CircRNAs are an important class of non-coding RNAs, which are produced via back-splicing of exons and/or intron sequences of precursor mRNAs and generally cannot be translated into proteins as they do not bind to ribosomes. There is varying evidence supporting the claim that circRNAs are abnormally expressed in cancer and play a crucial role in cancer initiation and progression. Ubiquitin is a highly stable protein that can be conjugated to target proteins. The most crucial role of ubiquitination is to mediate the degradation of substrate proteins by the proteasome. An increasing amount of evidence indicates that circRNAs are involved in the precise degradation of proteins via the ubiquitin-proteasome system. This review systematically summarizes the intricate mechanisms by which circRNAs regulate target protein ubiquitination, modulate cancerous signaling pathways, and control tumorigenesis and tumor development. Although studies are continuously uncovering additional complex interactions between circRNAs and proteins, we believe that circRNAs are promising but challenging molecules that have the potential to facilitate precise cancer therapies in the future.

Mitophagy receptor-related genes (MRRGs) orchestrate mitochondrial quality control and may shape glioma progression and immune tolerance, yet their integrated prognostic and immunobiological significance remains unclear.

Acetyl-CoA carboxylase alpha (ACACA), a crucial rate-limiting enzyme governing de novo biosynthesis of fatty acids, drives oncogenic metabolic reprogramming in diverse malignancies. However, the multiomics investigation and immunological implications of ACACA across cancers remain unclear.

Lung adenocarcinoma (LUAD) is the most prevalent and lethal subtype of non-small cell lung cancer (NSCLC), with its progression closely associated with aberrant succinylation modifications. This study aimed to systematically identify succinylation-related genes in LUAD and evaluate their diagnostic and prognostic significance. By integrating four Gene Expression Omnibus (GEO) datasets, 45 differentially expressed succinylation-related candidate genes were identified. Feature selection using three machine learning methods-Lasso regression, support vector machine recursive feature elimination (SVM-RFE), and Random Forest-yielded seven core genes: TIMP1, SLC2A1, JUP, F12, B3GALNT1, DSP, and MMP1. ROC analysis showed that all core genes achieved AUC values greater than 0.7, indicating strong diagnostic potential. A diagnostic model constructed from these seven genes achieved an AUC of 0.912 in the training cohort, significantly outperforming single-gene models, and was validated in The Cancer Genome Atlas (TCGA) cohort (AUC = 0.893). Prognostic analysis revealed that Kaplan-Meier curves for all seven core genes demonstrated p < 0.05 and HR > 1, indicating that high expression was associated with poor outcomes. A risk prediction nomogram was also developed based on these genes. SHAP analysis clarified each gene's contribution to the model, while drug enrichment and transcriptional regulatory network analyses provided further insights into potential therapeutic targets. Notably, JUP exhibited the highest diagnostic efficacy (AUC = 0.921) and was significantly correlated with immune cell infiltration and tumor microenvironment regulation. Molecular docking suggested stable binding between JUP and potential therapeutic compounds, single-cell analysis confirmed its marked overexpression in tumor and epithelial cells, and experimental validation further established its oncogenic role. In conclusion, this study systematically defines the diagnostic and prognostic value of seven succinylation-related core genes in LUAD, with JUP playing a particularly pivotal role. These findings provide robust evidence supporting its potential as a novel biomarker and therapeutic target.

Hypopharyngeal squamous cell carcinoma is a rare and aggressive malignancy of the upper aerodigestive tract. While tobacco and alcohol remain the primary etiologic factors, hereditary cancer predisposition syndromes-particularly those involving germline TP53 mutations-can contribute to early onset disease.

Hepatocellular carcinoma (HCC), the most common primary liver cancer, remains a major global health burden due to its aggressive metastatic behavior and poor prognosis. Clarification of the molecular basis underlying metastasis and recurrence is essential for advancing therapeutic development. The present study examines the contribution of hyaluronan-mediated motility receptor (HMMR) to HCC progression and its clinical implications.

Atypical teratoid rhabdoid tumors (AT/RT) are characterized by a poor prognosis and a manifestation within the first 2 years of life. Genetic hallmark of these tumors is the homozygous inactivation of SMARCB1 or, in some rare cases, of SMARCA4. While heterozygous pathogenic variants of SMARCA4 have been described, inter alia, in the context of other CNS malignancies such as medulloblastoma or glioblastoma, the co-occurrence of pathogenic variants in both, SMARCB1 and SMARCA4, in the same AT/RT has to our knowledge not been reported previously. Liquid biopsy, a rapidly developing and promising technique measuring cell-free DNA (cfDNA) in body fluids such as the cerebrospinal fluid (CSF), offers a minimally invasive method to assess disease status. It has yet to be established as a standard procedure in the diagnostic workup of CNS tumors. We present the case of a three-year-old male diagnosed with an AT/RT that exhibits both biallelic alterations of SMARCB1 due to a frameshift mutation and loss of heterozygosity as well as a heterozygous missense variant in SMARCA4 presenting with early disease progression. We employed liquid biopsy successfully to monitor disease progression throughout treatment and the subsequent relapse. We highlight the ramifications that simultaneous alterations in two chromatin-modifying genes may have for tumor biology and clinical course.

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML), characterized by a fusion between the PML and RARA genes and by a block in the myeloid maturation at the promyelocytic stage.

Lung adenocarcinoma (LUAD), a subtype of non-small cell lung cancer (NSCLC), has high incidence and poor prognosis. Although anti-programmed cell death protein 1 (PD1) therapy and epidermal growth factor receptor (EGFR) inhibitors benefit some patients, many remain unresponsive. Genome-wide association studies (GWAS) can identify risk loci, while single-cell transcriptomics enables exploration of genetic variations and mechanisms in LUAD.

Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis and limited targeted therapies. The Hippo signaling pathway, critical in tumor progression, may harbor key genes influencing TNBC behavior. However, the specific genes and their clinical significance remain unclear.

High grade serous carcinoma (HGSC) is the most common and lethal subtype of ovarian cancer, yet its prognosis has remained unchanged in the past 3 decades. HGSC is known to have evolved immune evasion strategies to promote survival, but these mechanisms are not well understood. Podocalyxin (PODXL), a CD34-related sialomucin, is often expressed in HGSC patients with poor prognosis. We have recently reported that PODXL promotes the formation of compact and chemoresistant HGSC spheroids to boost their survival.

The role of Microphthalmia-associated Transcription Factor (MITF) in gastrointestinal stromal tumors (GISTs) remains unclear, although previous studies suggest it contributes to tumor growth regulation. Previously, we demonstrated that MITF depletion reduces GIST cell proliferation and viability, accompanied by decreased expression of BCL-2 and CDK2. To elucidate the mechanisms underlying MITF function in GISTs, we performed chromatin immunoprecipitation and sequencing (ChIP-seq) as well as RNA sequencing. Integrated analyses revealed that MITF directly regulates genes involved in lysosome biogenesis, vesicle trafficking, autophagy, and the mTOR signaling pathway. Transcriptomic profiling following MITF silencing further demonstrated enrichment of differentially expressed genes in PI3K/ mTOR signaling, with downstream effects on tumor growth and autophagy. We next examined the functional consequences of MITF loss on mTOR inhibition-induced autophagy and on extracellular vesicle (EV) content and secretion, given their known interplay in tumor progression. MITF depletion reduced LC3-II levels and impaired autophagy flux, confirming its role in regulating autophagy in GISTs. EV size and number remained unaffected; however, silencing MITF altered EV cargo and notably decreased KIT expression in both cells and EVs. As KIT-containing EVs have been implicated in GIST invasion, these findings suggest that MITF contributes to tumor progression through coordinated regulation of autophagy and EV-mediated signaling. Collectively, our results identify MITF as a key regulator of GIST biology, highlighting its potential as a therapeutic target to limit tumor growth and metastasis.

Bladder cancer exhibits marked spatial heterogeneity in gene expression and immune infiltration. In this exploratory pilot study, we integrate multiplex fluorescence in situ hybridization (mFISH) with AI-assisted digital pathology to characterize the spatial distribution of a previously validated three-gene arsenic-responsive risk model (NKIRAS2, AKTIP, HLA-DQA1). Initially identified in arsenic-exposed individuals and associated with bladder cancer risk, this gene panel achieved 94% training and 75% validation AUC in prior genomic models (PMC8760535). We analyzed five bladder tumor specimens using whole-slide mFISH imaging and HoverNet-based nuclear segmentation to quantify gene expression at single-cell resolution. Spatial profiling revealed elevated expression scores in tumor-adjacent regions, with a strong positive correlation to tumor grade (Pearson's r = 0.83). These gene-enriched regions exhibited spatial clustering of tumor cells. Additionally, tumor-infiltrating lymphocyte (TIL) density was inversely correlated with tumor grade, suggesting immune exclusion in high-grade tumors. Our findings demonstrate the feasibility of combining spatial transcriptomics with AI-driven histopathological analysis for biomarker validation. This integrative framework provides a foundation for future population-scale studies leveraging spatial omics to evaluate arsenic-associated gene signatures and assess their relevance in bladder cancer risk stratification and disease progression.

Recent studies have demonstrated that for various diseases, incorporating polygenic risk scores (PRSs) for other traits and diseases into the PRS-based risk prediction model may improve predictive performance - known as Multiple Polygenic Score (MPS) approach. We aimed to examine whether the MPS approach improves colorectal cancer (CRC) risk prediction. We included 2,187 non-CRC PRSs from the polygenic Score (PGS) Catalog and used machine learning (ML) models to select the most predictive non-CRC PRSs, utilizing individual-level data from 31,257 CRC cases and 33,408 controls. An independent dataset from the Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort (4,852 cases and 67,939 controls) was randomly split into subsets for model estimation and validation. The model combined MPS with two existing CRC-PRSs based on known loci and genome-wide genotyping. We then assessed model performance by calculating the area under the receiver operating curve (AUC) in the validation set and performed 1,000 bootstrapped iterations to evaluate AUC improvements. The ML model selected 337 non-CRC PRSs predictive of CRC risk. Adding MPS to the CRC-PRSs significantly improved AUC by 0.017 (95% CI: 0.011-0.022, p < 0.0001) when combined with known-loci CRC-PRS, 0.005 (95% CI: 0.002-0.007, p = 0.0005) with genome-wide CRC-PRS, and 0.004 (95% CI: 0.002-0.006, p = 0.0005) with both the known loci and genome-wide CRC-PRSs. These findings demonstrate MPS's potential to refine CRC risk prediction models and highlight opportunities for further advancements in risk prediction.

Pancreatic cancer (PC) is characterized by aggressive progression, chemoresistance, and immune evasion, largely driven by its hypoxic tumor microenvironment (TME). The extensive desmoplastic reaction in PC, characterized by dense stromal fibrosis, exacerbates hypoxia by impairing blood flow, creating a hostile environment that limits therapeutic efficacy. Hypoxia-induced microRNAs (HypoxamiRs) have emerged as critical regulators of these processes, modulating cellular pathways that promote tumor survival and therapy resistance. HypoxamiRs exert their effects by interacting with hypoxia-inducible factors, including HIF-1α and HIF-2α. Beyond their direct impact on tumor cells, HypoxamiRs modulate the behavior of immune and stromal cells within the hypoxic TME. Key contributors to hypoxia, such as cancer-associated fibroblasts, pancreatic stellate cells, macrophages, and natural killer (NK) cells, facilitate HypoxamiR transfer via exosomes. This review explores the multifaceted roles of HypoxamiRs in key processes such as immune modulation, chemoresistance, epithelial-mesenchymal transition (EMT), autophagy, angiogenesis, and apoptosis in pancreatic cancer. We also highlight the complex interplay between HypoxamiRs and other non-coding RNAs (ncRNAs) in regulating hypoxia-driven pathways. Investigating these complex interactions provides critical insights for developing novel therapeutic strategies to overcome chemoresistance and immune evasion in pancreatic cancer.

Liver cancer is one of the deadliest cancers worldwide. There is a growing need for natural therapeutic options due to the rising global morbidity incidence of liver cancer. Due to its crucial function in angiogenesis, vascular endothelial growth factor (VEGF) signaling is considered as an ideal target for therapeutic intervention. In this in silico study, we have screened 16 microRNAs (miRNAs) that target the KDR gene, which encode VEGFR-2, and 113 natural compounds derived from Persicaria hydropiper for their anti-angiogenic properties. MicroRNA, hsa-miR-17-3p was identified with potentials of downregulating KDR gene, using several in silico tools. Two possible compounds- 6-Hydroxyluteolin and Isorhamnetin were also identified after performing ADMET profiling and molecular docking. Furthermore, 100 ns molecular dynamics simulations were run to evaluate the stability and conformational changes of protein-ligand complexes. This study identified one microRNA and two natural compounds that showed strong interaction with KDR and its encoded VEGFR-2 receptor, respectively. To validate their effectiveness as therapeutic agents against hepatocellular carcinoma, additional wet lab studies using in vitro and in vivo techniques are necessary.

Interleukin-15 receptor alpha (IL15RA) demonstrates critical regulatory function in oncogenesis and immunomodulation across various malignancies. However, the role of IL15RA in cancers, such as Clear Cell Renal Cell Carcinoma (ccRCC) remains unclear. Therefore, integrated pan-cancer analysis and mechanism investigation assays are essential for IL15RA-directed therapeutic strategy optimization in ccRCC. The comprehensive pan-cancer analysis reveals IL15RA as a plausible diagnostic and prognostic biomarker, as well as a promising immunotherapeutic target across various cancers, particularly ccRCC. IL15RA promotes ccRCC metastasis based on the data of the investigation. Mechanistically, STAT1 binds to IL15RA promoter region, thereby enhancing IL15RA mRNA expression, while METTL3 modulates RNA m6A methylation patterns to stabilize IL15RA transcription. Furthermore, IL15RA potentiates metastasis via NF-κΒ/ZEB1 axis in ccRCC. Drug sensitivity profiling further indicates that IL15RA expression increases sensitivity to chemotherapeutic agents in ccRCC patients. The findings demonstrate that IL15RA emerges as a critical prognostic indicator and immunotherapeutic biomarker particularly in ccRCC. Our findings underscore the necessity for comprehensive mechanistic studies to elucidate IL15RA's roles and are beneficial for advancing targeted therapeutic strategies in oncological interventions.

Head and neck squamous cell carcinoma (HNSCC) is a highly prevalent and heterogeneous malignancy. Normal cells maintain their homeostasis through Anoikis, and tumor cells enhance their own invasion and migration by resisting Anoikis. The search for biomarkers of resistance to Anoikis in head and neck tumors could be helpful in evaluating the prognosis of patients as well as in finding therapeutic targets for HNSCC due to the lack of more definitive biomarkers in HNSCC. HNSCC cells were cultured in suspension, and HNSCC cells were found to undergo apoptosis after losing the support of ECM.LASSO-Cox regression analysis was applied to the TCGA-HNSC cohort to evaluate the prognostic value of apoptosis-associated genes, resulting in the construction of an apoptosis-related prognostic model (CTTN, PLAU, PLK1, BID, MAPK11, SPINK1, VEGFA, PIK3R2, CEACAM1, MAD2L1, SLCO1B3, TFDP1, SFRP1, SPP1, SPHK1). A risk score-based nomogram was developed to optimally predict survival in HNSCC patients. The role of the prognostic model gene CTTN in HNSCC apoptosis was validated via PI staining, IF, and WB. Knockdown of CTTN affected FAK expression levels in cells, reducing their anti-apoptotic capacity by impairing cytoskeletal formation. We validated CTTN function in HNSCC-PDOs. We analyzed the role of CTTN and its major subpopulations in pan-cancer and HNSCC. Silencing CTTN significantly suppressed growth in patient-derived organoids (PDOs) from HNSCC patients. CTTN was highly expressed in most tumors and predominantly detected in epithelial and fibroblast cells of HNSCC. This study established an association between ARGs and HNSCC. We developed a novel ARG-associated signature capable of predicting prognosis in HNSCC patients. Furthermore, we found that inhibiting the apoptosis-related gene CTTN suppresses the anti-apoptotic capacity of HNSCC. Results from HNSCC-PDOs suggest that CTTN may represent a key target for HNSCC invasion and treatment.

The 2021 WHO glioma classification integrates molecular profiling, but outcome data for these patients are limited. We retrospectively analyzed 179 patients (median age 53) with WHO 2021-classified gliomas (grade 2: n = 45, grade 3: n = 51, grade 4: n = 83) treated with surgery and radio(chemo)therapy across four centers in Poland and France. Chemotherapy was administered to 74.9% of patients, with a median radiotherapy dose of 60 Gy (range 32.5-80 Gy). IDH1/2 mutations were identified in 55.3% and 1p/19q codeletion in 22.4%. Patients with IDH1/2 mutations had significantly longer progression-free survival (PFS, 7.7 vs. 1.0 years) and overall survival (OS, 8.2 vs. 2.5 years), both p < 0.01. 1p/19q codeletion was associated with prolonged PFS (7.7 vs. 1.6 years, p < 0.01). In grade 3 gliomas, chemotherapy improved PFS (6.8 vs. 3.6 years) and OS (6.9 vs. 3.9 years), both p < 0.01. Leukopenia grade 0-2 correlated with better PFS (3.6 vs. 1.2 years, p = 0.02) and OS (7.2 vs. 3.2 years, p = 0.04). Absolute lymphocyte count ≤ 1 × 103/mm3 predicted worse OS (5.3 vs. 8.7 years, p = 0.0043). CTV < 127 cm3 predicted longer OS in grade 4 gliomas (3.2 vs. 1.7 years, p = 0.012). Our findings provide new real-world evidence on survival and prognostic factors in this population, for which contemporary RWE and OS/PFS data remain scarce.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer. Although neoadjuvant chemotherapy (NACT) has some effectiveness in TNBC, a portion of patients still do not benefit from them. The critical role of DNA replication stress (DRS) in cancer therapy has been recognized, but its study in TNBC NACT remains relatively limited. Affymetrix microarray data were obtained from the GEO database for both training and test sets. These data were processed using the "affy" R package. The Boruta algorithm and SVM-RFE method were employed for key gene selection, and an integrated model based on multiple algorithms was developed to establish a risk score. Additionally, the tumor microenvironment (TME) was analyzed, and the correlation between risk score and drug sensitivity was explored, incorporating several drug databases. Through the analysis of TNBC patients' responses to NACT, we found a close correlation between DRS and TNBC treatment responses and identified eight key genes. The developed ensemble model (ENS) demonstrated high AUC values of 0.922, 0.886, and 0.858 across the three independent datasets, respectively, indicating its strong ability to accurately predict the effectiveness of NACT. The study also revealed that patients with higher risk score are more prone to recurrence and metastasis, and have a rich TME composition. Additionally, drug sensitivity analysis offers potentially effective personalized treatment options for high-risk TNBC. This study successfully constructed an ensemble model to predict TNBC patients' response to NACT. Additionally, it was discovered that the risk score held significant value in analyzing the correlation between TNBC patients' TME and drug sensitivity. These findings offer important new insights into personalized treatment strategies for TNBC.