Gastric Cancer (GC) is the fifth most frequently diagnosed malignancy and the third leading cause of cancer-related mortality worldwide. The aggressive nature of GC, coupled with late clinical presentation and limited therapeutic options, underscores the urgent need for a deeper molecular understanding of its pathogenesis. In the past, microRNAs (miRNAs)-evolutionarily conserved, 19-25-nucleotide, non-protein-coding RNAs-have emerged as pivotal post- transcriptional regulators that simultaneously modulate dozens of messenger RNAs through seed-sequence-mediated binding to 3' untranslated regions. In GC, the most intensively studied axes include Notch, Wnt/β-catenin, Hippo, Hedgehog, TGF-β, MAPK, PI3K-AKT-mTOR, and JAK/STAT. Importantly, these pathways do not operate in isolation; instead, they form interconnected networks wherein a single miRNA can create feed-forward or feedback loops that amplify or attenuate oncogenic signaling. Decoding such miRNA-orchestrated crosstalk is not merely an academic exercise; it offers tangible translational opportunities. Restoration of tumor-suppressive miRNAs using synthetic mimics delivered by lipid nanoparticles, or selective silencing of oncomiRs with antagomirs locked by 2'-O-methoxyethyl modifications, has already shown synergistic efficacy with chemotherapy, HER2-targeted agents, and immune checkpoint blockade in preclinical GC models. Moreover, circulating exosomal miRNA signatures that reflect pathway activation states are being vigorously pursued as minimally invasive biomarkers for early detection, molecular subtyping, and real-time monitoring of therapeutic response. In this comprehensive review, we therefore synthesize current mechanistic insights into miRNA- mediated regulation of the aforementioned signaling highways, highlight context-dependent controversies arising from tumor heterogeneity and microbial influence, and outline rational combinatorial strategies that may accelerate the development of next-generation, highly selective, low-toxicity interventions against gastric cancer.
Prostate cancer is one of the most frequently diagnosed malignancies in men and a leading cause of cancer-related mortality worldwide. The androgen receptor (AR) remains the principal driver of prostate cancer progression and castration-resistant prostate cancer (CRPC), with its stability, localization, and transcriptional activity being tightly regulated by the ubiquitin-proteasome system (UPS). E3 ubiquitin ligases and deubiquitinases (DUBs) critically govern AR turnover and signalling output, thereby influencing tumour growth, therapeutic resistance, and disease progression. Emerging evidence further highlights a complex interplay between ubiquitination, DNA damage response (DDR) pathways, and ADP-ribosylation (ADPr) signalling, collectively shaping genomic stability and treatment responsiveness in prostate cancer. This review is organized into four major themes: (i) ubiquitin-mediated regulation of AR signalling, (ii) ubiquitination and DNA damage response in AR-driven prostate cancer, (iii) crosstalk between ubiquitination, ADPr, and AR-associated signalling pathways, and (iv) therapeutic strategies targeting the UPS and AR axis. This study also discusses recent advances in targeted protein degradation, modulation of E3 ligases, inhibition of deubiquitinases, and PARP-based therapeutic approaches. These emerging insights into the interconnected regulation of ubiquitination, AR signalling, DDR pathways, and ADP-ribosylation may facilitate the development of next-generation therapeutic approaches for advanced prostate cancer.
INTRODUCTION/BACKGROUND:Limited RON expression by cancer cells is detrimental for the therapeutic efficacy of Antibody-Drug Conjugates (ADCs). The present study aimed to validate a pharmaceutical strategy of using ADCs in vitro to target cancer cells with RON expression below the therapeutic threshold. MATERIALS AND METHODS:Anti-RON ADCs Zt/g4-MMAE and H5B14-DCM, with distinct epitope-binding properties and different payload-effect mechanisms, were formulated to form anti-RON ADC doublets. Hydrophobic interaction chromatography was used to determine ADC conjugation profile and stability. Flow cytometry was used to study RON internalization. Liquid chromatography-mass spectrometry was used to detect intracellular payload molecules. Various biochemical and biological methods were used to determine cell viability, cell cycle, and cell death. RESULTS:Anti-RON ADC doublets at a 50:50 ratio were effective, with increased efficacy in inducing RON internalization by cancer cells with variable RON expression. This effect increased intracellular payload accumulation, particularly in cells with limited RON expression. Treatment of ADC doublets also caused significant cell cycle arrest, dramatic reductions in cell viability, and increased cell apoptosis. Moreover, cancer cells with limited RON expression responded well to the ADC doublets, exhibiting a dramatic decrease in cell viability and an increase in apoptotic death. Payload synergy within the ADC doublets was responsible for these activities. Finally, the ADC doublets effectively kill cancer cells displaying acquired-payload resistance. This activity was particularly prominent in cancer cells insensitive to ADCs with a single mechanism of action. DISCUSSION:By binding to 2 different antigenic epitopes to deliver 2 payloads possessing different effect mechanisms, anti-RON ADC doublets overcome several shortcomings, such as limited target antigen expression, insufficient target internalization, and acquired payload resistance, observed in anticancer studies following a single ADC treatment. CONCLUSION:Anti-RON ADC doublets with unique pharmacological features demonstrate enhanced in vitro activity compared to single ADCs, delivering sufficient payloads to achieve cytotoxicity against cancer cells with RON expression below the therapeutic threshold. These findings provide an opportunity to optimize ADC treatment regimens in vivo for cancers expressing low levels of RON.
INTRODUCTION:Ferroptosis and autophagy are recently identified forms of non-apoptotic regulated cell death with strong therapeutic implications for hepatocellular carcinoma (HCC). Mitochondrial ribosomal protein L35 (MRPL35), a mitochondria- specific component of mitoribosomes, has been proposed as a potential therapeutic target for liver cancer. The study focused on autophagy-dependent ferroptosis in HCC, with an emphasis on the functional significance of MRPL35. METHODS:Bioinformatics approaches, RT-qPCR, along with western blotting, were used to determine MRPL35 expression in HCC. CCK-8, scratch, Matrigel, and flow cytometric assays were used to detect cell proliferation, migration, invasion, and apoptosis. JC-1 staining was used to detect mitochondrial function. Assay kits and C11-BODIPY assay were used to detect GSH, GSSG, MDA, ROS, Fe2+, ATP, and lipid ROS levels. MDA staining and western blotting assessed the presence of autophagosomes and autophagy-related proteins. In addition, western blotting was used to detect γ-H2AX, apoptosis-, ferroptosis, and AMPK/mTOR axis-related proteins. The in vivo effects of MRPL35 were confirmed by subcutaneous tumorigenesis assays in nude mice. RESULTS:MRPL35 showed abnormally high expression in HCC with a low survival rate. MRPL35 downregulation suppressed cell viability and metastasis, promoted cell apoptosis and autophagy, as well as ROS-dependent DNA damage, inhibited tumor growth, and promoted ferroptosis and autophagy in HCC-bearing mice. MRPL35 interference also promoted autophagy-mediated ferroptosis. In addition, MRPL35 modulated the AMPK/mTOR axis, and AMPK inhibitor Compound C or AMPKα interference reversed the effects of MRPL35 interference on autophagy-mediated ferroptosis. DISCUSSION:The elucidation of MRPL35's role in mediating the AMPK/mTOR axis is consistent with the well-established pro-tumorigenic role of MRPL35 and the significance of the AMPK/mTOR axis in HCC. The newly characterized MRPL35- AMPK/mTOR axis not only proposes MRPL35 as a therapeutic target for HCC but also advances our understanding of its carcinogenic mechanisms. CONCLUSION:Overall, a novel regulatory mode of autophagy-reliant ferroptosis was established by the MRPL35/AMPK/mTOR axis in HCC.
Introduction/ Objective: IL-6 is associated with carcinogenesis, tumor burden, and poor prognosis in multiple malignancies, including Colorectal Cancer (CRC) and Cholangiocarcinoma (CCA). This study aimed to establish and evaluate the in vitro anti-cancer effect of Peripheral Blood Mononuclear Cell (PBMC)-derived soluble gp130Fc (PBMC Sgp130FcH) on CRC and CCA. Methods: Freshly isolated PBMCs and HCT116 cells were transfected with plasmids encoding Sgp130FcH and hyper-IL-6 (HIL6), respectively. mRNA expression was semi-quantified by RT-qPCR with gene-specific primers. The concentration of Sgp130 in the culture supernatant was measured by ELISA. The anti-cancer effects of PBMC Sgp130FcH, including its effects on cell proliferation, migration, and colony formation, were assessed through direct co-culture with CRC (HCT116) and CCA (TFK1) cell lines. Results: Stable establishment of constitutively activated IL-6 trans-signaling (HCT116 HIL6) and Sgp130FcH-secreting PBMCs (PBMC Sgp130FcH) was achieved. HCT116 HIL6 cells exhibited significantly increased proliferation, migration, and colony formation compared with HCT116 WT (p < 0.05). PBMC Sgp130FcH expressed Sgp130FcH mRNA and secreted high concentrations of Sgp130 ten days after transfection. Compared with PBMC WT, PBMC Sgp130FcH significantly and persistently suppressed proliferation, migration, and colony formation of both CCA and CRC cells in a dose-dependent manner. Discussion: Sustained overexpression of IL-6 trans-signaling in CRC cells promoted a carcinogenic phenotype in vitro. Compared with PBMC WT, PBMC Sgp130FcH showed superior in vitro inhibition on both CRC and CCA cell lines, supporting the functional activity of PBMC-secreted Sgp130FcH as a negative regulator of IL-6 trans-signaling. Conclusion: Our data demonstrate the inhibition of PBMC Sgp130FcH on CRC and CCA cells in vitro, providing preliminary proof-of-concept evidence. Further mechanistic studies and in vivo validation are warranted.
INTRODUCTION:Breast cancer remains a major global health concern, creating an urgent need for safer and more effective treatments. This study aimed to identify novel progesterone receptor modulators as potential candidates for targeted breast cancer therapy using an integrated in silico approach. MATERIALS AND METHODS:The X-ray-validated three-dimensional structure of the human progesterone receptor (PDB ID: 7AXK) was refined using PDB-REDO. Ulipristal acetate, aso-prisnil, and mifepristone were selected as reference ligands. Additional structurally similar compounds were identified through SwissSimilarity using the canonical SMILES of ulipristal acetate. A three-dimensional pharmacophore model describing the essential chemical features required for receptor binding was applied to screen compounds from the ChEMBL database. The selected molecules underwent molecular docking to determine their binding affinities and interactions with important receptor residues. ADME-Tox analysis was subsequently conducted to evaluate their drug-likeness, pharmacokinetic properties, and potential toxicity. RESULTS:PDB-REDO refinement improved the overall structural quality of the 7AXK protein, as assessed using Kleywegt's methodology. Docking and pharmacophore screening identified several compounds with strong predicted binding affinities and favourable interactions within the progesterone receptor's binding site. Selected compounds also demonstrated acceptable drug-like properties, promising pharmacokinetic behaviour, and comparatively favourable predicted safety profiles. DISCUSSION:The combined computational strategy effectively identified promising progesterone receptor modulators. These candidates show potential for developing targeted breast cancer treatments; however, molecular dynamics simulations and experimental validation are required. CONCLUSION:Several potential progesterone receptor modulators with favourable binding and ADME-Tox characteristics were identified. These findings demonstrate the value of computational methods in accelerating early-stage breast cancer drug discovery.
BACKGROUND/INTRODUCTION:Patients with non-small cell lung cancer (NSCLC) harboring HER2 mutations remain at high risk of recurrence, even following radical resection for early-stage disease. Currently, there is a paucity of research investigating the clinicopathological characteristics and disease-free survival (DFS) outcomes of this specific postoperative population. METHODS:This retrospective study investigated the clinicopathological and molecular characteristics of 77 patients with surgically resected HER2-mutant NSCLC. HER2 mutation status was identified via next-generation sequencing (NGS). RESULTS:HER2 exon 20 insertions were the most prevalent variant in this cohort. Overall, 76.6% of patients exhibited invasive adenocarcinoma phenotypes. Histopathological examination revealed highly invasive papillary and micropapillary components in 51.9% and 45.5% of patients, respectively. The median DFS was 17.0 months (95% CI, 11.4-22.5), with significant variation across disease stages (P = 0.004). The cumulative number of high-risk recurrence factors (0, 1-3, >3) was significantly associated with DFS (median, 29.3 vs. 14.2 vs. 7.1 months; P = 0.045). However, PD-L1 expression status, TP53 alterations, and histological phenotypes demonstrated no significant impact on DFS. Among the entire cohort, 80.5% of patients experienced postoperative recurrence, with the lung being the most frequent site of metastasis. CONCLUSION:HER2-mutant NSCLC constitutes a distinct subtype characterized by unique clinicopathological and molecular features. For postoperative patients presenting with advanced disease or an increased burden of high-risk recurrence factors, more aggressive therapeutic strategies should be considered.
Objective: While bevacizumab is a key anti-angiogenic therapy for ovarian cancer, its long-term clinical efficacy is frequently limited by acquired resistance. This study aimed to investigate whether the tetraspanin CD82 mediates the packaging of VEGF-A into extracellular vesicles (EVs) to evade antibody neutralization, and to explore EV inhibition as a potential strategy to overcome this therapeutic resistance. Methods: Tumor cells were treated with bevacizumab, and conditioned supernatants were collected. Human umbilical vascular endothelial cells (HUVECs) were treated with the above-mentioned conditioned supernatants for tube formation and migration assays, and angiogenesis was evaluated in vivo using a zebrafish model. Intracellular VEGF-A was detected by WB, while extracellular VEGF-A was analyzed by ELISA and WB. EV secretion was inhibited using GW4869 (a widely established cell-permeable inhibitor of neutral sphingomyelinase that effectively blocks the ceramide-dependent biogenesis and release of EVs), and EV membranes were disrupted by RIPA or Triton X-100. The EVs in the supernatant were extracted with a kit. PCR and WB were used to examine cargo-sorting-related molecules. Protein interactions were analyzed using STRING, and CD82-VEGF-A interactions were validated by immunofluorescence and immunoprecipitation. Patient survival was analyzed using the Kaplan-Meier method. Results: Conditioned supernatants from bevacizumab-treated ovarian cancer cells enhanced HUVEC migration, tube formation, and angiogenesis in zebrafish. Bevacizumab increased both intraand extracellular VEGF-A protein levels in ovarian cancer cells, but not in other tumor cell lines. The persistent discrepancy between ELISA-quantified extracellular VEGF-A levels and WB analyses prompted us to hypothesize that a fraction of VEGF-A might be physically shielded within EVs. Inhibition of EV secretion reduced the pro-angiogenic effects of the conditioned supernatant. Disruption of EV membranes increased the detectable levels of VEGF-A. Bevacizumab upregulated CD82, which bound VEGF-A and sequestered it into EVs, enabling escape from bevacizumab neutralization. Discussion: The findings provide preliminary evidence that CD82 may facilitate EV-mediated loading of VEGF-A following bevacizumab treatment, potentially contributing to compensatory angiogenic responses. This finding provides a possible explanation for persistent angiogenic signaling despite VEGF blockade and supports further evaluation of the CD82–EV pathway in ovarian cancer. Conclusion: This study investigated how CD82 may promote EV-mediated loading of VEGF-A in response to bevacizumab, using in vitro systems and embryonic zebrafish models of ovarian cancer, and provides preliminary insight into compensatory angiogenesis.
BACKGROUND:The development and progression of Colorectal Cancer (CRC) are closely linked to gut microbiota dysbiosis. However, the pathogenic functions and mechanisms of specific microbiota-derived factors in CRC are not well defined. In this study, we focused on Morganella morganii (M. morganii), a commensal bacterium significantly enriched in the gut of CRC patients, to investigate its potential role in promoting CRC progression. METHODS:We first compared the fecal abundance of M. morganii between patients with CRC and healthy controls in a clinical cohort. From its culture supernatant, a high-molecularweight secreted protein mixture, designated M-T3, was purified. In vitro, HCT116 human CRC cells were treated with M-T3 to assess its effects on proliferation, clonogenic potential, and migration. The role of the NF-κB pathway was examined using pharmacological inhibition. In vivo, an HCT116 xenograft mouse model was established, and M-T3 was administered intratumorally. Tumor growth was monitored, and excised tumors were analyzed for expression of CD137 and proliferative activity. RESULTS:Analysis of a clinical cohort revealed a significant enrichment of M. morganii in fecal samples from CRC patients compared to healthy controls. Mechanistically, treatment with M-T3 activated the NF-κB signaling pathway and consequently was associated with upregulation of CD137 in vitro. M-T3 treatment significantly enhanced the proliferation, clonogenicity, and migration of HCT116 cells, which were effectively reversed by NF-κB pathway inhibition. In vivo, intratumoral delivery of M-T3 accelerated tumor growth in HCT116 xenografts, accompanied by elevated tumor expression of CD137 and an increase in the proliferation marker Ki-67. DISCUSSION:This work demonstrates that M. morganii promotes CRC progression via its secreted protein mixture, M-T3, through NF-κB signaling, and is associated with CD137 upregulation in tumor cells. Contrary to the classical view of CD137 as an immune costimulator, its tumor cell-intrinsic expression is associated with malignant phenotypes rather than confirmed functional causality. These findings establish a "bacterial secretome-tumor signaling axis" as a novel mechanism in microbiota-driven carcinogenesis. CONCLUSION:Collectively, our work showed that M. morganii promotes colorectal cancer progression via the secreted protein mixture M-T3, which activates the NF-κB signaling pathway and is associated with upregulation of CD137. These findings suggest a potential bacterial secretome-tumor signaling link in CRC. Further studies are required to identify the upstream sensing mechanism of M-T3 and determine the functional contribution of CD137 to M-T3-induced malignant phenotypes.
Introduction: Cytokines play an important role in modulating the tumor microenvironment (TME) in glioblastoma multiforme (GBM). However, little work has focused on developing a prognostic model for GBM using cytokine signatures. Methods: Herein, we combined several GBM datasets, such as GSE163120, TCGA-GBM, CGGA-693, CGGA-325, GSE16011, the Rembrandt dataset, and GTEx. We combined the characteristic genes of different cell types in GBM samples with cytokine-associated genes identified in our previous research to identify single-cell cytokine-related genes (scCRGs). The enrichment scores of scCRGs in each cell were computed, and cells were stratified into a high-expression group and a low-expression group based on the median enrichment score. Differentially expressed scCRGs in the high-expression group were identified using the “limma” R package. Then, 117 combinations of machine learning (ML) algorithms were used to construct the new cytokine-related signature (CRS) prediction model. Moreover, we used consensus clustering algorithms to perform novel clustering analyses on GBM and subsequently conducted comprehensive immune profiling, response-to-immune-therapy prediction, and drug-sensitivity evaluation. Finally, we validated the key molecules in the model using tissue microarrays. Results: We identified 17 scCRGs that are mostly highly expressed in microglia. The new CRS model we proposed demonstrated strong predictive performance across the three independent cohorts, outperforming existing GBM models. Based on the CRS model, we identified distinct subgroups of GBM patients who may respond favorably to immunotherapy. The key gene AEBP1 in the model is highly expressed in GBM tissues. Discussion: Here, we present, for the first time, a highly reproducible and patient-specific prognostic prediction model based on a cytokine-related gene signature, combining several ML techniques and a large set of bioinformatic features. Compared with other published models, the proposed model is more stable and produces better predictions. Based on the model, we could identify separate subgroups of GBM patients who might respond better to immunotherapy, providing actionable information for the development of precision medicine approaches to treating GBM. Conclusion: CRS has the potential to be an effective and promising strategy for improving clinical outcomes in patients with GBM.
Bladder cancer remains a formidable malignancy of the urinary system, with treatment significantly challenged by the frequent development of resistance to Immune Checkpoint Inhibitors (ICIs). The review is an in-depth and methodical account of the several causes of this immune resistance, and reviews new ways of reversing it. We suggest a unified model based on three fundamental dimensions: (1) characterized by T-cell exhaustion, with high expression of co-inhibitory receptors such as TIM-3 and LAG-3 that SELLs the anticancer immune function and limits efficacy of PD-1/PD-L1 blockade; (2) systemic regulation of immunity through the gut-bladder axis in which microbiota, particularly commensals like Akkermansia muciniphila, regulate host immune responses and affect immunotherapy results; and (3) adaptive tumor evolution caused by an immunosuppressive Tumor Microenvironment (TME), along with genetic changes to help escape immune destruction. The interaction between these factors highlights the intricacy of treatment resistance. This limitation can be successfully overcome through rationalized combination therapies. We revisit changing strategies, including ICI plus Antibody Drug Conjugates (ADC), enfortumab vedotin. These ADCs have the ability to destroy tumor cells selectively and kill the tumor simultaneously through the induction of immunogenic cell death, which has the potential to alter TME, promote T-cell infiltration, and demonstrate synergistic effects with ICIs. However, other promising techniques are the simultaneous interference with TIM3/LAG3 or microbiome manipulation. By combining general knowledge with recent clinical information, this review also gives an ordered perspective of immune resistance and assists in the creation of multi-target treatments. In general, these developments have potential for improved patient care and long-term survival in advanced bladder cancer
In 2022, the Global Cancer Observatory (GLOBOCAN) predicted that female Breast Cancers (BCs) are the second most diagnosed cancer worldwide, accounting for 11.6% of all new cancer cases and estimated to account for 6.9% of all cancer deaths glob-ally. BC treatment options depend on factors such as tumor grade, stage, molecular subtype, and personalized considerations, including age, menopausal status, overall health, safety, and treatment efficacy. The traditional assessment of BC prognosis and treatment involves evaluating hormone receptor status (HRs: ER, PR, AR), human epidermal growth factor receptor 1 and 2 (HER1/EGFR, HER2), immune checkpoint markers (e.g., PD-L1), and cell signalling molecules (e.g., CDK4/6, PARP), among others. While TNBCs (ER-, PR-, HER2-) are mainly treated with chemotherapy, targeted therapy, and immunotherapy, either alone or in combination, HRs and/or HER2 remain the primary therapeutic targets for ER/PR+HER2+ and ER/PR+HER2- BCs, respectively. However, challenges such as de novo and acquired resistance, toxicity, and side effects limit the effectiveness of targeted therapies. This review discusses the advancement of conventional targeted therapies against BCs by introducing new generations of targeted molecules, including advanced SERMs, SERDs, AIs, CDK4/6, and PARP inhibitors, various ADCs, PROTACs, CERANs, and SERCAs.
Ferroptosis-cell death driven by iron-is gaining traction in oncology. A study published in Current Cancer Drug Targets (CCDT) shows that a natural compound, Macranthoside B (MB), inhibits the activity of Adenocarcinoma of the Esophagogastric Junction (AEG) and that NRF2-mediated ferroptosis is involved in its regulation. This editorial discusses the mechanistic implications of that study, with particular attention to the NRF2/NCOA4-related ferritinophagy axis, while also emphasizing the limitations that should be addressed before clinical translation. Although the findings provide a useful preclinical rationale for exploring ferroptosis-oriented therapeutic strategies in AEG, key questions remain regarding the validation of the causal pathway, pharmacokinetics, systemic toxicity, tumor selectivity, model representativeness, and biomarker-based patient stratification. Therefore, Macranthoside B should currently be viewed as a promising experimental compound rather than a clinically established therapeutic candidate. Further in vivo studies and carefully designed translational investigations are required to determine whether this natural compound can be advanced toward AEG treatment.
In the above-mentioned article published in Current Cancer Drug Targets, 2026, 26(4), 393-395, the citation for Fig. (1) was inadvertently omitted. The original article can be found online at: https://www.benthamscience.com/article/150331 Details of the correction are as follows: Original: These findings suggested that the metabolic features associated with metastasis could be utilized as potential therapeutic targets. The authors proposed that, for cancer cells, oxidative metabolism could play an ad-vantageous role in the process of metastasis. However, the exact molecular events underlying increased metastatic burden are unclear and require further investi-gation. Corrected: These findings suggested that the metabolic features associated with metastasis could be utilized as potential therapeutic targets. The authors proposed that, for cancer cells, oxidative metabolism could play an ad-vantageous role in the process of metastasis. However, the exact molecular events underlying increased metastatic burden are unclear and require further investigation (Fig. 1).
INTRODUCTION:Long noncoding RNAs (lncRNAs) have emerged as important modulators in the molecular pathology of cancer. lncRNA ABCA9-AS1 is a newly identified lncRNA, and its role in gastric cancer has not yet been reported. OBJECTIVE:To investigate the effects of lncRNA ABCA9-AS1 on the proliferation and metastasis of gastric cancer cells and to explore its role in the miR-497-5p/KIF23 signalling cascade. METHODS:A gastric cancer-specific ceRNA network (lncRNA-miRNA-mRNA) was constructed using RNA-seq and miRNA-seq data from TCGA. qRT-PCR was used to detect the expression levels of the target genes in gastric cancer cells (AGS, HGC-27, MKN28) and human gastric mucosal epithelial cells (GES-1). Knockdown of lncRNA ABCA9-AS1 was achieved using specific siRNA, while overexpression of KIF23 was achieved using a pcDNA3.1-based overexpression plasmid. The proliferative capacity of gastric cancer cells was assessed using CCK-8 and colony formation assays. Cell migration and invasion were evaluated by Transwell migration and Matrigel invasion assays, respectively. RESULTS:A gastric cancer-specific lncRNA-associated ceRNA network was constructed. qRT-PCR showed significant upregulation of lncRNA ABCA9-AS1 in gastric cancer cells (AGS, HGC-27, MKN28), with concomitant downregulation of miR-497-5p and upregulation of KIF23. In AGS cells, ABCA9-AS1 knockdown increased miR-497-5p expression and reduced KIF23 expression, while miR-497-5p mimics suppressed KIF23 expression. Functional assays confirmed that ABCA9-AS1 knockdown and miR-497-5p overexpression inhibited the proliferation, migration, and invasion of AGS cells. Conversely, KIF23 restoration or miR-497-5p inhibition reversed these effects, as did KIF23 co-expression with miR-497-5p mimics. DISCUSSION:Our results highlight lncRNA ABCA9-AS1 as a novel and promising prognostic biomarker that promotes gastric cancer progression by acting as a ceRNA to modulate the miR-497-5p/KIF23 axis. CONCLUSION:lncRNA ABCA9-AS1 is aberrantly upregulated in gastric cancer. As a ceRNA, it sponges miR-497-5p to increase KIF23 expression and enhance the proliferation, migration, and invasion of gastric cancer cells.
Renal cell carcinoma (RCC), a highly aggressive kidney malignancy, presents significant challenges in early diagnosis, therapeutic resistance, and metastatic progression. Conventional treatment modalities, including surgery, radiotherapy, and chemotherapy, remain essential but are often limited by non-specific toxicity, resistance development, and suboptimal long-term outcomes in advanced stages. In response, molecular-targeted therapies, such as monoclonal antibodies (mAbs) and tyrosine kinase inhibitors, have significantly improved RCC management by selectively disrupting key signaling pathways, including vascular endothelial growth factor (VEGF), plateletderived growth factor (PDGF), and mammalian target of rapamycin (mTOR). However, these therapies still have limitations, including transient responses and systemic adverse effects. Emerging technologies represent promising approaches. Notably, circulating tumor cells (CTCs) are recognized as critical biomarkers in the metastatic cascade, enabling real-time disease monitoring through liquid biopsy. Concurrently, nanotechnology-based platforms, including lipidic and polymeric nanoparticles, have enabled precision drug delivery with enhanced therapeutic efficacy and reduced toxicity. Drug carriers such as liposomes, solid-lipid nanoparticles, and PLGA-based systems successfully deliver chemotherapeutics, siRNAs, and natural compounds targeting key oncogenic pathways, including PI3K–AKT–mTOR (phosphoinositide 3-kinase-protein kinase B (AKT)– mTOR) and VHL-HIF (von Hippel–Lindau tumor suppressor-hypoxia-inducible factor) signaling. Furthermore, multifunctional theranostic platforms integrate diagnostic imaging and therapeutic functions, advancing personalized treatment strategies. Collectively, these innovations represent a paradigm shift from conventional broad-spectrum treatments to intelligent, patient-specific approaches, with the potential to redefine RCC management and improve clinical outcomes.
BACKGROUND:Glioma-Related Epilepsy (GRE) is a hallmark comorbidity of Low-Grade Glioma (LGG), yet the cellular and molecular mechanisms through which germline epilepsy susceptibility converges with tumor biology to shape clinical outcomes remain poorly understood. METHODS:Genome-Wide Association Studies (GWAS), expression quantitative trait loci (eQTL) data, single-cell RNA sequencing, and spatial transcriptomics were integrated. Causal inference, phenotype-driven single-cell analyses, and machine learning were applied to identify genetically informed cellular mechanisms underlying GRE. RESULTS:A total of 68 germline loci shared by glioma and epilepsy (FDRIVW < 0.05) were integrated, with microglia and excitatory neurons as the principal mediating cell types. Four seizure-associated genes (WFIKKN1, WDSUB1, SPARCL1, and CALD1) were subsequently identified in TCGA-LGG, with high-confidence enhancer-promoter support for three of them (colco.PP4 > 0.9). A four-gene signature consistently stratified overall survival across three independent cohorts (TCGA-LGG, CGGA_325, and GSE16011) and correlated with immune checkpoint gene expression. High-risk patients showed higher sensitivity to cyclopamine, according to in silico drug response. DISCUSSION:These findings support a neuroimmune model in which pleiotropic germline variants act via microglia and excitatory neurons to link seizure biology with tumor immunity and prognosis. At the same time, in silico therapeutic predictions require functional and multi-ancestry validation. CONCLUSION:These results reveal a common genetic architecture between glioma and epilepsy, offering candidate biomarkers and therapeutic strategies for the management of GRE.
INTRODUCTION:Clinical management of RAS wild-type colorectal cancer liver metastases (CRLM) remains challenging because many patients exhibit primary resistance to anti-EGFR therapy. Our research centered on the development of a multi-omics deep learning framework, designed to bridge the gap between complex multi-omics data and the necessity for precise therapeutic response forecasting in this specific cohort. MATERIALS AND METHODS:Patient cohorts receiving cetuximab from a prior investigation (PMID: 30305811) constituted the training and testing sets. For external validation, an independent cohort of consecutive patients with RAS wild-type CRLM patients was prospectively enrolled from other institutions between January and December 2018. Utilizing the PyTorch deep learning framework, we initially developed individual radiomic and genetic signatures. Subsequently, computed tomography (CT) images and genetic data were processed through pre-trained ResNet18 and Random Forest models, respectively. The final classification probability of the integrated model was calculated by weighted summation of the output probabilities from the two models, with weights of 3 and 7, respectively. RESULTS:The developed signature demonstrated predictive capability for cetuximab sensitivity, with area under the curve (AUC) values of 0.75 for the radiomic model, 0.81 for the genetic model, and 0.86 for the combined model. In contrast, it did not predict response to chemotherapy (fusion signature AUC: 0.54). Within cohorts treated with cetuximab, the fusion signature proved superior to established biomarkers for identifying treatment-sensitive cases (hazard ratio (HR), 17.9; 95% confidence interval (CI), 3.22-154.31; P = 0.003). Furthermore, it showed a significant correlation with progression-free survival (PFS), with a median PFS of 9.0 versus 5.0 months (HR, 0.44; 95% CI, 0.20-0.99; P = 0.047). DISCUSSION:The proposed multi-omics signature showed a promising ability to identify RAS wild-type CRLM patients more likely to benefit from anti-EGFR therapy using routinely available pretreatment CT and genomic data. Although the external validation cohort was relatively small and further validation is still needed, it may provide a practical tool for early treatment stratification and individualized decision-making. CONCLUSIONS:The developed multi-omics signature demonstrated promising performance in predicting sensitivity to anti-EGFR therapy and may help refine survival-based treatment stratification in patients with RAS wild-type CRLM.
Both adaptive immune cells, particularly T cells, and innate lymphoid cells, such as Natural Killer (NK) cells, play critical yet complementary roles in tumor immunity. While T cells mediate antigen-specific cytotoxic responses, NK cells provide rapid, innate recognition and elimination of transformed cells, and their interplay can significantly enhance antitumor immunity, offering potential improvements in immunotherapeutic efficacy. Recent studies indicate that NK cells are essential for recruiting type 1 conventional dendritic cells (cDC1) into the tumor microenvironment, which in turn promotes the activation and expansion of tumor-specific CD8+ T cells. Conversely, activated T cells secrete interleukin-2 (IL-2), a cytokine crucial for NK cell proliferation, survival, and cytotoxic function, establishing a positive feedback loop that amplifies immune responses against malignancies. Tumors, however, exploit immune evasion mechanisms, including modulation of the activating receptor NKG2D and its ligands MICA and MICB, to escape detection by both NK and T cells. Furthermore, these lymphocytes share important inhibitory and activating receptor pairs, such as CD161-CLEC2D, TIGIT-CD155, and NKG2A/CD94-HLA-E, which regulate cytotoxic potential and maintain immune homeostasis. Targeting these shared checkpoints or modulating receptor-ligand interactions represents a promising strategy to overcome tumor immune evasion. By elucidating the coordinated actions of NK and T cells and their shared regulatory pathways, novel immunotherapeutic approaches can be developed to enhance antitumor responses, improve treatment efficacy, and ultimately improve clinical outcomes for cancer patients.
Introduction: Periodontitis (PD) and oropharyngeal cancer (OPC) are distinct diseases, but emerging evidence suggests potential molecular and immunological intersections, particularly in chronic inflammation influencing carcinogenic processes. Methods: Transcriptomic analysis combining bulk RNA-seq and single-cell RNA-seq data (PD: GSE10334; OPC: GSE3292) was performed. Co-expression networks were constructed, and feature selection was conducted using Random Forest and LASSO regression. Survival analysis, ROC validation, immune profiling, and molecular docking were used for further validation. Functional assays, including CCK-8, colony formation, and wound healing assays, were performed to evaluate the effects of overexpression of FAM117B and ZDHHC21 in FaDu cells. Results: Transcriptome analysis revealed 3,450 DEGs in PD and 447 in OPC. Twelve shared genes, including FAM117B and ZDHHC21, were identified. These genes showed significant survival benefits (HR = 0.71, p < 0.05) and strong diagnostic performance (FAM117B AUC = 0.87 in PD, 0.89 in OPC). Immune profiling showed correlations with macrophages, NK cells, dendritic cells, and plasma cells. Functional assays demonstrated that overexpression of FAM117B and ZDHHC21 significantly inhibited cell proliferation, colony formation, and migration. Cephaeline and Sanguinarine showed strong binding affinities for FAM117B and ZDHHC21, respectively, with MD simulations confirming their potential as computationally predicted binders. Discussion: The shared molecular signatures between PD and OPC suggest that chronic peri-odontal inflammation may foster an oncogenic microenvironment conducive to OPC progression. FAM117B and ZDHHC21 appear central in this convergence, linking immune dysregulation with tumor biology. The therapeutic potential of Cephaeline and Sanguinarine could bridge insights with clinical applications. Conclusion: FAM117B and ZDHHC21 are key molecular targets linking PD and OPC. Ceph-aeline and Sanguinarine are promising therapeutic agents that offer novel insights into the PD-OPC molecular convergence, providing a basis for further experimental validation and clinical translation.
