dynamics. Results: Under stimulation of TME, the chemoamplifier decomposes, accompanied by a substantial release of chemotherapeutic agents and metal ions. Excessive Mg²⁺ induces significant tumor cell apoptosis by triggering mitochondrial dysfunction and generating reactive oxygen species (ROS), and reinforces chemotherapy sensitivity by depressing P-gp expression. Furthermore, MMSN@Dox weakens the stemness of tumor cells, further enhancing chemotherapy. The remarkable tumor-killing capability of chemoamplifier MMSN@Dox led to a remarkable immunogenic cell death (ICD) effect. Combined with the regulatory function of Mg²⁺ on T cells, it ultimately activates anti-tumor immune responses and achieves exceptional anti-tumor performance in both in vitro and in vivo models. Conclusions: This approach, leveraging Mg²⁺ to enhance chemotherapy efficacy, establishes a new paradigm for overcoming chemotherapy resistance and offers a novel strategic avenue for advancing nanomedicine in breast cancer treatment. Full article

Background: Growth Differentiation Factor 15 (GDF15) has emerged as a key biomarker and therapeutic target in oncology, with roles extending beyond cancer cachexia. Elevated GDF15 levels correlate with poor prognosis across several solid tumors, including colorectal, gastric, pancreatic, breast, lung, prostate, and head and neck cancers. GDF15 modulates tumor progression through PI3K/AKT, MAPK/ERK, and SMAD2/3 signaling, thereby promoting epithelial-to-mesenchymal transition, metastasis, immune evasion, and chemoresistance via Nrf2 stabilization and oxidative stress regulation. Methods: We performed a narrative review of the literature focusing on the role of GDF15 in solid tumors, with a particular emphasis on head and neck cancers. Results: In head and neck squamous cell carcinoma (HNSCC), GDF15 overexpression is linked to aggressive phenotypes, radioresistance, poor response to induction chemotherapy, and failure of immune checkpoint inhibitors (ICIs). Similar associations are observed in colorectal, pancreatic, and prostate cancer, where GDF15 contributes to metastasis and therapy resistance. Targeting the GDF15-GFRAL axis appears therapeutically promising: the monoclonal antibody ponsegromab improved cachexia-related outcomes in the PROACC-1 trial, while visugromab combined with nivolumab enhanced immune response in ICI-refractory tumors. Conclusions: Further investigation is warranted to delineate the role of GDF15 across malignancies, refine patient selection, and evaluate combinatorial approaches with existing treatments. Full article

Background: Cervical cancer remains a major global health concern, with existing chemotherapy facing limited effectiveness owing to resistance. Polo-like kinase 1 (PLK1) overexpression in cervical cancer cells is a promising target for developing novel therapies to overcome chemoresistance and improve treatment efficacy. Methods: In this study, we developed a novel PROTAC, NC1, targeting PLK1 PBD via the N-end rule pathway. Results: This PROTAC effectively depleted the PLK1 protein in HeLa cells by inducing protein degradation. The crystal structure of the PBD-NC1 complex identified key PLK1 PBD binding interactions and isothermal titration calorimetry (ITC) confirmed a binding affinity of 6.06 µM between NC1 and PLK1 PBD. NC1 significantly decreased cell viability with an IC₅₀ of 5.23 µM, induced G2/M phase arrest, and triggered apoptosis in HeLa cells. In vivo, NC1 suppressed tumor growth in a HeLa xenograft mouse model. Conclusions: This research highlights the potential of N-degron-based PROTACs targeting the PLK1 protein in cancer therapies, highlighting their potential in future cervical anticancer treatment strategies. Full article

Chemotherapy remains a cornerstone in the treatment of esophageal cancer (EC), yet chemoresistance remains a critical challenge, leading to poor outcomes and limited therapeutic success. Mitochondrial DNA (mtDNA) has emerged as a pivotal player in mediating these responses, influencing cellular metabolism, oxidative stress regulation, and apoptotic pathways. This review provides a comprehensive overview of the mechanisms by which mtDNA alterations, including mutations and copy number variations, drive chemoresistance in EC. Specific focus is given to the role of mtDNA in metabolic reprogramming, including its contribution to the Warburg effect and lipid metabolism, as well as its impact on epithelial–mesenchymal transition (EMT) and mitochondrial bioenergetics. Recent advances in targeting mitochondrial pathways through novel therapeutic agents, such as metformin and mitoquinone, and innovative approaches like CRISPR/Cas9 gene editing, are also discussed. These interventions highlight the potential for overcoming chemoresistance and improving patient outcomes. By integrating mitochondrial diagnostics with personalized treatment strategies, we propose a roadmap for future research that bridges basic mitochondrial biology with translational applications in oncology. The insights offered in this review emphasize the critical need for continued exploration of mtDNA-targeted therapies to address the unmet needs in EC management and other diseases associated with mitochondria. Full article

Chemoresistance is a major challenge in the treatment of triple-negative breast cancer (TNBC). Multicellular spheroids are an attractive platform for investigating chemoresistance in TNBC, as they replicate the cues of the tumour microenvironment in vivo. We conducted a comprehensive literature search to summarise the multifactorial and interlinked mechanisms driving chemoresistance in TNBC spheroids. These mechanisms include spatial heterogeneity, hypoxia, extracellular matrix remodelling, tumour–stroma crosstalk, drug efflux, apoptotic resistance, and cancer stem cell signalling. Strategies for overcoming chemoresistance in TNBC spheroids include nanocarrier systems to overcome spatial diffusion limitations, pathway inhibition, and targeting tumour–microenvironment interactions. Despite their advantages, some spheroid models face challenges such as low reproducibility, a lack of heterogeneity, variability in size and shape, limited vascularisation, and constraints in long-term culture. Advanced culturing platforms such as clinostat bioreactors allow for extended culture periods, enabling mature spheroid drug testing. Furthermore, advanced analytical techniques provide spatially resolved spheroid data. These multifactorial and interlinked mechanisms reflect the tumour microenvironment in vivo that spheroids recapitulate, rendering them valuable models for studying chemoresistance. The incorporation of stromal components and advanced analytical workflows will enhance the utility and translational relevance of spheroids as reliable preclinical models for drug discovery in TNBC. Full article

Resistance to cytarabine (Ara-C) remains a major obstacle to the successful treatment of acute myeloid leukemia (AML). Therefore, modulating Ara-C resistance is indispensable for improving clinical outcomes. We previously demonstrated that sodium caseinate (SC), a salt derived from casein, the principal milk protein, inhibits proliferation and modulates the expression of Ara-C resistance-related genes in chemoresistant cells. However, it remains unclear whether the combination of SC with antineoplastic agents enhances apoptosis, modulates chemoresistance-related genes, and prolongs the survival of tumor-bearing mice implanted with chemoresistant cells. Here, we investigated the effects of SC in combination with Ara-C or daunorubicin (DNR) on cell proliferation, apoptosis, the expression of chemoresistance-associated genes, and the survival of tumor-bearing mice. Crystal violet assays, quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunofluorescence, flow cytometry, and Kaplan–Meier survival curves were used to evaluate the effects of combinations in chemoresistant cells. We demonstrate that the IC₂₅ concentration of SC, when combined with antileukemic agents, increases the sensitivity of chemoresistant WEHI-CR50 cells to Ara-C by downregulating SIRT1 and MDR1, upregulating the expression of ENT1 and dCK, enhancing apoptosis, and prolonging the survival of WEHI-CR50 tumor-bearing mice. Our data suggest that SC in combination with antileukemic agents could be an effective adjuvant for Ara-C-resistant AML. Full article