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PubMed2026

An Integrative Proteomic Approach to Reveal Altered Signaling Modules During Alzheimer's Disease Progression in PS19 Tauopathy Mice.

Alzheimer's disease (AD) is a slowly progressive neurodegenerative disease that is characterized by cognitive, functional, and behavioral impairments. These changes occur owing to the progressive accumulation of extracellular amyloid-beta plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. AD is associated with the dysfunction of several essential neurotransmitter systems, such as dopamine, and impaired neurotransmission. Despite the association of neurotransmitter changes within the brain and AD pathology, in-depth profiling studies on neurotransmitters and their related proteomic changes are limited. This study was conducted to profile and integrate the proteomes and neurotransmitters in seven brain regions of PS19 (Tau P301S) mice according to AD progression between 4 and 7 months. Proteomic analysis revealed significantly altered canonical pathways in various brain regions, including metabolic abnormalities. In the neurotransmitter profile, we found significant alterations in the levels of six neurotransmitters-dopamine, serotonin, homovanillic acid, norepinephrine, 3-methoxytyramine, and 3,4-dihydroxyphenylacetic acid-during AD progression. Using an integrative approach between proteome and neurotransmitter profiles, we found that AD progression-dependent dopamine- and serotonin-related signaling modules are closely related to neurotransmitter changes, especially in the hippocampus and cerebellum. This integrative approach could provide new signaling modules to help understand AD progression and thereby enable improved treatment and clinical outcomes.

Animals↗
PubMed2026

From genes to trajectories: mapping genetic influences on Huntington's disease progression.

MOTIVATION: There are many diseases with established genetic factors, such as Huntington's disease (HD), that are characterized by variable rates of progression. However, beyond the contribution of the known genetic factors - in this case the Huntingtin (HTT) gene - the impact of the full human genome on the natural progression of such diseases throughout a patient's life remains largely unknown. The increased availability of genome wide association (GWA) data in HD gene expansion carriers (HDGECs), combined with the clinical assessment scores on the same set of patients, has provided a perfect opportunity to assess the potentially broader genetic impact on the natural progression of HD. RESULTS: We present a genetics-driven, probabilistic disease progression model designed to identify and investigate the ways in which a range of genetic factors affect the natural progression of HD. When applied to a clinico-genomic HD dataset, our model identified several single nucleotide polymorphisms (SNPs) with previously unreported effects on disease progression that act at distinct stages and with varying magnitudes. This discovery may shed light on the potential mechanistic impact of previously unidentified genes on HD that may have implications for clinical management. As increasing amounts of GWA data become available more generally, we anticipate that this modeling framework will be broadly applicable to other diseases with strong genetic components. AVAILABILITY AND IMPLEMENTATION: The source code for IHDPM is available at https://github.com/BiomedSciAI/IHDPM.

Huntington Disease↗
PubMed2026

Progressive cardiac phenotypes and reduced reversibility from long-term CUGexp RNA expression in a DM1 mouse model.

Myotonic dystrophy type 1 (DM1) is caused by an expanded CTG repeat in the DMPK gene, resulting in mutant transcripts that form expanded CUG (CUGexp) RNA foci and sequester muscleblind-like (MBNL) RNA-binding proteins. DM1 is multisystemic, with progressive worsening of disease manifestations in affected tissues. Disease progression is attributed to somatic expansion of the CTG repeats with age, resulting in production of CUGexp RNA with enhanced intrinsic toxicity due to increased MBNL sequestration. To determine the degree to which cardiac disease progression can occur independently of repeat expansion, we used a transgenic DM1 mouse model with inducible heart-specific expression of a stable, interrupted 960-CUG-repeat RNA. Sustained CUGexp RNA expression caused progressive cardiac enlargement, contractile dysfunction, conduction delay, myocardial fibrosis, and reduced survival, while MBNL-dependent splicing defects remained static, consistent with the stable repeat length. We also determined the degree of reversibility after different periods of CUGexp RNA expression by shutting off the repeat-containing transgene. Suppression of CUGexp RNA expression rescued cardiac abnormalities, but reversibility declined with longer exposure to the toxic RNA. These findings demonstrate that prolonged expression of stable CUGexp RNA drives progressive cardiac pathology, revealing a mechanism of disease progression in DM1 in addition to somatic expansion.

Animals↗
PubMed2026

Multiomic study of cutaneous T-cell lymphoma reveals single-cell clonal evolution in progression and therapy resistance.

Cutaneous T-cell lymphoma (CTCL) remains a challenging disease due to its significant heterogeneity, therapy resistance, and relentless progression. Multiomics technologies offer the potential to provide uniquely precise views of disease progression and response to therapy. Here, we present a comprehensive multiomics view of CTCL clonal evolution, incorporating exome, whole-genome, epigenome, bulk, single-cell T-cell receptor, and single-cell RNA sequencing of 99 clinically annotated serial skin, peripheral blood, and lymph node samples from 34 patients with CTCL. We leveraged this extensive data set to define the molecular underpinnings of CTCL progression in individual patients at single-cell resolution with the goal of identifying clinically useful biomarkers and therapeutic targets. Our studies identified recurrent progression-associated clonal genomic alterations; we highlight mutation of CCR4, phosphoinositide 3-kinase inhibitor signaling, and programmed cell death protein 1 (PD-1) checkpoint pathways as evasion tactics deployed by malignant T cells. We identified a gain-of-function mutation in STAT3 (D661Y) and demonstrated, using cleavage under targets and release using nuclease (CUT&RUN) and RNA sequencing, that it enhances binding to and transcription of genes in Rho GTPase pathways. With our previous work implicating this pathway in histone deacetylase inhibitor-resistant CTCL, these data provide further support for a previously unrecognized role for Rho GTPase pathway dysregulation in CTCL progression. Recurrent progression-associated mutations were common in the epigenetic modifier EZH2, suggesting that EZH2 inhibition may benefit patients with CTCL. Our findings support an approach in which genomic analysis is widely used for improved disease monitoring, biomarker-informed clinical trial design, and genome-guided therapeutic decision-making. Moreover, these molecular changes present new opportunities for therapeutic targeting in this challenging and incurable cancer.

Multiomics↗
PubMed2026

Targeting super-enhancer-driven SKIL transcription by CDK7 inhibitor THZ1 to suppress gastric cancer progression.

BACKGROUND: Gastric cancer (GC) is a lethal malignancy characterized by high incidence, mortality, and limited treatment options. Transcriptional addiction is a key cancer hallmark that drives tumor pathogenesis, making its inhibition a promising therapeutic strategy for GC. The study aims to investigate the roles and mechanisms of super-enhancer (SE)-driven oncogenic transcriptional addiction in GC progression and to identify novel targetable vulnerabilities. METHODS: We utilized cellular and animal models to assess the effects of THZ1 treatment and CDK7 knockdown on GC progression. RNA sequencing was employed to elucidate the potential molecular mechanism of THZ1 treatment. ChIP-seq was performed to establish SE landscape in GC. Integrative analysis of transcriptomic and SE profiling was used to identify THZ1-targeted oncogenic genes. Rescue experiments were conducted to confirm that THZ1 treatment suppresses GC malignant progression by targeting SE-driven SKIL transcription. RESULTS: GC cells exhibited pronounced sensitivity to THZ1 compared to normal gastric mucosa cells, and the treatment potently suppressed tumor growth and migration in both cellular and animal models. CDK7 was significantly upregulated in GC tissues, and its knockdown inhibited malignant progression in vitro and in vivo, whereas its overexpression accelerated tumor progression. Mechanistically, SE-driven oncogenic transcriptional amplification underlies GC cell susceptibility to THZ1, supported by the identification of novel oncogenic genes such as SKIL. SKIL, a key Hippo pathway regulator, was highly expressed in GC cells, and its elevated expression predicted poor patient prognosis. SKIL silencing attenuated malignant phenotypes, while its overexpression diminished THZ1’s suppression of GC cell proliferation and migration. CONCLUSION: Our findings demonstrate that THZ1 inhibits GC progression by disrupting SE-driven oncogenic transcription, thereby offering CDK7 inhibition as a promising therapeutic intervention for GC.

Stomach Neoplasms↗
PubMed2026

Prion disease mimicking rapidly progressive Alzheimer disease: case series and systematic review.

BACKGROUND: Prion disease and Alzheimer disease (AD) are common causes of rapidly progressive dementia (RPD). Although most patients with prion disease are distinguished by MRI and CSF findings, selected cases mimic rapidly progressive AD. We characterized AD-prion disease mimics within a prospective cohort and the extant literature to identify the clinical features and tests that support accurate diagnoses in these patients. METHODS: Patients with prion disease initially diagnosed as rapidly progressive AD were identified from a prospective cohort study at Mayo Clinic (February 2020-June 2026) and through systematic review of MEDLINE and Embase. RESULTS: Of 204 patients with RPD, five (2.5%) were initially diagnosed with clinically probable AD but ultimately determined to have prion disease. Systematic review identified 10 additional cases (n=15, median age-at-onset, 59 years; 67% male). Presentations reproduced amnestic (53%), dysexecutive (27%), primary progressive aphasia (13%), and posterior cortical atrophy (7%) AD phenotypes; median time from AD diagnosis to consideration of prion disease was 2 months. Diffusion-weighted MRI abnormalities were absent in Mayo Clinic cases and absent/equivocal (n=2) or overlooked (n=8) in published cases. CSF biomarkers were consistent with AD in 6/9 tested patients, with elevated total tau levels in 11/13 patients and total-tau/p hosphorylated-tau181 ratios in 5/9 patients. Real-time quaking-induced conversion assays for prions were positive in the CSF of 9/12 patients. Prion disease was confirmed by neuropathology (n=7), genetics (n=2), or real-time quaking-induced conversion (n=6) assays. CONCLUSIONS: Prion disease may rarely mimic rapidly progressive AD. Disproportionate elevations in CSF total-tau levels or total-tau/p hosphorylated-tau181 ratios should prompt consideration of prion disease.

Humans↗
PubMed2025

A MGMT Enhancer Variant is Associated with Glioma Susceptibility and Progression.

The O6-methylguanine-DNA methyltransferase (MGMT) plays a significant role in the pathogenesis and progression of glioma. Numerous enhancer variants, including those within the MGMT gene region and adjacent gene regions, have been found to be associated with cancer development and progression. We investigated the significance of enhancer variants located in the intergenic spacer far from the MGMT gene in relation to glioma susceptibility and progression. We recruited 402 glioma patients and 654 controls for this investigation using Sequenom MassARRAY genotyping. We identified a significantly elevated risk of glioma among carriers with the rs11016629 TG genotype compared to those with the GG genotype (OR = 1.41, 95% CI 1.03-1.93; P = 0.034). Subgroup analyses revealed that rs11016629 was significantly associated with glioma risk in subjects with WHO grade IV tumor (OR = 1.59, 95% CI 1.07-2.38; P = 0.023) and high-grade glioma (OR = 1.57, 95% CI 1.11-2.21; P = 0.011). Patients who underwent gross total resection with TG/TT genotypes exhibited a 2.66-fold higher risk of disease progression than GG carriers (HR = 2.66, 95% CI 1.23-5.79; P = 0.014). The study demonstrates that a MGMT enhancer variant rs11016629 contributes to both glioma susceptibility and progression.

Humans↗
PubMed2025

Integrative metabolomic and proteomic analysis of diabetic kidney disease progression with younger-onset type 2 diabetes.

AIM: Younger-onset type 2 diabetes (YT2D) confers a disproportionately high risk of diabetic kidney disease (DKD), yet early biomarkers and underlying mechanisms remain poorly defined. We aimed to identify metabolites associated with DKD progression and integrate metabolomic and proteomic data to elucidate pathways involved in a multi-ethnic Asian cohort. MATERIALS AND METHODS: In this prospective study, 787 YT2D patients (diagnosed at ≤ age 40) were followed for a median of 5.7 years. DKD progression was defined as an annual decline in estimated glomerular filtration rate (eGFR) of ≥3 mL/min/1.73 m2 or ≥ 40% reduction in eGFR from baseline. Plasma metabolites were measured by nuclear magnetic resonance spectroscopy. Multivariable regression analysis was performed in a discovery (N = 550) and internal validation cohort (N = 237). Integrative metabolomic-proteomic analysis (N = 428) was performed using sparse partial least squares discriminant analysis (sPLS-DA). RESULTS: Ninety-eight metabolites were differentially expressed between DKD progressors and non-progressors, of which total branched-chain amino acids (BCAAs) (OR = 0.60, 95% CI 0.46-0.79), valine (OR = 0.62, 95% CI 0.48-0.81), and leucine (OR = 0.56, 95% CI 0.43-0.74) associated with DKD progression, independent of metabolic risk factors. Integrative analysis identified three components comprising 23 proteins and 30 metabolites, involved in the citrate cycle and apoptosis, which improved prediction of DKD progression beyond clinical risk factors (AUC 0.69-0.83). CONCLUSION: Lower plasma BCAA levels are independently associated with DKD progression in YT2D. Integrative multi-omics analysis highlights disruptions in metabolic and apoptotic pathways, providing insights into DKD pathophysiology and potential biomarkers for early risk stratification.

Humans↗
PubMed2026

Characteristics of early-onset, rapidly progressive scoliosis in spinal muscular atrophy type I treated with disease-modifying therapy -a multicenter retrospective study conducted in Japan.

In the era of disease-modifying therapy (DMT), almost all patients with spinal muscular atrophy (SMA) type I treated after onset, but before 6 months of age, develop early-onset, rapidly progressive scoliosis by 2 years of age, despite improvements in their motor function. Seven symptomatic patients with SMA type I who were treated before the age of 6 months were included in this retrospective observational study. Scoliosis had developed in all patients by 27 months of age. Among them, the patients who could stand with support or independently (standing patients; n = 3) tended to present with more progressive scoliosis than the sitters (n = 4). All standing patients demonstrated thoracic hyperkyphosis before or at the time of their scoliosis diagnosis. Despite receiving DMT, these patients continued to show residual key manifestations of SMA type I. Chronic difficulty maintaining posture due to trunk muscle weakness in the lying, sitting, or standing position was considered to be the main contributor to the development and progression of the scoliosis. The development and progression of such scoliosis, which begins in infancy, may be related to inappropriate postural management, which is not currently recognized as such by clinicians, caregivers, or guardians. In this population, it is important to closely monitor patients for such scoliosis from soon after the diagnosis of SMA. As this type of scoliosis progresses rapidly during the early developmental stage, when surgery is not possible, it is necessary to establish a proactive non-surgical management strategy for it.

Humans↗
PubMed2026

Apolipoprotein E promotes papillary thyroid carcinoma progression by activating PINK1/Parkin-mediated mitophagy.

BACKGROUND: Increasing evidence supports a progression-related role of apolipoprotein E (APOE) in papillary thyroid carcinoma (PTC), yet a clear mechanistic explanation for this association is still lacking. Considering the pivotal role of mitochondrial homeostasis in tumorigenesis, the potential role of APOE in promoting PTC progression through mitophagy regulation was investigated. Additionally, the involvement of the PINK1/Parkin-associated pathway in this process was examined to provide insights into its contribution to tumor progression. METHODS: APOE in thyroid carcinoma was characterized in terms of its expression profile, diagnostic relevance, and potential biological functions, based on integrative evidence derived from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. APOE and mitophagy-related protein expression were further examined in PTC tissues by immunohistochemistry. Further evaluation of APOE in PTC cell lines focused on its association with proliferation, apoptosis, and mitophagy, with bidirectional functional perturbation serving as the basis for assessment. Pharmacological inhibitors were used to assess the involvement of mitophagy-related signaling in the observed APOE-dependent phenotypes. Additionally, the in vivo impact of APOE on PTC tumor growth and mitophagy was further investigated through a nude mouse xenograft model, providing insight into its potential role in tumor progression. RESULTS: A significant upregulation of APOE was observed in thyroid carcinoma tissues and PTC cell lines, supporting its potential relevance as a diagnostic biomarker. The modulation of APOE expression significantly influenced PTC cell proliferation and apoptosis, with overexpression promoting cell proliferation and inhibiting apoptosis, while knockdown led to the opposite effects. Mechanistically, APOE overexpression increased AMP-activated protein kinase (AMPK) phosphorylation and decreased mammalian target of rapamycin (mTOR) phosphorylation, accompanied by increased PINK1 and Parkin expression and mitophagy-related changes, including altered mitochondrial membrane potential, reduced overall reactive oxygen species levels, and increased autophagosome formation. Pharmacological inhibition of mitophagy attenuated the proliferative and antiapoptotic effects of APOE. CONCLUSIONS: These findings demonstrate that APOE promotes PTC progression in association with PINK1/Parkin-related mitophagy and modulation of the AMPK/mTOR axis. The APOE-associated mitophagy axis may provide a rationale for future preclinical investigation in PTC.

Apolipoprotein E (APOE)↗
PubMed2026

An individualized nomogram for predicting progression-free survival in systemic anaplastic large cell lymphoma: a multicenter, retrospective, and internally validated study.

OBJECTIVES: To develop an individualized nomogram for predicting disease progression risk in systemic anaplastic large cell lymphoma (sALCL). METHODS: Independent predictors of progression-free survival (PFS) were identified using Cox regression in a multicenter retrospective cohort of 109 sALCL patients (2010-2022). These were incorporated into a three-factor nomogram, evaluated via bootstrapped internal validation (1000 resamples), ROC analysis, C-index, decision curve analysis (DCA), and clinical impact curve (CIC). RESULTS: A total of 29 PFS events occurred during a median follow-up of 31 months. Multivariable modelling selected serum β2-microglobulin elevation, extranodal disease, and front-line chemotherapy choice (CHOP versus CHOPE or BV+CHP) as autonomous progression drivers. Upon internal bootstrap validation, the nomogram yielded strong prognostic accuracy, achieving AUCs of 0.81, 0.85 and 0.87 for 1-, 3- and 5-year progression-free survival, alongside a corrected C-index of 0.779 (95% CI: 0.699 - 0.861). Calibration plots showed close agreement between predicted and observed outcomes, while DCA confirmed superior net clinical benefit versus conventional IPI or Ann Arbor stratification across multiple decision thresholds. CONCLUSION: This first sALCL-specific nomogram integrates clinical and treatment variables to provide personalized PFS risk estimation. While internally validated, this exploratory, observation-based tool requires external validation and recalibration in prospective cohorts before clinical implementation.

Humans↗
PubMed2026

A refined MASH-HCC model identifies macrophage Gadd45b as a key orchestrator of inflammation-driven neoplastic progression.

Metabolic dysfunction-associated steatohepatitis (MASH) is emerging as a leading driver of hepatocellular carcinoma (HCC), yet the molecular mechanisms linking metabolic stress, chronic inflammation and tumorigenesis remain poorly understood. Here we established a metabolically relevant, time-efficient MASH-to-HCC model in C57BL/6N mice by combining a MASH diet with controlled CCl4 administration, enabling stepwise recapitulation of MASH-associated neoplastic progression. Using this model, we identified growth arrest and DNA damage 45b (Gadd45b) as a novel MASH-derived protumorigenic regulator selectively activated under metabolic stress. Integrated analyses of human bulk and single-cell transcriptomic datasets and mouse transcriptomic deconvolution revealed concordant macrophage remodeling and GADD45B/Gadd45b expression dynamics during MASH-to-HCC progression. Mechanistically, fatty acids and TNFα preferentially induced Gadd45b in macrophages, where it amplified TNFα-NF-κB signaling. Macrophage-derived inflammatory signals subsequently induced Gadd45b and NF-κB activation in hepatocytes, establishing a feed-forward inflammatory loop that promoted fibrogenic and partial EMT-like programs and tumor spheroid formation. Importantly, temporal profiling during spheroid formation and progression revealed transient induction of Gadd45b during early spheroid establishment, but not during later progression, indicating that Gadd45b-mediated inflammatory signaling primarily promotes tumor initiation rather than subsequent growth. Consistent with human data, Gadd45b expression increased with disease severity and positively correlated with inflammatory factors in the MASH-HCC model, whereas pharmacological inhibition attenuated the Gadd45b-inflammation signaling axis. Collectively, our findings establish macrophage Gadd45b as a key orchestrator linking metabolic stress, chronic inflammation, and neoplastic transformation during MASH-to-HCC progression. Our refined MASH-HCC model provides a robust platform for mechanistic studies and preclinical evaluation of inflammation-targeted therapies.

Journal Article↗
PubMed2025

Nanopore-based sequencing of active DNA replication reveals key principles of metazoan replication fork progression, origin and termination sites.

Balancing replication fork progression and origin usage is essential to maintain genome stability, but measuring replication fork progression rates and origin usage throughout the genome has been challenging. Here, we use nanopore sequencing combined with DNAscent to measure replication fork progression together with origin and termination site usage with single-molecule precision throughout the Drosophila genome with nearly full genome coverage. We find that replication fork progression rates are not uniform throughout the genome. Rather, fork progression is slowest in euchromatin, and this is not correlated with active transcription. Replication origins are also influenced by chromatin, but the exact position of initiation is highly variable and are often several kilobases away from ORC binding sites. Termination sites lack any chromatin or sequence motifs and appear nearly random throughout the genome. By measuring DNA replication dynamics at near full genome coverage, our work reveals key principles of metazoan replication dynamics.

Journal Article↗
PubMed1979

Radiographic caries diagnosis. A study of caries progression and observer performance.

A detailed index and score system was employed in radiographic studies of the progression of proximal caries during a three and a six year interval after the termination of the regular school dental care. It was demonstrated that the score system offers advantages compared with systems for estimating caries progression only taking into account the number of new lesions, since the former also reveals progression of already existing lesions. Most of the new lesions being developed during a six year interval was found in the enamel. The progression of already existing carious lesions was slow. Fewer new lesions and a slower progression of already existing lesions were found with the increasing age of the patients. Wide variations between observers were found at radiographic examinations of extracted teeth. The influence of such variations on the results of epidemiological caries investigations was elucidated. The importance of minimizing the rate of false positive diagnoses in investigations comparing the caries prevalence between different groups of patients was demonstrated. Data from the dental literature were used to estimate the probabilities of clinical cavities at different extents of the radiographically registered carious lesions. These probabilities were lower, the lower the prevalence of cavities and the smaller the extent of the radiographic lesion. Receiver operating characteristic curves based on the extents of the radiographic carious lesions were employed in assessing optimal criteria for restorative treatment, taking into account the prevalence of carious cavities and the costs of errors in the decision-making. The lower the cavity prevalence and the higher the cost of overtreatment, the greater the extent of the radiographic lesion that should be used as criterion for restorative treatment. The results of radiographic examinations of carious lesions were found to be greatly influenced by information given to the examiners and by the opinions of other observers. Such an influence, if occurring in epidemiological investigations, may give misleading results. Different densities in radiographs of different groups of patients to be compared may also give rise to inaccurate results. Ways of minimizing the influence of observer variations are discussed.

Adolescent↗
PubMed2025

EIF2B5 promotes malignant progression of hepatocellular carcinoma by activating the PI3K/AKT signaling pathway through targeting RPL6.

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with limited treatment options and poor prognosis. In this study, we demonstrated the critical role of EIF2B5 in driving HCC progression. We found EIF2B5 expression is significantly upregulated in HCC tumor tissues in several bioinformatics datasets, including The Cancer Genome Atlas, and that high expression of EIF2B5 predicts poor prognosis for HCC patients. Through a series of in vitro cell biology experiments, we found that EIF2B5 knockdown significantly attenuated Hep3B and HepG2 proliferation, migration, and invasion and increased cell cycle arrest, whereas EIF2B5 overexpression promoted HCC progression. Through mass spectrometry and immunoprecipitation validation, we found that EIF2B5 directly interacted with RPL6 and that when EIF2B5 was overexpressed in HCC cells, it promoted the expression of the downstream protein RPL6, which was able to activate the phosphatidylinositol kinase (PI3K)/serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR) pathway and thereby increase the proliferation and invasion ability of HCC cell lines, as verified by second-generation sequencing analysis and western blot. We further verified these findings using the mouse ectopic tumor assay, and the results showed that EIF2B5 knockdown significantly inhibited tumor progression in HCC mice. The present study suggests that EIF2B5 promotes malignant progression of HCC by interacting with RPL6 and activating the PI3K/AKT/mTOR signaling pathway and may serve as a potential target for the treatment of HCC.

Humans↗
PubMed2025

Proteomic hub proteins CDKN2B, TRAPPC2L, WFS1, and ARPP19 drive biochemical recurrence and metastatic progression in prostate cancer: Protein macromolecule action.

The biological characteristics and metastasis mechanism of prostate cancer are complex, involving the important role of many proteins in cell transcriptional regulation. This study focused on the role of the proteomic hub proteins CDKN2B, TRAPPC2L, WFS1 and ARPP19 in the biochemical recurrence and metastasis progression of prostate cancer. Cross-platform transcriptome integration and differential expression analysis were used to evaluate transcriptome characteristics in a prostate cancer cohort. Functional enrichment analysis was performed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation, and weighted gene co-expression network analysis (WGCNA) was used to investigate cancer progression subtypes. It was found that prostate cancer progression showed significant transcriptome heterogeneity, and low-expression genes dominated. We reveal the important role of epithelial-immune interactions and inflammatory signaling in transcriptional remodeling in prostate cancer. The co-expression network topology analysis showed that the immune-metabolic center module plays a central role in cancer progression. CDKN2B was identified as a key transcriptional determinant in prostate cancer typing, while TRAPPC2L and WFS1 acted as core transcriptional regulators, driving metastatic heterogeneity. ARPP19 and LOC650152 also show important transcriptional driving effects in advanced prostate cancer.

Humans↗
PubMed2026

ARL6IP1 Inhibits Breast Cancer Tumor Progression by Targeting OLFM4 to Regulate Glycolysis.

INTRODUCTION: ARL6IP1 has been linked to cancer progression, but its precise role in BC, particularly in metabolism and its interaction with an OLFM4, remains unclear. AIMS: This study aimed to investigate the role of ADP-ribosylation factor-like 6 interacting protein 1 (ARL6IP1) in breast cancer (BC) cell behavior and metabolism and explore its interaction with an olfactomedin-4 (OLFM4) as a potential therapeutic target. OBJECTIVE: The objective of this study was to determine the effects of ARL6IP1 knockdown on BC cell proliferation, invasion, migration, apoptosis, oxidative stress, and glycolysis. Additionally, this study also explored the interaction between ARL6IP1 and OLFM4 and their combined role in BC progression and metabolism. METHODS: Key gene modules in the GSE73540 dataset were identified through weighted gene co-expression network analysis (WGCNA). Three BC-related datasets (GSE73540, GSE22820, and GSE36295) and The Cancer Genome Atlas (TCGA) were applied for additional examination of differentially expressed genes (DEGs). Intersection analysis selected ARL6IP1 as a hub gene for prognostic analysis. In vitro experiments investigated how ARL6IP1 knockdown influences BC cell proliferation, invasion, migration, apoptosis, epithelial-mesenchymal transition (EMT), oxidative stress, and glycolysis. The connection between ARL6IP1 and an OLFM4 was confirmed using Co-immunoprecipitation (Co-IP), and their roles in BC tumor progression and glycolysis were evaluated. RESULTS: ARL6IP1 was elevated in BC datasets and linked with poor BC prognosis. Experiments demonstrated that knockdown of ARL6IP1 significantly reduced BC cell growth while promoting apoptosis and oxidative stress. Besides, ARL6IP1 knockdown reduced glycolysis, as manifested by decreased extracellular acidification rate (ECAR), glucose consumption, adenosine triphosphate (ATP) levels, and lactate production while increasing mitochondrial respiration (OCR). Co-IP validated the connection between ARL6IP1 and OLFM4, and OLFM4 overexpression partially counteracted the suppression of glycolysis and cell behavior resulting from ARL6IP1 knockdown. CONCLUSION: ARL6IP1 is a critical regulator of BC progression, influencing glycolysis, mitochondrial function, and key cellular behaviors. Targeting the ARL6IP1-OLFM4 axis offers a promising therapeutic strategy for managing BC.

Humans↗
PubMed2026

Chromatin Remodeling Subunit ARID1A Negatively Regulates the Malignant Progression of Gastrointestinal Stromal Tumors by Targeting the MEMO1 Promoter.

Gastrointestinal stromal tumors (GISTs) are the most common sarcomas of the alimentary tract and are primarily characterized by malignant progression, a major cause of mortality. AT-rich interaction domain 1A (ARID1A), a core component of the chromatin-remodeling SWI/SNF complex, has been found to correlate with GIST tumor grade, although the underlying mechanism remains unclear. Its frequent inactivation across diverse cancer types reveals pleiotropic roles that intersect multiple hallmarks of cancer. In this study, we aimed to investigate the potential relationship between ARID1A and malignant progression in GISTs, as well as the underlying mechanism. Western blotting, real-time polymerase chain reaction, and immunohistochemistry were used to assess ARID1A expression in GIST tissues. Cell Counting Kit-8 (CCK-8) assays were performed to evaluate cell proliferation. Wound-healing and Transwell assays were conducted to assess cell migration and invasion. Flow cytometry was used to analyze apoptosis and cell cycle distribution. Label-free quantitative proteomics and chromatin immunoprecipitation sequencing (ChIP-seq) were employed to identify top candidate downstream targets of ARID1A. ARID1A expression was decreased in high-risk GIST tissues. Furthermore, ARID1A knockdown in GIST cells promoted proliferation and metastasis both in vitro and in vivo, and led to reduced apoptosis and impaired cell cycle arrest. We further demonstrated that ARID1A suppresses GIST proliferation and metastasis by inhibiting MEMO1 expression and inactivating the ERK1/2 signaling pathway. Notably, this regulatory axis was observed in KIT-null GIST cells, indicating that the ARID1A-MEMO1 pathway may function independently of canonical KIT signaling. Thus, ARID1A inhibits malignant progression in GISTs, providing new insights into its role in the prevention and treatment of human GISTs and suggesting its potential as a biomarker of malignant progression in GISTs.

Humans↗