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Search Results (1,165)

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Keywords = The Cancer Genome Atlas (TCGA)

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16 pages, 4092 KiB  
Article
Ribosome Biogenesis Underpins Tumor Progression: A Comprehensive Signature for Survival and Immunotherapy Response Prediction
by Amr R. Elhamamsy, Salma M. Aly, Rajeev S. Samant and Lalita A. Shevde
Cancers 2025, 17(15), 2576; https://doi.org/10.3390/cancers17152576 - 5 Aug 2025
Abstract
Background: RiBi is integral to cell proliferation, and its dysregulation is increasingly recognized as a hallmark of aggressive cancers. We sought to develop and validate a composite “PanRibo-515 score” reflecting RiBi activity across multiple tumor types, assess its prognostic significance, and explore [...] Read more.
Background: RiBi is integral to cell proliferation, and its dysregulation is increasingly recognized as a hallmark of aggressive cancers. We sought to develop and validate a composite “PanRibo-515 score” reflecting RiBi activity across multiple tumor types, assess its prognostic significance, and explore its relationship with immune checkpoint therapy outcomes. Methods: We curated 515 RiBi–associated genes (PanRibo-515) and used a LASSO regression-based strategy on a training dataset (GSE202203) to select the prognostically most relevant subset of 68 genes (OncoRibo-68). Directionality (positive or negative impact on survival) was assigned based on the sign of the LASSO coefficients. We integrated a forward selection approach to identify a refined subset of genes for computing the OncoRibo-68 score. For validation, patients in The Cancer Genome Atlas (TCGA) were stratified into high or low OncoRibo-68 score groups for survival analyses. Additional validation for immunotherapy response was conducted using bioinformatic platforms used for immunotherapy response analysis. Results: A higher OncoRibo-68 score consistently correlated with poorer overall and progression-free survival across multiple cancers. Elevated OncoRibo-68 score was linked to an immunosuppressive tumor microenvironment, but interestingly to increased response to checkpoint inhibitors. Conclusions: Our findings highlight RiBi as an important determinant of tumor aggressiveness and identify the OncoRibo-68 score as a promising biomarker for risk stratification and therapy selection. Future research may evaluate whether targeting RiBi pathways could enhance treatment efficacy, particularly in combination with immunotherapy. Full article
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15 pages, 1257 KiB  
Article
Androgen receptors and Zinc finger (ZNF) Transcription Factors’ Interplay and Their miRNA Regulation in Prostate Cancer Prognosis
by Laura Boldrini, Savana Watts, Noah Schneider, Rithanya Saravanan and Massimo Bardi
Sci 2025, 7(3), 111; https://doi.org/10.3390/sci7030111 - 5 Aug 2025
Abstract
Transcription factors play crucial roles in regulating gene expression, and any dysregulation in their levels could be involved in cancer progression. The role of androgen receptors (AR) and zinc finger (ZNF) proteins in tumors, like prostate cancer (PC), remains poorly understood. Moreover, due [...] Read more.
Transcription factors play crucial roles in regulating gene expression, and any dysregulation in their levels could be involved in cancer progression. The role of androgen receptors (AR) and zinc finger (ZNF) proteins in tumors, like prostate cancer (PC), remains poorly understood. Moreover, due to the multifaceted transcriptional behavior of ARs and ZNFs, their biological role in cancer progression may also depend on the interplay with micro-RNAs (miRNAs). Based on The Cancer Genome Atlas (TCGA) database, we analyzed the expression levels of zinc finger transcripts and ARs in PC. Specifically, exploring their involvement in cancer progression and regulation by miRNAs. The analysis relied on several tools to create a multivariate combination of the original biomarkers to improve their diagnostic efficacy. Multidimensional Scaling (MDS) identified two new dimensions that were entered into a regression analysis to determine the best predictors of overall survival (OS) and disease-free interval (DFI). A combination of both dimensions predicted almost 50% (R2 = 0.46) of the original variance of OS. Kaplan–Meier survival analysis also confirmed the significance of these two dimensions regarding the clinical output. This study showed preliminary evidence that several transcription factor expression levels belonging to the zinc family and related miRNAs can effectively predict patients’ overall PC survivability. Full article
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21 pages, 3562 KiB  
Article
scRNA-seq Can Identify Different Cell Populations in Ovarian Cancer Bulk RNA-seq Experiments
by Sofia Gabrilovich, Eric Devor, Nicholas Cardillo, David Bender, Michael Goodheart and Jesus Gonzalez-Bosquet
Int. J. Mol. Sci. 2025, 26(15), 7512; https://doi.org/10.3390/ijms26157512 - 4 Aug 2025
Viewed by 52
Abstract
High-grade serous ovarian cancer (HGSC) is a heterogeneous disease. RNA sequencing (RNAseq) of bulk solid tissue is of limited use in these populations due to heterogeneity. Single-cell RNA-seq (scRNA-seq) allows for the identification of diverse genetic compositions of heterogeneous cell populations. New computational [...] Read more.
High-grade serous ovarian cancer (HGSC) is a heterogeneous disease. RNA sequencing (RNAseq) of bulk solid tissue is of limited use in these populations due to heterogeneity. Single-cell RNA-seq (scRNA-seq) allows for the identification of diverse genetic compositions of heterogeneous cell populations. New computational methodologies are now available that use scRNAseq results to estimate cell type proportions in bulk RNAseq data. We performed bulk RNA-seq gene expression analysis on 112 HGSC specimens and 12 benign fallopian tube (FT) controls. We identified several publicly available scRNAseq datasets for use as annotation and reference datasets. Deconvolution was performed with MUlti-Subject SIngle Cell Deconvolution (MuSiC) to estimate cell type proportions in the bulk RNA-seq data. Datasets from the Cancer Genome Atlas (TCGA). HGSC repositories were also evaluated. Clinical variables and percentages of cell types were compared for differences in clinical outcomes and treatment results. Pathway enrichment analysis was also performed. Different annotations for referenced scRNA-seq datasets used for deconvolution of bulk RNA-seq data revealed different cellular proportions that were significantly associated with clinical outcomes; for example, higher proportions of macrophages were associated with a better response to primary chemotherapy. Our deconvolution study of bulk RNAseq HGSC samples identified cell populations within the tumor that may be associated with some of the observed clinical outcomes. Full article
(This article belongs to the Section Molecular Informatics)
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11 pages, 6272 KiB  
Communication
A Natural Language Processing Method Identifies an Association Between Bacterial Communities in the Upper Genital Tract and Ovarian Cancer
by Andrew Polio, Vincent Wagner, David P. Bender, Michael J. Goodheart and Jesus Gonzalez Bosquet
Int. J. Mol. Sci. 2025, 26(15), 7432; https://doi.org/10.3390/ijms26157432 - 1 Aug 2025
Viewed by 97
Abstract
Bacterial communities within the female upper genital tract may influence the risk of ovarian cancer. In this retrospective cohort pilot study, we aim to detect different communities of bacteria between ovarian cancer and normal controls using topic modeling, a natural language processing tool. [...] Read more.
Bacterial communities within the female upper genital tract may influence the risk of ovarian cancer. In this retrospective cohort pilot study, we aim to detect different communities of bacteria between ovarian cancer and normal controls using topic modeling, a natural language processing tool. RNA was extracted and analyzed using the VITCOMIC2 pipeline. Topic modeling assessed differences in bacterial communities. Idatuning identified an optimal latent topic number and Latent Dirichlet Allocation (LDA) assessed topic differences between high-grade serous ovarian cancer (HGSOC) and controls. Results were validated using The Cancer Genome Atlas (TCGA) HGSOC dataset. A total of 801 unique taxa were identified, with 13 bacteria significantly differing between HGSOC and normal controls. LDA modeling revealed a latent topic associated with HGSOC samples, containing bacteria Escherichia/Shigella and Corynebacterineae. Pathway analysis using KEGG databases suggest differences in several biologic pathways including oocyte meiosis, aldosterone-regulated sodium reabsorption, gastric acid secretion, and long-term potentiation. These findings support the hypothesis that bacterial communities in the upper female genital tract may influence the development of HGSOC by altering the local environment, with potential functional implications between HGSOC and normal controls. However, further validation is required to confirms these associations and determine mechanistic relevance. Full article
(This article belongs to the Section Molecular Oncology)
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30 pages, 5307 KiB  
Article
Self-Normalizing Multi-Omics Neural Network for Pan-Cancer Prognostication
by Asim Waqas, Aakash Tripathi, Sabeen Ahmed, Ashwin Mukund, Hamza Farooq, Joseph O. Johnson, Paul A. Stewart, Mia Naeini, Matthew B. Schabath and Ghulam Rasool
Int. J. Mol. Sci. 2025, 26(15), 7358; https://doi.org/10.3390/ijms26157358 - 30 Jul 2025
Viewed by 279
Abstract
Prognostic markers such as overall survival (OS) and tertiary lymphoid structure (TLS) ratios, alongside diagnostic signatures like primary cancer-type classification, provide critical information for treatment selection, risk stratification, and longitudinal care planning across the oncology continuum. However, extracting these signals solely from sparse, [...] Read more.
Prognostic markers such as overall survival (OS) and tertiary lymphoid structure (TLS) ratios, alongside diagnostic signatures like primary cancer-type classification, provide critical information for treatment selection, risk stratification, and longitudinal care planning across the oncology continuum. However, extracting these signals solely from sparse, high-dimensional multi-omics data remains a major challenge due to heterogeneity and frequent missingness in patient profiles. To address this challenge, we present SeNMo, a self-normalizing deep neural network trained on five heterogeneous omics layers—gene expression, DNA methylation, miRNA abundance, somatic mutations, and protein expression—along with the clinical variables, that learns a unified representation robust to missing modalities. Trained on more than 10,000 patient profiles across 32 tumor types from The Cancer Genome Atlas (TCGA), SeNMo provides a baseline that can be readily fine-tuned for diverse downstream tasks. On a held-out TCGA test set, the model achieved a concordance index of 0.758 for OS prediction, while external evaluation yielded 0.73 on the CPTAC lung squamous cell carcinoma cohort and 0.66 on an independent 108-patient Moffitt Cancer Center cohort. Furthermore, on Moffitt’s cohort, baseline SeNMo fine-tuned for TLS ratio prediction aligned with expert annotations (p < 0.05) and sharply separated high- versus low-TLS groups, reflecting distinct survival outcomes. Without altering the backbone, a single linear head classified primary cancer type with 99.8% accuracy across the 33 classes. By unifying diagnostic and prognostic predictions in a modality-robust architecture, SeNMo demonstrated strong performance across multiple clinically relevant tasks, including survival estimation, cancer classification, and TLS ratio prediction, highlighting its translational potential for multi-omics oncology applications. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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18 pages, 1337 KiB  
Article
Dysregulated Alternative Splicing in Breast Cancer Subtypes of RIF1 and Other Transcripts
by Emma Parker, Laura Akintche, Alexandra Pyatnitskaya, Shin-ichiro Hiraga and Anne D. Donaldson
Int. J. Mol. Sci. 2025, 26(15), 7308; https://doi.org/10.3390/ijms26157308 - 29 Jul 2025
Viewed by 285
Abstract
Genome instability is a hallmark of cancer, often driven by mutations and altered expression of genome maintenance factors involved in DNA replication and repair. Rap1 Interacting Factor 1 (RIF1) plays a crucial role in genome stability and is implicated in cancer pathogenesis. Cells [...] Read more.
Genome instability is a hallmark of cancer, often driven by mutations and altered expression of genome maintenance factors involved in DNA replication and repair. Rap1 Interacting Factor 1 (RIF1) plays a crucial role in genome stability and is implicated in cancer pathogenesis. Cells express two RIF1 splice variants, RIF1-Long and RIF1-Short, which differ in their ability to protect cells from DNA replication stress. Here, we investigate differential expression and splicing of RIF1 in cancer cell lines following replication stress and in patients using matched normal and tumour data from The Cancer Genome Atlas (TCGA). Overall RIF1 expression is altered in several cancer types, with increased transcript levels in colon and lung cancers. RIF1 also exhibits distinct splicing patterns, particularly in specific breast cancer subtypes. In Luminal A (LumA), Luminal B (LumB), and HER2-enriched breast cancers (HER2E), RIF1 Exon 31 tends to be excluded, favouring RIF1-Short expression and correlating with poorer clinical outcomes. These breast cancer subtypes also tend to exclude other short exons, suggesting length-dependent splicing dysregulation. Basal breast cancer also shows exon exclusion, but unlike other subtypes, it shows no short-exon bias. Surprisingly, however, in basal breast cancer, RIF1 Exon 31 is not consistently excluded, which may impact prognosis since RIF1-Long protects against replication stress. Full article
(This article belongs to the Special Issue New Advances in Cancer Genomics)
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20 pages, 6555 KiB  
Article
Construction of a Genetic Prognostic Model in the Glioblastoma Tumor Microenvironment
by Wenhui Wu, Wenhao Liu, Zhonghua Liu and Xin Li
Genes 2025, 16(8), 861; https://doi.org/10.3390/genes16080861 - 24 Jul 2025
Viewed by 295
Abstract
Background: Glioblastoma (GBM) is one of the most challenging malignancies in all of neoplasms. These malignancies are associated with unfavorable clinical outcomes and significantly compromised patient wellbeing. The immunological landscape within the tumor microenvironment (TME) plays a critical role in determining GBM prognosis. [...] Read more.
Background: Glioblastoma (GBM) is one of the most challenging malignancies in all of neoplasms. These malignancies are associated with unfavorable clinical outcomes and significantly compromised patient wellbeing. The immunological landscape within the tumor microenvironment (TME) plays a critical role in determining GBM prognosis. By mining data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and correlating them with immune responses in the TME, genes associated with the immune microenvironment with potential prognostic value were obtained. Method: We selected GSE16011 as the training set. Gene expression profiles were substrates scored by both ESTIMATE and xCell, and immune cell subpopulations in GBM were analyzed by CIBERSORT. Gene expression profiles associated with low immune scores were performed by lasso regression, Cox analysis and random forest (RF) to identify a prognostic model for the multiple genes associated with immune infiltration in GBM. Then we constructed a nomogram to optimize the prognostic model using GSE7696 and TCGA-GBM as validation sets and evaluated these data for gene mutation and gene enrichment analysis. Result: The prognostic correlation between the six genes (MEOX2, PHYHIP, RBBP8, ST18, TCF12, and THRB) and GBM was finally found by lasso regression, Cox regression, and RF, and the online database obtained that all six genes were differentially expressed in GBM. Therefore, a prognostic correlation model was constructed based on the six genes. Kaplan–Meier (KM) survival analysis showed that this prognostic model had excellent prognostic ability. Conclusions: Prognostic models based on tumor microenvironment and immune score stratification and the construction of related genes have potential applications for prognostic analysis of GBM patients. Full article
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19 pages, 7071 KiB  
Article
Differential Role of CD318 in Tumor Immunity Affecting Prognosis in Colorectal Cancer Compared to Other Adenocarcinomas
by Bhaumik Patel, Marina Curcic, Mohamed Ashraf Eltokhy and Sahdeo Prasad
J. Clin. Med. 2025, 14(14), 5139; https://doi.org/10.3390/jcm14145139 - 19 Jul 2025
Viewed by 391
Abstract
Background/Objectives: CD318 (also known as CDCP1) is a transmembrane protein that is overexpressed in many cancers and contributes to tumor progression, invasion, and metastasis by activating SRC family kinases through phosphorylation. Emerging evidence also suggests that CD318 plays a role in modulating [...] Read more.
Background/Objectives: CD318 (also known as CDCP1) is a transmembrane protein that is overexpressed in many cancers and contributes to tumor progression, invasion, and metastasis by activating SRC family kinases through phosphorylation. Emerging evidence also suggests that CD318 plays a role in modulating the tumor immune microenvironment, although its precise mechanism in tumor progression is still not well understood. Methods: To investigate this, we analyzed the expression and immune-related functions of CD318 using the publicly available data from The Cancer Genome Atlas (TCGA) across colorectal adenocarcinoma (COAD), cervical squamous cell carcinoma (CESC), lung adenocarcinoma (LUAD), and pancreatic adenocarcinoma (PAAD). Results: All four cancers exhibited a high level of CD318 expression. Notably, in CESC, LUAD, and PAAD, plasmin-mediated cleavage of CD318 leads to phosphorylation of SRC and protein kinase C delta (PKCδ), which activates HIF1α and/or p38 MAPK. These downstream effectors translocate to the nucleus and promote the transcriptional upregulation of TGFβ1, fostering an immunosuppressive tumor microenvironment through Treg cell recruitment. In contrast, this signaling cascade appears to be absent in COAD. Instead, our analysis indicate that intact CD318 in COAD interacts with the surface receptors CD96 and CD160, which are found on CD8+ T cells and NK cells. Conclusions: This interaction enhances cytotoxic immune responses in COAD by promoting CD8+ T cell and NK cell activity, offering a possible explanation for the favorable prognosis associated with high CD318 expression in COAD, compared to the poorer outcomes observed in CESC, LUAD, and PAAD. Full article
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14 pages, 1827 KiB  
Article
Unique Biological Characteristics of Patients with High Gleason Score and Localized/Locally Advanced Prostate Cancer Using an In Silico Translational Approach
by Shiori Miyachi, Masanori Oshi, Takeshi Sasaki, Itaru Endo, Kazuhide Makiyama and Takahiro Inoue
Curr. Oncol. 2025, 32(7), 409; https://doi.org/10.3390/curroncol32070409 - 18 Jul 2025
Viewed by 346
Abstract
Gleason score (GS) is one of the best predictors of prostate cancer (PCa) aggressiveness; however, its biological features need to be elucidated. This study aimed to explore the biological characteristics of localized/locally advanced PCa stratified using in silico GS analysis. Biological features were [...] Read more.
Gleason score (GS) is one of the best predictors of prostate cancer (PCa) aggressiveness; however, its biological features need to be elucidated. This study aimed to explore the biological characteristics of localized/locally advanced PCa stratified using in silico GS analysis. Biological features were analyzed using gene set variation analysis and the xCell algorithm with mRNA expression in two independent public databases: The Cancer Genome Atlas (TCGA) (n = 493; radical prostatectomy cohort) and GSE116918 (n = 248; radiation therapy cohort). GS levels were positively correlated with the activity levels of cell proliferation-related gene sets, including E2F targets, the G2M checkpoint, the mitotic spindle, and MYC targets v1 and v2 in both cohorts. Furthermore, GS levels were positively associated with the activity levels of immune-related gene sets and infiltrating fractions of immune cells, including CD4+ memory T cells, dendritic cells, M1 macrophages, and Th2 cells, in both cohorts. Notably, GS levels were positively associated with the score levels of homologous recombination defects, intratumor heterogeneity, fraction genome alteration, neoantigens, and mutation rates in the TCGA cohort. In conclusion, PCa with high GS levels was associated with cancer cell proliferation, immune cell infiltration, and high mutation rates, which may reflect worse clinical outcomes. Full article
(This article belongs to the Section Genitourinary Oncology)
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26 pages, 19818 KiB  
Article
Evodiamine Boosts AR Expression to Trigger Senescence and Halt Proliferation in OSCC Cells
by Gang Chen, Hong-Liang Du, Jia-Nan Liu, Jie Cheng, Jing Chen, Xiao-Yang Yin, Hu-Lai Wei and Jing Wang
Curr. Issues Mol. Biol. 2025, 47(7), 558; https://doi.org/10.3390/cimb47070558 - 17 Jul 2025
Viewed by 384
Abstract
Oral squamous cell carcinoma (OSCC), an aggressive and poorly prognosed subtype of head and neck squamous cell carcinoma (HNSCC), has prompted urgent calls for innovative therapeutic approaches. Evodiamine (EVO), a natural alkaloid extracted from the Chinese herb Evodia rutaecarpa, has demonstrated significant [...] Read more.
Oral squamous cell carcinoma (OSCC), an aggressive and poorly prognosed subtype of head and neck squamous cell carcinoma (HNSCC), has prompted urgent calls for innovative therapeutic approaches. Evodiamine (EVO), a natural alkaloid extracted from the Chinese herb Evodia rutaecarpa, has demonstrated significant potential in curbing tumor cell proliferation and slowing tumor expansion. However, its specific effects on cell senescence within the context of OSCC have remained shrouded in uncertainty. This study delves into the mechanisms of EVO’s impact on OSCC by harnessing databases such as the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and CellAge to pinpoint potential targets and carry out in-depth bioinformatics analysis. The findings reveal that EVO can markedly enhance the expression of the androgen receptor (AR) in OSCC cells, inducing cellular senescence and thereby inhibiting tumor progression. Furthermore, the research indicates that AR expression is considerably lower in OSCC tissues than in normal tissues. This low expression of AR in tumor tissues is closely associated with advanced clinical stages and unfavorable prognoses in HNSCC patients. These discoveries open up new avenues for therapeutic strategies, and suggest that AR holds promise as a potential therapeutic target for OSCC, and EVO may amplify its antitumor effects by enhancing AR-mediated cellular senescence in the treatment of OSCC. Full article
(This article belongs to the Section Molecular Medicine)
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23 pages, 3053 KiB  
Article
MICA+ Tumor Cells Modulate Macrophage Phenotype and Function via PPAR/EHHADH-Mediated Fatty Acid Metabolism in Hepatocellular Carcinoma (HCC)
by Jingquan Huang, Yumeng Teng, Peng Yan, Yan Yang, Shixun Lin, Qiulin Wu, Qiang Du, Xicai Li, Ming Yao, Jianjun Li, Yubin Huang, Xiaoyong Cai, David A. Geller and Yihe Yan
Cancers 2025, 17(14), 2365; https://doi.org/10.3390/cancers17142365 - 16 Jul 2025
Viewed by 360
Abstract
Background: Tumor-associated macrophages (TAMs) play a crucial role in the tumor microenvironment (TME), and the metabolic activities of both tumor cells and TAMs have an impact on the TME. Moreover, the expression of MICA in tumor cells is closely associated with immune cells [...] Read more.
Background: Tumor-associated macrophages (TAMs) play a crucial role in the tumor microenvironment (TME), and the metabolic activities of both tumor cells and TAMs have an impact on the TME. Moreover, the expression of MICA in tumor cells is closely associated with immune cells in hepatocellular carcinoma (HCC). However, it remains unclear whether MICA expression correlates with TAMs and influences the switch in macrophage phenotype by mediating metabolic alterations. Methods: Various biostatistical tools, qPCR, and IHC staining experiments were utilized to analyze data from The Cancer Genome Atlas (TCGA) and collected HCC tumor tissues. Single-cell RNA sequencing (scRNA-seq) analyses and a co-culture model of HCC cells with macrophages were performed to validate the findings from the biostatistical analyses. Results: Through the intersection of differentially expressed genes (DEGs), metabolism-related genes (MRGs), and co-expression genes (CEGs) with MICA in HCC, the EHHADH gene was identified. Gene set enrichment analyses were conducted to further confirm the role of EHHADH. EHHADH expression is decreased in HCC tumors and can serve as a prognostic biomarker for HCC. Expressions of MICA and EHHADH exhibited significant correlations with various phenotypic macrophages and exerted opposing effects on M1-like and M2-like macrophages infiltrating HCC. The underlying metabolic and molecular mechanisms revealed that MICA in tumor cells induced M2-like polarization through the PPAR/EHHADH pathway, which regulates the fatty acid oxidation (FAO) in macrophages. Conclusions: The metabolic gene EHHADH, which is associated with MICA, led to alterations in M2-like macrophages by promoting heightened fatty acid uptake and augmenting levels of FAO within macrophages. Full article
(This article belongs to the Section Tumor Microenvironment)
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20 pages, 8199 KiB  
Article
Piezo-Type Mechanosensitive Ion Channel Component 1 (PIEZO1) as a Potential Prognostic Marker in Renal Clear Cell Carcinoma
by Paulina Antosik, Martyna Szachniewicz, Michał Baran, Klaudia Bonowicz, Dominika Jerka, Ewelina Motylewska, Maciej Kwiatkowski, Maciej Gagat and Dariusz Grzanka
Int. J. Mol. Sci. 2025, 26(14), 6598; https://doi.org/10.3390/ijms26146598 - 9 Jul 2025
Viewed by 374
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of kidney cancer and is often diagnosed at advanced stages. PIEZO1, a mechanosensitive ion channel, has been implicated in cancer progression, but its prognostic relevance in ccRCC remains unclear. This study [...] Read more.
Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of kidney cancer and is often diagnosed at advanced stages. PIEZO1, a mechanosensitive ion channel, has been implicated in cancer progression, but its prognostic relevance in ccRCC remains unclear. This study aimed to evaluate the expression pattern of PIEZO1 in ccRCC and its association with clinicopathological characteristics and patient survival. Immunohistochemical analysis was performed on formalin-fixed, paraffin-embedded tumor tissues from 111 patients with ccRCC, along with 23 matched peritumoral non-cancerous tissues. Protein expression was quantified using the H-score system. Associations with tumor grade, staging, and overall survival (OS) were analyzed. mRNA expression data were retrieved from The Cancer Genome Atlas (TCGA) to validate the protein-level findings. Functional enrichment and pathway analyses were conducted to explore the biological context of PIEZO1-related gene expression. PIEZO1 showed predominantly cytoplasmic localization, with significantly lower expression in tumor tissues compared to adjacent non-malignant tissue (p < 0.0001). High PIEZO1 expression was correlated with higher tumor grade (p = 0.0147) and shorter OS (p = 0.0047). These findings were confirmed at the mRNA level in the TCGA cohort. Multivariate Cox regression analysis identified PIEZO1 as an independent prognostic factor for OS. In conclusion, PIEZO1 may serve as a clinically relevant biomarker in ccRCC. Its overexpression is associated with more aggressive tumor characteristics and poor prognosis, underscoring the need for further investigation into its functional role and potential as a therapeutic target. Full article
(This article belongs to the Section Molecular Oncology)
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17 pages, 1435 KiB  
Article
Evaluation of GDF15 Significance as a Biomarker in Laryngeal Squamous Cell Carcinoma
by Aleksandra Romanowicz, Oskar Komisarek, Anna Klimaszewska-Wiśniewska, Paulina Antosik, Kacper Naglik, Joanna Czech, Witold Wrzesiński, Marta Kodzik, Magdalena Bodnar, Dariusz Grzanka and Paweł Burduk
J. Clin. Med. 2025, 14(14), 4870; https://doi.org/10.3390/jcm14144870 - 9 Jul 2025
Viewed by 380
Abstract
Background/Objectives: Laryngeal squamous cell carcinoma (LSCC) is a common malignancy with unsatisfactory survival rates, highlighting the need for reliable biomarkers to improve its diagnosis and prognosis. Growth differentiation factor 15 (GDF15), a protein implicated in various cancers, has not been thoroughly investigated [...] Read more.
Background/Objectives: Laryngeal squamous cell carcinoma (LSCC) is a common malignancy with unsatisfactory survival rates, highlighting the need for reliable biomarkers to improve its diagnosis and prognosis. Growth differentiation factor 15 (GDF15), a protein implicated in various cancers, has not been thoroughly investigated in LSCC. This study aimed to evaluate the significance of GDF15 expression in LSCC by integrating immunohistochemical analysis of archival tissue samples with RNA sequencing data from public databases (TCGA and GEO) to provide comprehensive clinical insights. Methods: We analyzed archival tissue samples from 65 patients with LSCC using immunohistochemistry and evaluated GDF15 expression profiles from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Statistical analyses included Kaplan–Meier survival analysis and Cox proportional hazards regression to assess the correlation between GDF15 expression, clinicopathological variables, and survival outcomes. Results: GDF15 expression did not significantly differ between tumor and adjacent normal tissues. However, in the tissue macroarray (TMA) cohort, high GDF15 expression was significantly associated with a lower TNM stage and less advanced pT status. Kaplan–Meier analysis revealed that high GDF15 expression correlated with reduced overall survival in the TMA cohort, suggesting its utility in risk stratification. Multivariate analysis identified GDF15 as an independent prognostic factor for disease-free survival in LSCC. Conclusions: Our findings suggest that GDF15 may serve as a prognostic biomarker for LSCC, particularly in early-stage disease. Elevated GDF15 levels, which are associated with poorer overall survival, could be integrated into diagnostic panels to enhance risk stratification and inform treatment decisions. Furthermore, GDF15 may be a promising target for therapeutic intervention. Further research is warranted to validate these results and explore their potential in clinical practice. Full article
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20 pages, 18100 KiB  
Article
Targeting p-FGFR1Y654 Enhances CD8+ T Cells Infiltration and Overcomes Immunotherapy Resistance in Esophageal Squamous Cell Carcinoma by Regulating the CXCL8–CXCR2 Axis
by Hong Luo, Liwei Wang, Hui Gao, Daijun Zhou, Yu Qiu, Lijia Yang, Jing Li, Dan Du, Xiaoli Huang, Yu Zhao, Zhongchun Qi, Yue Zhang, Xuemei Huang, Lihan Sun, Tao Xu and Dong Li
Biomedicines 2025, 13(7), 1667; https://doi.org/10.3390/biomedicines13071667 - 8 Jul 2025
Viewed by 496
Abstract
Background: Esophageal squamous cell carcinoma (ESCC) is a fatal malignant tumor. Several studies have demonstrated that immune checkpoint inhibitors can provide clinical benefits to patients with ESCC. However, the single-agent efficacy of these agents remains limited. Although combination therapies (e.g., radiotherapy, chemotherapy) can [...] Read more.
Background: Esophageal squamous cell carcinoma (ESCC) is a fatal malignant tumor. Several studies have demonstrated that immune checkpoint inhibitors can provide clinical benefits to patients with ESCC. However, the single-agent efficacy of these agents remains limited. Although combination therapies (e.g., radiotherapy, chemotherapy) can help to overcome immunotherapy resistance in ESCC, their severe side effects limit clinical application. This study aimed to explore new resistance mechanisms to immunotherapy in ESCC and identify novel molecular targets to overcome immunotherapy resistance. Methods: We employed immunohistochemistry staining to examine the p-FGFR1Y654 in tumor samples obtained from 103 patients with ESCC, in addition to evaluating CD8+ T cell infiltration. In vitro expression, western blotting, CCK-8, 5-bromo-2′-deoxyuridine incorporation assays, and migration assays were used to confirm the impact of AZD4547 on p-FGFR1Y654 expression and the proliferation and migration in ESCC cell lines. Through RNA sequencing analysis, databases such as the Cancer Genome Atlas (TCGA) and Gene Set Cancer Analysis (GSCA), and the reconstruction of transgenic mice using the humanized immune system, we validated the correlation between the expression of p-FGFR1Y654 and CD8+ T cell infiltration. We also explored how p-FGFR1Y654 recruits myeloid-derived suppressor cells (MDSCs) through the CXCL8–CXCR2 axis to suppress the therapeutic efficacy of immunotherapy in ESCC. Finally, the tumor-suppressive effects of AZD4547 combined with immunotherapy were confirmed in vivo in tumor-bearing mice with a humanized immune system. Results: We found that the inhibition of p-FGFR1Y654 expression in ESCC can enhance CD8+ T cell infiltration by suppressing the CXCL8-–XCR2 recruitment of MDSCs. AZD4547, combined with immunotherapy, further promotes immunotherapeutic efficacy in ESCC. Conclusions: In conclusion, our study presents a promising model for combination therapy in ESCC immunotherapy. Full article
(This article belongs to the Section Immunology and Immunotherapy)
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32 pages, 4374 KiB  
Article
Predictive and Prognostic Relevance of ABC Transporters for Resistance to Anthracycline Derivatives
by Rümeysa Yücer, Rossana Piccinno, Ednah Ooko, Mona Dawood, Gerhard Bringmann and Thomas Efferth
Biomolecules 2025, 15(7), 971; https://doi.org/10.3390/biom15070971 - 6 Jul 2025
Viewed by 597
Abstract
Anthracyclines have been clinically well established in cancer chemotherapy for decades. The main limitations of this drug class are the development of resistance and severe side effects. In the present investigation, we analyzed 30 anthracyclines in a panel of 59 cell lines of [...] Read more.
Anthracyclines have been clinically well established in cancer chemotherapy for decades. The main limitations of this drug class are the development of resistance and severe side effects. In the present investigation, we analyzed 30 anthracyclines in a panel of 59 cell lines of the National Cancer Institute, USA. The log10IC50 values varied from −10.49 M (3′-deamino-3′-(4″-(3″-cyano)morpholinyl)-doxorubicin, 1) to −4.93 M (N,N-dibenzyldaunorubicin hydrochloride, 30). Multidrug-resistant NCI-ADR-Res ovarian cancer cells revealed a high degree of resistance to established anthracyclines (between 18-fold to idarubicin (4) and 166-fold to doxorubicin (13) compared to parental, drug-sensitive OVCAR8 cells). The resistant cells displayed only low degrees of resistance (1- to 5-fold) to four other anthracyclines (7, 18, 28, 30) and were even hypersensitive (collaterally sensitive) to two compounds (1, 26). Live cell time-lapse microscopy proved the cross-resistance of the three chosen anthracyclines (4, 7, 9) on sensitive CCRF/CEM and multidrug-resistant CEM/ADR5000 cells. Structure–activity relationships showed that the presence of tertiary amino functions is helpful in avoiding resistance, while primary amines rather increased resistance development. An α-aminonitrile function as in compound 1 was favorable. Investigating the mRNA expression of 49 ATP-binding cassette (ABC) transporter genes showed that ABCB1/MDR1 encoding P-glycoprotein was the most important one for acquired and inherent resistance to anthracyclines. Molecular docking demonstrated that all anthracyclines bound to the same binding domain at the inner efflux channel side of P-glycoprotein with high binding affinities. Kaplan–Meier statistics of RNA sequencing data of more than 8000 tumor biopsies of TCGA database revealed that out of 23 tumor entities high ABCB1 expression was significantly correlated with worse survival times for acute myeloid leukemia, multiple myeloma, and hepatocellular carcinoma patients. This indicates that ABCB1 may serve as a prognostic marker in anthracycline-based chemotherapy regimens in these tumor types and a target for the development of novel anthracycline derivatives. Full article
(This article belongs to the Special Issue Current Advances in ABC Transporters in Physiology and Disease)
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