BACKGROUND/AIM:Colon cancer is a prevalent and life-threatening malignancy worldwide. Recent studies have focused on how microRNAs (miRNAs) act as post-transcriptional modulators in colon cancer progression. Herein, this study aimed to identify the impact of miRNAs that are decreased in colon cancer and to investigate their regulatory mechanisms. MATERIALS AND METHODS:Differentially expressed miRNAs (DEmiRNAs) and genes (DEGs) were identified through analysis of miRNA sequencing and RNA sequencing data from normal and tumor tissues in The Cancer Genome Atlas (TCGA). Expression levels were validated by quantitative polymerase chain reaction (qPCR) in both tissues and cell lines. Functional effects of miRNAs were evaluated by assessing cell viability, proliferation, migration, and invasion following transfection with miRNA mimics. RESULTS:Analysis of miRNA-seq data from the TCGA database identified hsa-miR-328-3p as a miRNA consistently downregulated across all stages of colon cancer. This downregulation was independently validated in colon cancer patient tissues by qPCR. Functional assays demonstrated that enforced expression of hsa-miR-328-3p significantly reduced cell viability, proliferation, migration, and invasion in colon cancer cell lines, supporting its tumor-suppressive role. To elucidate the molecular mechanism underlying these inhibitory effects, target gene analysis was performed. Engrailed homeobox 2 (EN2) was identified as a potential target of hsa-miR-328-3p, and a dual-luciferase assay confirmed that EN2 is directly regulated by hsa-miR-328-3p. CONCLUSION:Collectively, these findings indicate that hsa-miR-328-3p is frequently downregulated in colon cancer and functions as a tumor suppressor by negatively regulating its target gene, EN2, thereby contributing to colon cancer malignancy. EN2 may serve as a potential diagnostic biomarker for colon cancer, while restoration of hsa-miR-328-3p expression represents a promising therapeutic strategy. Further studies are needed to clarify the precise molecular mechanisms linking the hsa-miR-328-3p/EN2 axis to colon cancer progression.
Giant cell-rich tumors of soft tissue present a significant diagnostic challenge due to pronounced morphological overlap, particularly in limited tissue samples. This review provides a streamlined update on the clinicopathological and molecular features of nine distinct entities: nodular fasciitis, juvenile xanthogranuloma, phosphaturic mesenchymal tumor, tenosynovial giant cell tumor, giant cell fibroblastoma, giant cell-rich solitary fibrous tumor, giant cell tumor of soft tissue, keratin-positive giant cell-rich tumor, and undifferentiated pleomorphic sarcoma. While these neoplasms are unified by a prominence of multinucleated giant cells, recent genomic insights have identified signature, diagnostically defining molecular drivers. We highlight characteristic gene fusions, including USP6, NTRK1, FN1, CSF1, COL1A1-PDGFB, NAB2-STAT6, and HMGA2-NCOR2, as well as entities characterized by non-recurrent or highly complex genomic alterations. Synthesizing these data, this review underscores the critical role of advanced molecular testing in resolving diagnostic ambiguities, refining tumor classification, and guiding targeted therapeutic strategies.
BACKGROUND/AIM:Microsatellite-stable (MSS) colorectal cancer (CRC) generally responds poorly to immune checkpoint blockade, but some MSS tumors are T-cell rich. We examined whether such infiltration reflected effective immunity or functional immune constraint. CASE REPORT:A 77-year-old woman underwent resection of a mismatch repair-proficient (pMMR), MSS, low-mutational-burden CRC with a synchronous adenoma. Whole-exome sequencing of tumor, adenoma and adjacent normal tissue detected no shared high-confidence somatic mutations between tumor and adenoma within the sensitivity of this WES analysis and identified tumor-specific APC, KRAS and TP53 alterations. Tumor single-cell RNA sequencing yielded 7,569 cells, with T-lineage populations comprising 83.5%. Cytotoxic T cells showed cytolytic and dysfunction-associated features, regulatory T cells (Tregs) showed suppressive remodeling, and Th17 cells showed inflammatory/profibrotic programs. CellChat nominated stromal MIF/FN1-CD74/CD44 and extracellular-matrix communication with T-cell compartments. CONCLUSION:This molecular case report shows that T-cell abundance and immune effectiveness can be uncoupled in MSS CRC.
BACKGROUND/AIM:Lung adenocarcinoma (LUAD) exhibits substantial molecular heterogeneity and variable clinical outcomes, highlighting the need for biomarkers that reflect core tumor biological processes. Centrosome-associated proteins regulate mitotic fidelity and genome stability, yet their roles in LUAD remain incompletely defined. In this study, we systematically characterized mitotic spindle organizing protein 1 (MOZART1; MZT1) and related family members in LUAD. MATERIALS AND METHODS:We performed integrated analyses combining bulk transcriptomic datasets, survival modeling, gene set enrichment, immune deconvolution, machine-learning based prognostic modeling, and single-cell RNA sequencing. Expression patterns and clinical associations of MZT family genes were evaluated across pan-cancer and LUAD cohorts. RESULTS:MZT family genes were consistently upregulated in tumor tissues, with MZT1 showing the most robust expression pattern. Elevated MZT1 expression was significantly associated with reduced overall survival. Functional analyses revealed coordinated activation of proliferative and genome maintenance pathways, including G2/M checkpoint regulation, E2F and MYC signaling, and DNA repair. A multivariable analysis indicated that the prognostic association of MZT1 was reduced after adjusting for canonical proliferation markers, suggesting partial overlap with established proliferation signals. The LASSO-based Cox model demonstrated stable time-dependent predictive performance at 1-, 3-, and 5-year survival. Immune analyses indicated associations between MZT1 expression and tumor microenvironmental features. Single-cell analysis showed that MZT1 expression was predominantly enriched in malignant epithelial cells and associated with proliferative cellular states. Protein-level validation supported concordance with transcriptomic findings. CONCLUSION:MZT1 is a proliferation-associated marker that integrates clinical risk, transcriptional programs, cellular heterogeneity, and predictive modeling in LUAD, providing a potential framework for biomarker development and risk stratification.
BACKGROUND/AIM:Metastatic spread defines the lethality of cervical cancer (CC). Connective tissue growth factor (CTGF/CCN2) regulates cell- extracellular matrix interactions but its role in CC is not well-defined. This study investigates the role of CTGF in driving CC invasive growth and its prevalence in patient tissues. MATERIALS AND METHODS:CC spheroids (C33A, HT3) were treated with recombinant human CTGF (rhCTGF) or a function-blocking antibody (IgG CTGF). Invasive growth was assessed via 3D spheroid assay using a Celigo imaging cytometer. Cancer stem cell (CD133, CD44) and epithelial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin) were analyzed by immunofluorescence. CTGF expression was evaluated using a tissue microarray containing 69 cases in triplicate from pre-invasive, invasive (FIGO I-III), and metastatic cervical lesions, quantified via immunofluorescence scoring. RESULTS:Functional blockade of CTGF significantly reduced 3D spheroid invasive growth in C33A and HT3 cells (p<0.0001). Immunofluorescence revealed that CTGF modulation altered spatial distribution of key proteins: rhCTGF induced surface clustering of CD133 and peripheral N-cadherin enrichment, while CTGF blockade was associated with apparent nuclear/perinuclear enrichment of CD133 and E-cadherin and reduced N-cadherin signal. In patient tissue cores, metastatic samples exhibited the highest CTGF fluorescence intensity. High CTGF expression [immunoreactivity score (IRS) ≥ 6] was most prevalent in FIGO stage I (35.5%) compared to stage III (10.0%). Kaplan-Meier analysis revealed that high CTGF mRNA expression was associated with significantly reduced recurrence-free survival (log-rank p=0.0032). CONCLUSION:In 3D models of CC, CTGF appears to regulate an invasive phenotype, presumably by controlling aberrant localization of stemness and EMT markers. Its apparently elevated expression in early-stage cervical carcinomas and metastases, combined with its prognostic value for recurrence-free survival, suggests that CTGF may be involved in triggering the potential for metastasis and could therefore serve as an early prognostic biomarker.
Mutual information (MI)-based approaches have increasingly been applied to cancer genomics; however, their use for genome-wide prognostic biomarker discovery remains relatively underexplored. The present article summarizes the conceptual workflow of Mutual Information-based Prognostic Omics Gene (MI-POG) based on previously published applications in breast cancer, lower-grade glioma, and other cancer datasets. The framework consists of clinical endpoint discretization, genome-wide MI-based screening, candidate ranking, and downstream validation using conventional survival-analysis approaches. Previous MI-POG applications identified solute carrier family 20 member 1 (SLC20A1) as a prognostic biomarker in hormone receptor-positive breast cancer. Elevated SLC20A1 expression was associated with unfavorable survival outcomes and was independently validated in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort. Methodological analyses demonstrated how survival endpoints can be integrated into an information-theoretic framework through fixed-time outcome discretization, enabling model-independent assessment of molecular-clinical dependencies. Applications across multiple cancer datasets suggested the potential applicability of the framework across biologically distinct tumor types, although further validation will be required to establish its robustness and generalizability. In conclusion, MI-POG can be formalized as an information-theoretic framework for genome-wide identification of prognostic biomarkers by quantifying molecular-clinical dependencies using mutual information. Representative applications from previously published studies suggest that MI-POG may complement conventional survival-analysis approaches and provide a useful strategy for biomarker discovery, although additional benchmarking and prospective validation will be required.
BACKGROUND/AIM:Kinase inhibitors (KIs) can cause cardiotoxicity through mechanisms overlapping with statin cardioprotective pathways, yet their effects on these pathways in cardiomyocytes remain uncertain. We evaluated six literature-defined statin-relevant gene sets using transcriptomic and proteomic data. MATERIALS AND METHODS:Pre-ranked gene set enrichment analysis was performed for 23 KIs in primary cardiac cells (GSE146096; n=319) and iPSC-derived cardiomyocytes (GSE217421; n=541), with cross-platform analysis of 21 KIs by shotgun proteomics (PXD014791; n=300). Pathway-specific concordance was assessed by Spearman correlation with Benjamini-Hochberg correction; protein scores were estimated after adjustment for cell line. RESULTS:KI effects were heterogeneous. The anti-fibrotic pathway showed nominal concordance across the two transcriptomic datasets (ρ=0.495, p=0.016, q=0.098; 91% direction concordance) and significant cell-line-adjusted transcriptomic-proteomic concordance (ρ=0.644, p=0.0016, q=0.0081). Nilotinib reproducibly upregulated NF-κB pathway genes [normalized enrichment score (NES)=+2.29 and +2.18 in discovery and validation], with targeted inter-gene-correlation-adjusted testing supporting higher NF-κB expression than under rosuvastatin (CAMERA p=3.54×10-8). No global cross-omics summary remained significant after harmonizing pathway universes and accounting for repeated pathways. CONCLUSION:KI effects on statin-relevant pathways were pathway-specific. Anti-fibrotic concordance and nilotinib-associated NF-κB upregulation are hypothesis-generating candidates for experimental validation.
BACKGROUND/AIM:Endoplasmic reticulum resident protein 44 (ERP44), a protein disulfide isomerase family member, has been implicated in tumor biology, but its role in lower-grade glioma (LGG) remains unclear. This study investigated the prognostic significance and biological function of ERP44 in LGG, focusing on proliferation and temozolomide (TMZ) resistance. MATERIALS AND METHODS:ERP44 expression, clinicopathological associations, and prognostic value were analyzed using The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Chinese Glioma Genome Atlas (CGGA) datasets. Time-dependent receiver operating characteristic (ROC) curves, Cox regression, and a prognostic nomogram were constructed. Differential expression, Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO) enrichment, immune infiltration, and drug sensitivity analyses were performed. Functional validation was conducted in SW1088 and SW1783 cells using shRNA-mediated ERP44 knockdown, followed by RT-qPCR, western blotting, CCK-8, colony formation, and TMZ IC50 assays. Subcutaneous xenograft models with or without TMZ treatment were used for in vivo validation. RESULTS:ERP44 was markedly upregulated in LGG and associated with higher WHO grade, IDH wildtype status, 1p/19q non-codeletion, and poor survival in TCGA and CGGA cohorts. ERP44 showed strong prognostic performance and improved risk stratification in a multivariable nomogram. Enrichment analyses linked high ERP44 expression to immune/inflammatory pathways and reduced neuronal functional signatures. ERP44 positively correlated with immune infiltration, proliferation/stemness markers, and predicted TMZ resistance, while its knockdown inhibited proliferation and colony formation, reduced TMZ IC50, suppressed xenograft growth, enhanced TMZ efficacy, and decreased Ki67 positivity. CONCLUSION:ERP44 is a prognostic biomarker that promotes LGG proliferation and TMZ resistance, suggesting its potential as a therapeutic target.
BACKGROUND/AIM:In breast cancer, knowledge of the associations between clinicopathologic characteristics, genetic changes, and subtype-specific patterns is expanding. This study investigated how pathological and clinical variables affect the actionability of Next Generation Sequencing (NGS)-based tumor molecular data. MATERIALS AND METHODS:227 breast cancer patients referred to Genekor's laboratory for tumor molecular profile analysis were included in the study. Pathology records were used to assess critical clinicopathological features, including HER2, ER, PR, Ki67, grade, metastatic site, and age. A 1021-gene NGS-based multigene panel was utilized to assess tumor biology alongside tumor mutational burden (TMB) and microsatellite instability (MSI). RESULTS:Comprehensive genomic profiling revealed that 95.6% of the patients harbored at least one oncogenic or likely oncogenic alteration, highlighting the high diagnostic yield of NGS-based testing. Distinct subtype-specific patterns were observed: HR+/HER2- tumors were enriched for PIK3CA and ESR1 gene alterations, whereas triple-negative breast cancer (TNBC) was dominated by TP53 alterations. Clinically actionable alterations were most common in HR+/HER2- tumors (~60% on-label), whereas TNBC more often harbored off-label or trial-associated targets. The inclusion of tumor-agnostic biomarkers (TMB/MSI) increased on-label actionability up to 64.5% in HR+/HER2- tumors, primarily driven by TMB-high cases. Median TMB values were low, and age was the only independent predictor. Furthermore, the presence of actionable alterations was significantly higher in metastatic tumors, and TP53 alterations were associated with aggressive tumor characteristics. CONCLUSION:Comprehensive NGS-based genomic profiling identifies clinically actionable alterations in over half of breast cancer patients, with substantial variability across molecular subtypes. The HR+/HER2- subtype demonstrates the highest prevalence of on-label actionable biomarkers. These findings support the routine implementation of comprehensive genomic profiling, especially in metastatic HER2-negative breast cancer, to guide precision oncology strategies and enable enrollment in biomarker-driven clinical trials.
BACKGROUND/AIM:Ewing sarcoma is a fusion-driven malignancy with low tumor mutational burden, making recurrent tumor-associated antigens with favorable tumor-to-normal contrast central to immunotherapy development. We converted the Deng et al.-defined 32-gene Ewing Sarcoma Specific Signature (ESS32) into a practical target atlas by integrating tumor RNA expression with normal-tissue context, protein evidence, subcellular localization, and therapeutic accessibility. MATERIALS AND METHODS:A 38-gene set was analyzed, including ESS32 and six comparator antigens (STEAP1, LINGO1, PRAME, CD99, CD276/B7-H3, and ENPP1). Eight Gene Expression Omnibus datasets (n=854 samples) were assigned predefined roles spanning tumor-versus-skeletal-muscle comparison, broad normal-organ context, EWSR1::FLI1 perturbation, tumor-only support cohorts, cell-line models, and cross-sarcoma comparison. Results were overlaid with Human Protein Atlas and published proteomic/surfaceome evidence. RESULTS:In GSE17674, the strongest tumor-enriched transcripts included NKX2-2, NPY1R, STEAP1, RBM11, RNF182, LIPI, CD99, STEAP2, LOXHD1, and DCDC2. Normal-tissue and compartment data substantially reordered RNA-only ranking. NKX2-2 showed the strongest Ewing-associated signal but encodes a nuclear transcription factor, favoring peptide-HLA/T-cell receptor (TCR) or vaccine development. RBM11 and LIPI emerged as high-interest intracellular/secretome-associated candidates, with an explicit epididymal/male reproductive caveat for LIPI. CD99 and NPY1R illustrated normal-cell reservoir and receptor-distribution constraints. CONCLUSION:ESS32 should be interpreted as an EWSR1::FLI1-associated RNA discovery set, not as a pre-validated target panel. Practical nomination requires integration of RNA enrichment, normal-tissue distribution, protein evidence, cellular compartment, and modality compatibility before nomination of TCR, vaccine, antibody-drug conjugate (ADC), chimeric antigen receptor (CAR), radioligand, or validation-first candidates.
BACKGROUND/AIM:Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide. Although immunotherapy has improved outcomes for a subset of patients, its limited efficacy in many cases highlights the need for a more comprehensive understanding of the CRC immune microenvironment. This study aimed to characterize the molecular landscape of the CRC immune microenvironment using an integrated multi-omics approach and to identify candidate regulatory molecules associated with immune remodelling. MATERIALS AND METHODS:We integrated structural variation, DNA methylation, chromatin accessibility, proteomic, and phosphoproteomic data generated from an in-house CRC cohort with transcriptomic data from The Cancer Genome Atlas (TCGA). Analyses focused on 1,539 immune-related genes (IRGs) associated with CD4+ T cells, B cells, and natural killer (NK) cells. Multi-layered genomic and proteomic analyses were performed to identify altered immune-related pathways, hub genes, candidate transcription factors, and upstream kinases. RESULTS:Higher infiltration of CD4+ T cells, B cells, and NK cells was associated with CRC. IRGs exhibited widespread alterations across genomic, epigenomic, transcriptomic, proteomic, and phosphoproteomic levels. IL10, LEP, ITGAM, and EGFR emerged as candidate hub genes. EGFR phosphorylation at S991 and T693 was significantly decreased in CRC. STAT2 and HSF1 were identified as candidate upstream transcription factors, while CDK2 emerged as a candidate upstream kinase associated with immune infiltration and immune checkpoint expression. CONCLUSION:This study provides a systematic multi-omics characterization of immune microenvironment remodelling in CRC and identifies candidate molecular regulators that may serve as potential targets for future immunotherapy research.
BACKGROUND/AIM:Epidermal growth factor receptor pathway substrate 8 (EPS8) is an adaptor protein implicated in tumor progression and therapeutic resistance; however, its role in mitochondrial homeostatic signaling and antioxidant regulation remains unclear. This study examined the effects of EPS8 modulation in lymph node carcinoma of the prostate (LNCaP) and enzalutamide-resistant LNCaP (LNCaP-Enz) cells. MATERIALS AND METHODS:LNCaP-Enz cells were generated by long-term exposure to enzalutamide and maintained in 5 μM enzalutamide. EPS8 expression was modulated by plasmid-mediated overexpression or shRNA-mediated knockdown. Superoxide dismutase (SOD) activity and cellular adenosine triphosphate (ATP) levels were measured using colorimetric assays. Mitochondrial membrane potential (ΔΨm) was evaluated using JC-1 fluorescence, and mitochondrial staining patterns were qualitatively examined using MitoTracker Green staining. Protein expression associated with antioxidant defense, mitochondrial dynamics, mitochondrial stress response, mitochondrial biogenesis, and AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling was analyzed by western blotting. RESULTS:EPS8 overexpression increased SOD activity and the expression of SOD1 and SOD2, whereas EPS8 knockdown reduced these antioxidant parameters. Conversely, EPS8 silencing increased cellular ATP levels and enhanced JC-1 red fluorescence patterns. EPS8 silencing increased MFN1 and OPA1 expression and reduced DRP1 expression, consistent with a fusion-associated mitochondrial profile. EPS8 silencing also increased SIRT1, PGC-1α, NRF1, TFAM, p-AMPK/AMPK, and p-mTOR/mTOR, but reduced HSP60, LONP1, ATF5, and CEBPβ expression. CONCLUSION:EPS8 differentially regulates SOD-associated antioxidant capacity and mitochondrial homeostatic signaling in LNCaP-based cell models. Further studies are required to determine whether EPS8 modulation affects enzalutamide responsiveness.
There is a significant need to improve treatment efficacy for patients with glioma. Therefore, we have analyzed the literature for the role of circular RNAs (circRNAs) with respect to selected pathology-related topics of glioma. We have focused on upregulated circRNAs with efficacy in preclinical in vivo models. The identified circRNAs cover the following topics: Temozolomide (TMZ) resistance, transmembrane and secreted proteins, wingless-related integration site (WNT) signaling, cytoskeleton dynamics, cell-cell and cell-extracellular matrix interactions, as well as circRNAs with additional functions. We describe possible therapeutic tools and challenges with respect to delivery of the corresponding inhibitory agents.
BACKGROUND/AIM:Notch signaling exerts context-dependent effects in cancer; however, the prognostic relevance of inherited variation in Notch-related genes in prostate cancer remains unclear. We investigated whether germline single-nucleotide polymorphisms (SNPs) in Notch pathway genes are associated with clinical outcomes in men receiving androgen deprivation therapy (ADT). PATIENTS AND METHODS:We genotyped 222 SNPs across 24 Notch pathway-related genes in 630 patients with advanced prostate cancer. Associations with cancer-specific survival (CSS) and overall survival (OS) were assessed using Cox proportional hazards models. Integrative bioinformatics analyses, including pooled transcriptomic dataset analysis, expression quantitative trait locus analysis, and pathway enrichment, were performed to assess functional relevance. RESULTS:Multiple SNPs were significantly associated with CSS and OS, with Yes1-associated transcriptional regulator (YAP1) rs1894116 showing the strongest prognostic signal. The minor G allele was associated with a 26% reduction in prostate cancer-specific mortality and a 22% reduction in all-cause mortality, independent of established clinical predictors. Functional annotation suggested that rs1894116 may be linked to increased YAP1 expression. Pooled transcriptomic analyses showed lower YAP1 expression in tumors than in normal tissue, while higher YAP1 expression correlated with more favorable outcomes. YAP1-correlated genes were enriched in the focal adhesion pathway, suggesting a tumor-suppressive YAP1-focal adhesion axis, particularly involving vinculin. CONCLUSION:Germline variation in the Notch-YAP axis, notably YAP1 rs1894116, predicts survival in patients with prostate cancer treated with ADT. Elevated YAP1 expression and coordinated activation of focal adhesion components may be associated with less aggressive disease. These findings provide mechanistic insight into Notch signaling in prostate cancer and highlight YAP1 and its variants as potential biomarkers for risk stratification and personalized therapy.
BACKGROUND/AIM:Cancer metabolism is often viewed as a cooperative reliance on glucose and glutamine; however, whether these nutrients can enforce discrete, non-overlapping metabolic states remains unclear. This study aimed to isolate nutrient-specific regulatory programs. MATERIALS AND METHODS:MDA-MB-231 human breast cancer cells were cultured under four distinct metabolic environments: glucose/glutamine nutrient-repleted (fed), dual glucose/glutamine deficiency, and isolated repletion of either glucose or glutamine. Groups were evaluated for integrated transcriptomic, metabolomic, and lipidomic profiles to identify only the non-redundant, nutrient-enforced architectures. RESULTS:The data show a mutually restrictive mechanistic state. Glutamine functions as a metabolic architect, restoring glycolytic enzyme transcripts (without lactate production), while inducing PDK1/3 which would decouple glycolysis from the TCA cycle. These changes are concomitant with a glutamine flux toward reductive TCA-driven lipogenesis, citric acid overflow, sterol synthesis (SREBF1/2), structural membrane expansion (phospholipids/sphingolipids) and the unique production of alanine as a nitrogen pool, independent of glycolytic flux. Conversely, glucose alone acts as the executor, licensing chromatin engagement, DNA replication, and mitotic progression. Glucose alone resolved ER stress, restored hexose-phosphate-derived glycosylation (mannose-6-phosphate), enabled lactic acid production, and diverted excess carbon into a triglyceride storage pool (>40% of lipids). Notably, each nutrient suppressed core elements of the other's program, revealing a reciprocal activation-braking system. Interestingly, ATP yield from glucose or glutamine alone were comparable, but not arbitrary; instead, aligned with the functional state of the cell. Glucose alone supported glycolytic phosphorylation and proliferative execution, as marked by lactate accumulation, whereas glutamine alone supported Krebs cycle-related phosphorylation, characterized by citrate accumulation and the maintenance of cellular structure and membrane infrastructure. CONCLUSION:Glucose and glutamine enforce a balance of two independent, reciprocally regulated metabolic states. This data provides a systems-level explanation for metabolic resilience in cancer and may lead to the identification of nutrient-specific targets for combination therapy.
BACKGROUND/AIM:MAPK13 (p38δ) is a frequently identified but often ignored MAP kinase in epithelial gene signatures. This study aimed to characterize p38δ expression in normal and cancerous epithelial tissues, investigate its possible role in epithelial identity, epithelial-mesenchymal transition (EMT), cancer progression, drug resistance, and evaluate its prognostic value. MATERIALS AND METHODS:Quantitative analysis assessed p38δ expression across diverse normal human epithelial tissues and correlated it with epithelial markers in cancer cell lines. A p38δ gene signature was analyzed for pathway enrichment in epithelial processes. p38δ expression was compared between epithelial and mesenchymal lung cancer models and in EGFR inhibitor-resistant cells. Prognostic data on cancer patient survival was collected for various cancer types. Functional studies included p38δ knockdown to evaluate EMT markers, E-cadherin/EpCAM, Vimentin and proliferation, and exogenous p38δ expression to assess cell growth/migration. p38δ mRNA and protein levels were measured in Osimertinib-resistant cell lines. RESULTS:p38δ was predominantly expressed across diverse normal epithelial tissues and correlated strongly with epithelial markers in cancer cells. Its gene signature enriched pathways vital for epithelial architecture, adhesion, and differentiation. p38δ was consistently higher in epithelial-enriched lung cancer models and suppressed in EGFR inhibitor-resistant cells. Prognostic impact was context-dependent: high expression correlated with favorable overall survival in ovarian, lung, and rectum cancers, but inversely with outcomes in liver, breast, and pancreatic cancers. Functionally, p38δ knockdown induced EMT and increased proliferation. Conversely, exogenous p38δ suppressed cell growth/migration. Crucially, acquired Osimertinib resistance consistently corresponded with significant reductions in p38δ levels. CONCLUSION:p38δ is a critical marker and regulator of epithelial identity. Its dysregulation and loss are systematically linked to EMT and drug resistance in cancer. Given its complex, context-dependent prognostic value and functional significance, p38δ holds significant potential as a therapeutic target.
BACKGROUND/AIM:The inflammatory microenvironment plays a critical role in stomach adenocarcinoma (STAD); however, the clinical relevance of inflammation-related genes remains unclear. This study aimed to identify key inflammation-related hub genes and evaluate their prognostic, immunological, and therapeutic significance in STAD. MATERIALS AND METHODS:This study integrated six transcriptomic datasets from GEO and TCGA databases to identify differentially expressed genes (DEGs) between STAD and normal tissues. Inflammation-related DEGs were enriched using the MSigDB hallmark gene set, followed by protein-protein interaction (PPI) network analysis to identify hub genes. The expression, diagnostic value, prognostic significance, immune microenvironment associations, and drug sensitivity of the key hub gene, NOX4, were comprehensively evaluated using TCGA clinical data and diverse bioinformatics platforms. RESULTS:NOX4 was identified as a significantly overexpressed inflammation-related hub gene in STAD, correlating with Helicobacter pylori infection and advanced pathological staging. High NOX4 expression predicted a poor prognosis. A nomogram integrating NOX4 expression, age, and T stage achieved AUC values of 0.730, 0.719, and 0.706 for 1-, 3-, and 5-year overall survival, respectively. Functional enrichment revealed NOX4's involvement in pathways such as cytoskeletal organization and ECM-receptor interactions. Immunologically, high NOX4 expression correlated with increased M2 macrophage infiltration, decreased memory B cells and resting CD4+ memory T cells, and higher TIDE scores, suggesting potential immunotherapy resistance. Mutation analysis showed distinct high-frequency mutations (e.g., TP53, TTN) associated with NOX4 levels. Furthermore, drug sensitivity analysis indicated that high NOX4 expression was linked to higher IC50 values for 14 chemotherapeutic agents, including cisplatin and sorafenib, indicating potential chemoresistance. CONCLUSION:NOX4 emerges as a key regulator of the STAD inflammatory microenvironment and a robust prognostic biomarker. Its role in immune modulation and chemoresistance provides novel insights for developing precision therapeutic strategies in STAD.
BACKGROUND/AIM:Colorectal cancer (CRC) is a major global health burden with increasing incidence and significant mortality, particularly in advanced stages. Genetic susceptibility and inflammation-related pathways, including cytokine signaling, are increasingly recognized as key contributors to CRC pathogenesis. Interleukin-13 (IL-13) polymorphisms, particularly rs1800925 and rs20541, have been implicated in cancer biology; however, their roles in CRC remain inconclusive. MATERIALS AND METHODS:A hospital-based case-control study was conducted in Taiwan, including 362 CRC patients and 362 age- and sex-matched controls. Genomic DNA was extracted from peripheral blood, and IL-13 rs1800925 and rs20541 genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism. Associations between genotypes and CRC risk and clinicopathological features were estimated using odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS:The genotype distributions of rs1800925 and rs20541 in controls conformed to the Hardy-Weinberg equilibrium (p=0.2098 and 0.7888, respectively). No overall significant associations were observed between IL-13 polymorphisms and CRC susceptibility. For rs1800925, the CT and TT genotypes showed ORs of 1.20 (95%CI=0.88-1.65, p=0.2772) and 1.42 (95%CI=0.80-2.54, p=0.2844), respectively. For rs20541, the AG and AA genotypes exhibited ORs of 1.11 (95%CI=0.82-1.51, p=0.5581) and 1.21 (95%CI=0.74-1.98, p=0.5185). However, rs1800925 CT+TT genotypes were associated with significantly increased risk of distant metastasis at diagnosis (OR=2.12, 95%CI=1.40-3.20, p=0.0005), while rs20541 AG+AA genotypes were associated with advanced stage (OR=1.50, 95%CI=1.03-2.19, p=0.0423) and metastatic disease at diagnosis (OR=2.16, 95%CI=1.39-3.36, p=0.0007). CONCLUSION:Although IL-13 rs1800925 and rs20541 polymorphisms are not associated with CRC susceptibility, they may be associated with clinicopathological aggressiveness at diagnosis, highlighting their potential utility in stratifying CRC severity, particularly in the Taiwanese population.
BACKGROUND/AIM:Glioblastomas (GBMs) are aggressive primary brain tumors characterized by immune evasion and therapeutic resistance. Here, we aimed to decipher the transcriptional landscape of disease aggressiveness in GBM by employing a multi-layered transcriptomic approach. MATERIALS AND METHODS:We performed transcriptome-wide differential expression analysis using TCGA IDH-wildtype GBM data after stratifying the tumors based on epithelial-mesenchymal transition (EMT) signature scores. Functional and pathway enrichment analyses, STRING-based protein-protein interaction (PPI) network assisted with centrality and random-walk analyses, univariate and multivariate Cox survival analyses, Gene Set Enrichment Analysis (GSEA), single-cell RNA (scRNA) sequencing analysis, CIBERSORTx immune deconvolution, and T cell exhaustion profiling were performed. Key findings were validated in independent datasets. RESULTS:We identified 2088 protein-coding genes associated with disease aggressiveness in GBM. Among 1070 upregulated genes, 432 were risk-associated and enriched for immune-inflammatory pathways. Network analysis identified IL1B and CD4 as top hub genes, both of which were independently prognostic for poor overall survival. scRNA-seq analysis attributed CD4 expression to tumor-infiltrating T cells, more than half of which also co-expressed IL1B. CIBERSORTx deconvolution suggested progressive accumulation and exhaustion of CD4+ T memory resting cells and Tregs along disease aggressiveness. CCL5 is preferentially expressed by tumor cells, whereas CCR1 and CCR5 by CD4+ T cells, supporting a CCL5-CCR1/CCR5-associated recruitment pattern. IL1B correlates with accumulation of exhausted CD4+ T memory cells and aligns with enrichment of disease aggressiveness and inflammatory signatures. IL1R1/NF-κB-related transcriptional targets downstream are coordinately upregulated in tumors having high EMT scores and high IL1B expression. CONCLUSION:CD4+ T cells are recruited to GBM tumors preferentially via the CCL5-CCR1/CCR5 axis, where their exhaustion-related IL1B upregulation along disease progression aligns with mesenchymal reprogramming that hallmarks disease aggressiveness in IDH-wildtype GBM.
BACKGROUND/AIM:Sialyltransferase ST6GAL1 is known to be upregulated in various cancer types, including rectal cancer, and is linked to poor prognosis. This enzyme catalyzes the addition of sialic acids to various proteins, altering their activity and function. Our lab has previously shown that ST6GAL1 causes resistance to chemoradiation therapy (CRT) in rectal cancer, via sialylation of tumor necrosis factor receptor 1 (TNFR1). This leads to decreased TNFR1 mediated cell death/apoptosis. We aimed to elucidate whether beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), which cleaves ST6GAL1, has a role in treatment response to CRT and whether its overexpression (OE) could improve response to CRT. MATERIALS AND METHODS:We first assessed BACE1 and ST6GAL1 in pre-treatment biopsies from rectal cancer patients. We then evaluated the effects of BACE1 modulation in CRC cell lines. The high BACE1-expressing CRC cell line SW1463 was utilized for inhibition studies, and SW620 CRC cells lines were additionally lentivirally transfected for OE of BACE1 (validated by flow cytometry, qPCR, Western Blotting, and activity assay). BACE1 OE cells were also utilized for response to CRT. RESULTS:Analysis of patient biopsies showed that BACE1 mRNA was significantly increased in patients with a complete response to CRT. SW1463 colorectal cancer cells treated with a BACE1 inhibitor had increased cell-surface sialylation and increased survival after CRT compared to vehicle-treated cells. BACE1 overexpressing SW620 CRC clones exhibited protein expression and activity of BACE1, with reduced ST6GAL1 protein. BACE1 OE colorectal cancer cells also had significantly increased apoptosis and decreased survival after CRT. BACE1 OE clones had decreased sialylation of the apoptosis receptor, TNFR1. CONCLUSION:Collectively, we found that overexpressing BACE1 altered ST6GAL1-mediated CRT resistance in CRC cells. BACE1 enzymatic cleavage of ST6GAL1 may be a potential target for improving therapeutic response to CRT in rectal cancer.
