Transl Oncol
· 2026 Jun · PMID 42335576
·
Full text
BACKGROUND AND AIMS: Current colorectal cancer (CRC) screening methods have limited sensitivity for precancerous lesions. Blood-based liquid biopsies are constrained by systemic dilution, highlighting the need for locali...BACKGROUND AND AIMS: Current colorectal cancer (CRC) screening methods have limited sensitivity for precancerous lesions. Blood-based liquid biopsies are constrained by systemic dilution, highlighting the need for localized, minimally invasive molecular approaches. We evaluated whether colonoscope-derived mucus serves as a high-fidelity source of cell-free DNA (cfDNA) for detecting KRAS-mutated colorectal neoplasia. METHODS: In this prospective pilot study, mucus samples (N = 43) were collected from the colonoscope sheath during routine colonoscopy. cfDNA was analyzed for KRAS codon 12 mutations using a competitive PCR assay. Diagnostic performance at variant allele frequency (VAF) thresholds (>1% and >0.1%) was compared with histology, fecal immunochemical testing (FIT), and carcinoembryonic antigen (CEA). RESULTS: At VAF >0.1%, mucus cfDNA achieved 80.0% sensitivity for colorectal neoplasia, outperforming FIT (40.0%) and CEA (10.0%, p = 0.005). Sensitivity reached 100% for adenocarcinoma (n=2) and 75.0% for advanced precancerous colorectal lesions. Specificity decreased to 29.6% at lower thresholds, likely due to inflammatory confounders. Importantly, KRAS mutations were detected in visually inconspicuous mucosa. CONCLUSIONS: Colonoscope-derived mucus is a promising localized cfDNA source for detecting early colorectal neoplasia. This approach may serve as a colonoscopy-integrated adjunct within existing screening pathways and may support post-procedure risk stratification and surveillance optimization.
Delahunty RL, Jayawardana M, Arnolda R
… +27 more, Koh TT, Hofman MS, Reid K, Lamont J, Nguyen-Ngo C, Johnston HM, Brooks NG, Wojtowicz P, Obers VJ, Jobling T, Shadbolt C, Smith PE, Sawyer BL, Xu H, Silva SSM, Neesham D, Ellis J, Goss G, Volchek M, Jones K, Hewitt CA, Fellowes A, Prince HM, McNally O, Wong SQ, Christie EL, Yannakou CK
Transl Oncol
· 2026 Jun · PMID 42330843
·
Full text
PURPOSE: Biomarkers to predict relapse and guide adjuvant therapy selection are needed in endometrial cancer (EC), one of the few cancers increasing in incidence and mortality. Assessment of circulating tumour DNA (ctDNA...PURPOSE: Biomarkers to predict relapse and guide adjuvant therapy selection are needed in endometrial cancer (EC), one of the few cancers increasing in incidence and mortality. Assessment of circulating tumour DNA (ctDNA) at multiple perioperative time points has not been explored in EC. This study aimed to evaluate the prognostic utility of ctDNA across four perioperative time points, explore ctDNA dynamics, and compare ctDNA-derived tumour burden with 18F-fluorodeoxyglucose (FDG)-PET/CT and MRI. PATIENTS AND METHODS: Participants with Type 2 EC planned for surgery and consenting to the collection of biospecimens were enrolled prior to surgery and followed prospectively. Participants had preoperative imaging, and tumour sequencing was performed using hybrid capture, which guided the design of droplet digital PCR (ddPCR) assays for ctDNA analysis. The primary study endpoint was relapse free survival. RESULTS: Fifty participants were enrolled in the CODEC study. Genomic findings were consistent with the established molecular landscape of EC. Detection of ctDNA postoperatively at 24 h (Time Point 2B) and at 2-6 weeks (Time Point 3) was associated with poorer relapse-free survival. No significant association with outcome was observed for preoperative (Time Point 1) or intraoperative (Time Point 2A) ctDNA. Preoperative ctDNA correlated with FDG-PET- and MRI-defined tumour volume. CONCLUSION: These findings are hypothesis-generating and support the prognostic relevance of postoperative ctDNA assessment in EC with the 2-6 week postoperative window the most clinically informative time point for detecting minimal residual disease. Further studies are required to validate these findings and determine whether ctDNA can guide adjuvant therapy selection.
Liu Y, Han J, Shioya A
… +5 more, Oyama T, Guo X, Yang Q, Uramoto H, Yamada S
Transl Oncol
· 2026 Jun · PMID 42322696
·
Full text
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive behavior, therapeutic resistance, and redox imbalance. Peroxiredoxin 4 (PRDX4), an endoplasmic reticulum-localized antioxidant enzyme, ha...BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive behavior, therapeutic resistance, and redox imbalance. Peroxiredoxin 4 (PRDX4), an endoplasmic reticulum-localized antioxidant enzyme, has been implicated in tumor progression, but its clinical significance and redox-associated role in PDAC remain unclear. METHODS: PRDX4 expression was assessed by immunohistochemistry in 128 resected PDAC specimens and correlated with clinicopathological features and disease-specific survival (DSS). Functional effects were examined in PRDX4-overexpressing PDAC cell lines. Intracellular reactive oxygen species (ROS) were evaluated under basal and oxidative stress conditions, with N-acetyl-l-cysteine (NAC) rescue. Signaling and redox-related proteins were analyzed by Western blotting. A PRDX4-transgenic mouse model was used to evaluate tumor growth, angiogenesis, and gemcitabine (GEM) responsiveness. RESULTS: High PRDX4 expression was associated with aggressive clinicopathological features and poor DSS. PRDX4 overexpression promoted cell proliferation and migration and reduced intracellular ROS levels. NAC treatment diminished ROS differences, supporting ROS-dependent redox modulation. PRDX4 overexpression was associated with increased ERK phosphorylation, suppressed JNK phosphorylation, increased total PI3K/AKT and p38 levels, reduced E-cadherin expression, and upregulation of NRF2 and HO-1. PRDX4 expression positively correlated with NRF2 and HO-1 in clinical specimens. In vivo, PRDX4 overexpression promoted tumor growth, increased microvessel density, and reduced GEM sensitivity. CONCLUSIONS: PRDX4 is associated with aggressive tumor behavior, redox adaptation, and might reduce gemcitabine responsiveness in PDAC in vivo, supporting its potential as a prognostic biomarker and a candidate molecule for future therapeutic investigation.
Transl Oncol
· 2026 Jun · PMID 42322695
·
Full text
BACKGROUND: An accumulation of evidence underscores the critical importance of both hypoxia and the immune microenvironment in driving the progression of osteosarcoma. Despite advancements in therapeutic strategies, oste...BACKGROUND: An accumulation of evidence underscores the critical importance of both hypoxia and the immune microenvironment in driving the progression of osteosarcoma. Despite advancements in therapeutic strategies, osteosarcoma continues to pose a formidable challenge due to its aggressive nature and high metastatic potential. Nonetheless, the identification of reliable gene signatures that combine information on hypoxia and immune status to predict osteosarcoma prognosis remains an unmet need. METHODS: To gain a deeper understanding of the impact of hypoxia on the invasion of osteosarcoma, we devised a data-driven modeling framework, termed Cellular Hypoxia Prediction Framework (CHPF), which integrates single-cell transcriptome profiling with hypoxia gene signatures to predict cellular hypoxia status. We applied dimensionality reduction, clustering, and various analytical tools such as WGCNA, GO enrichment, and CellChat for cell-cell communication analysis. RESULTS: We conducted a comprehensive analysis of the hypoxia status landscape within osteosarcoma cells and observed a distinct pattern, where hypoxic cells were predominantly confined to the tumor core region. Our analysis revealed distinct hypoxic subpopulations within osteosarcoma, with significant overexpression of genes like FGFBP2 and S100A1 in hypoxic cells. Remarkably, our investigation delved into the functional heterogeneity of tumor cells and uncovered a hypoxic subpopulation that exhibited a remarkably high invasive potential. We identified key genes (RPS28, ZC3HAV1, RPS8, S100A13, SERPINH1, EFNA5, RPL37A, USP11) that are associated with patient prognosis and developed a predictive model, which categorized patients based on their risk profiles. Hypoxia upregulates SERPINH1 expression in osteosarcoma cells in a HIF‑1α‑dependent manner, promotes proliferation and invasion, and SERPINH1 knockdown effectively reverses these hypoxia‑induced malignant phenotypes. CONCLUSION: Genes associated with hypoxia play a pivotal role in the biology of osteosarcoma, significantly impacting tumor behavior and patient survival outcomes. Our research findings offer valuable insights into the underlying mechanisms of osteosarcoma and could potentially pave the way for the development of innovative therapeutic approaches that specifically target the hypoxic tumor microenvironment.
da Costa FH, Kawabe M, Tsai TY
… +10 more, Okamoto K, Bartels MD, Cortes S, Veeramachaneni R, Rangel R, Frederick MJ, Sandulache VC, Sikora AG, Myers JN, Osman AA
OBJECTIVES: Oral cavity head and neck squamous cell carcinoma (HNSCC) represents a major global health burden, with over 40,000 new cases annually in the United States and >500,000 worldwide. Despite advances in surgery,...OBJECTIVES: Oral cavity head and neck squamous cell carcinoma (HNSCC) represents a major global health burden, with over 40,000 new cases annually in the United States and >500,000 worldwide. Despite advances in surgery, radiation therapy, chemotherapy, and immunotherapy, overall survival rates have remained largely stagnant over the past three decades, and over half of patients ultimately die from the disease. Although immune checkpoint inhibitors (ICIs) have improved outcomes for a subset of patients with recurrent or metastatic HNSCC, the majority gain limited benefit. Thus, novel therapeutic strategies that enhance responses to immunotherapy are urgently needed. The ATR-CHK1 signaling pathway has recently been implicated in immune modulation, suggesting that ATR inhibition may potentiate antitumor immunity. This study investigates the therapeutic efficacy of the novel ATR inhibitor AZD6738, alone and in combination with anti-PD-1 therapy, in a syngeneic mouse model of HNSCC. MATERIALS AND METHODS: An orthotopic syngeneic mouse model was used to assess in vivo treatment efficacy. Immune profiling of tumors following AZD6738 treatment was performed by immunohistochemistry and flow cytometry. Conditioned medium from cocultures of tumor and bone marrow cells treated with AZD6738 was analyzed by flow cytometry to evaluate immune cell populations. Additional coculture experiments with bone marrow-derived cells and splenic T cells assessed T cell activation and proliferation. In vitro assays, including clonogenic survival, western blotting, and ATR shRNA knockdown, were used to confirm drug specificity and explore molecular mechanisms. RNA sequencing of tumor samples was conducted to evaluate cytokine expression and immune-related gene signatures. RESULTS: AZD6738 significantly enhanced the efficacy of anti-PD-1 therapy by remodeling the tumor microenvironment. Treatment increased cytotoxic T cell infiltration and activity while reducing regulatory T cells and immunosuppressive myeloid cells. ATR inhibition promoted M1 macrophage polarization and modulated cytokines supporting T cell activation. Mechanistically, enhanced immune responses were associated with DNA damage-induced activation of the cGAS/STING pathway and reduced STAT3 phosphorylation. Transcriptomic analyses revealed that combination therapy upregulated interferon signaling and suppressed epithelial-mesenchymal transition pathways in the MOC1 tumor model. CONCLUSION: AZD6738 enhances antitumor immunity through cytotoxic T cells and innate immune mechanisms, supporting its further development in combination with anti-PD-1 therapy for HNSCC.
Luo W, Jia J, Wang Q
… +13 more, Li X, Yang F, Zhao Y, Li Z, Li L, Wang X, Meng M, Guo H, Zheng W, Wang L, Li D, Hou Z, Guo Y
Transl Oncol
· 2026 Jun · PMID 42320171
·
Full text
The spatial heterogeneity of the tumor immune microenvironment (TME) in lung adenocarcinoma (LUAD) limits the prognostic accuracy of traditional TNM staging. Moreover, conventional T cell based immune scores established...The spatial heterogeneity of the tumor immune microenvironment (TME) in lung adenocarcinoma (LUAD) limits the prognostic accuracy of traditional TNM staging. Moreover, conventional T cell based immune scores established for other solid tumors fail to effectively stratify patient outcomes in LUAD. To address this, we applied quantitative multiplex immunofluorescence to map the spatial immune contexture of LUAD and developed the Lung Cancer Immune Score (LCIS). This framework integrates four key biomarkers: CD68⁺HLA-DR⁺ macrophages, CD20⁺ B cells, PD-1⁺ cells and Ki67⁺ proliferating tumor cells, to quantify the balance between tumor proliferation and host anti-tumor immunity across the tumor core and invasive margin. High LCIS scores independently predicted improved overall survival in both the discovery (p = 0.02) and independent validation (p = 0.017) cohorts, outperforming conventional clinical parameters and single biomarkers. Specifically, LCIS effectively sub-stratified patients with Stage II and III LUAD into refined prognostic groups, resolving the prognostic ambiguity within the same TNM stage. Overall, by quantifying the interaction between tumor proliferation and antigen-directed immune activation, the LCIS serves as a spatial biomarker to refine prognosis and inform personalized therapy in LUAD.
Lan H, Li Y, Li H
… +3 more, Guo J, Wang C, Tang Q
Transl Oncol
· 2026 Jun · PMID 42320170
·
Full text
The metabolic reprogramming of tumor microenvironment is a critical driver of colorectal cancer (CRC) pathogenesis. In this context, dysregulated lactate metabolism plays a pivotal role in immunosuppression and therapeut...The metabolic reprogramming of tumor microenvironment is a critical driver of colorectal cancer (CRC) pathogenesis. In this context, dysregulated lactate metabolism plays a pivotal role in immunosuppression and therapeutic resistance. Integrating single-cell transcriptomics, spatial transcriptomics, and bulk sequencing datasets, this research delineated the lactate metabolic landscape across colorectal cancer (CRC) tumor ecosystems. Single-cell profiling revealed significant metabolic activity in both the epithelial and myeloid compartments. Consequently, a lactate metabolism score (LMscore) was developed, which is based on four core genes (COX15, SLC25A13, COX10, MPC1). An elevated LMscore has been demonstrated to reprogram epithelial developmental trajectories and reconfigure intercellular communication networks, notably through EFNA1-EPHA3-mediated crosstalk with fibroblasts and endothelial cells. Spatial transcriptomics corroborated intimate spatial colocalization and metabolic pathway co-enrichment between lactate-active epithelia and fibroblasts. Clinically, high LMscore independently predicts a decreased overall survival across multiple cohorts and defines a "cold" tumor immune phenotype. This phenotype is characterized by an accumulation of immunosuppressive cells including M2 macrophages and cancer-associated fibroblasts (CAFs) and a reduction in effector T-cell infiltration. This ultimately results in a refractory response to immune checkpoint blockade. Mechanistically, COX15 emerges as a central regulator of lactate metabolic dysregulation, coinciding with fibroblast-derived TGF-β secretion and immunosuppressive niche formation. Functional validation confirms that COX15 targeting suppresses tumor proliferation. This work establishes LMscore as a clinically robust biomarker for prognostication and immunotherapy response prediction, thereby providing a mechanistic foundation for metabolic reprogramming-targeted combinatorial therapies in CRC.
Hu J, Huang Y, Chen H
… +4 more, Xie Z, Yan H, Li H, Li R
Transl Oncol
· 2026 Jun · PMID 42320169
·
Full text
Osteosarcoma treatment outcomes are compromised by increased drug resistance, distant metastasis, and tumor recurrence. While Pyrrolidine-5-carboxylic acid reductase 1(PYCR1) knockdown has been shown to inhibit tumor pro...Osteosarcoma treatment outcomes are compromised by increased drug resistance, distant metastasis, and tumor recurrence. While Pyrrolidine-5-carboxylic acid reductase 1(PYCR1) knockdown has been shown to inhibit tumor proliferation and migration in certain cancers. Its effects in osteosarcoma and regulatory mechanisms within osteosarcoma cells have not been explored. This study investigated the role of PYCR1 in osteosarcoma proliferation and its potential molecular mechanisms. The expression of PYCR1 was assessed in osteosarcoma tissues by immunohistochemistry and its correlation with clinical outcomes was determined. Subsequently, lentivirus-mediated knockdown and over expression of PYCR1 was achieved in osteosarcoma cells to evaluate its impact on proliferation, colony formation, and migration ability. The PI3K/Akt signaling pathway and its downstream effector COL1A1 were investigated using a combination of biomarker analysis, transcriptome sequencing, and co-immunoprecipitation assays. Subsequent silencing of COL1A1 induced phenotypic changes and confirmed tumorigenicity in vivo. The ferroptosis agonist Erastin and its specific antagonist Ferrostatin-1 (Fer-1) were combined with PYCR1 knockdown to explore their correlation with ferroptosis. By applying the pathway inhibitor LY294002, it was confirmed that the PI3K/Akt pathway is crucial for osteosarcoma proliferation. This study confirms that PYCR1 drives osteosarcoma cell proliferation and migration through three key mechanisms: regulating downstream genes, inhibiting ferroptosis, and activating the PI3K/Akt signaling pathway.
Transl Oncol
· 2026 Jun · PMID 42314516
·
Full text
Despite therapeutic advances, lung adenocarcinoma (LUAD) remains difficult to treat, and the mechanisms by which hypoxia promotes tumor progression are still incompletely understood. Because the receptor for advanced gly...Despite therapeutic advances, lung adenocarcinoma (LUAD) remains difficult to treat, and the mechanisms by which hypoxia promotes tumor progression are still incompletely understood. Because the receptor for advanced glycation end products (RAGE) has been implicated in hypoxia-related signaling, we investigated the interaction between damage-associated molecular patterns (DAMPs) and RAGE in LUAD under hypoxic conditions using the RAGE inhibitor FPS-ZM1 in vitro and in vivo. RAGE expression was significantly reduced in LUAD samples and was associated with poor survival. LUAD tissues also showed evidence of hypoxia, including elevated hypoxia-inducible factor-1α (HIF-1α). Under hypoxia, S100A8/A9 redistributed from the nucleus to the cytoplasm, whereas intracellular HMGB1 levels decreased. In vitro, FPS-ZM1 suppressed NF-κB phosphorylation and inhibited LLC cell viability and migration. In contrast, in vivo FPS-ZM1 treatment was associated with enhanced tumor progression, increased HIF-1α and S100A8/A9 expression, and reactivation of NF-κB signaling. These findings suggest that RAGE blockade may trigger context-dependent compensatory responses within the tumor microenvironment. We therefore present a working model in which a hypoxia-associated HIF-1α/S100A8/A9 axis may bypass RAGE inhibition and restore pro-tumor signaling; however, this mechanism requires direct experimental validation. Overall, our data highlight the importance of tumor-microenvironment context when interpreting RAGE-targeted interventions in LUAD.
Zhao J, Wang X, Li T
… +4 more, Chen J, Zhu H, Yang L, Liang Y
Transl Oncol
· 2026 Jun · PMID 42314515
·
Full text
Ovarian cancer (OVCA) has the highest mortality rate among all gynecological malignancies. Epidermal growth factor receptor (EGFR) is commonly overexpressed in epithelial OVCA (30-98%) and is significantly positively cor...Ovarian cancer (OVCA) has the highest mortality rate among all gynecological malignancies. Epidermal growth factor receptor (EGFR) is commonly overexpressed in epithelial OVCA (30-98%) and is significantly positively correlated with poor patient prognosis. However, therapeutic drugs targeting EGFR have not shown promising results, indicating the existence of other potential mechanisms. G-protein-coupled receptor (GPCR) families were reported to crosstalk with EGFR, jointly affecting the activation of downstream signaling pathway networks. G protein-coupled receptor 107 (GPR107), a novel orphan GPCR, is overexpressed in tumors and is involved in cancer progression. Little is known about the role of GPR107 in OVCA progression. In this study, the underlying mechanism of GPR107-EGFR crosstalk and its critical function in OVCA progression were investigated. GPR107, which was highly expressed in OVCA and was associated with advanced clinical stages, could interact with EGFR on the cell membrane and promoted the invasion, migration, and epithelial mesenchymal transition (EMT) of OVCA. Mechanistically, GPR107-EGFR crosstalk promoted EGFR phosphorylation and downstream PI3K/AKT/NF-κB activation, resulting in autocrine IL-6 secretion, which facilitated OVCA metastasis both in vitro and in vivo. Monoclonal antibodies targeting IL-6 could inhibit OVCA metastasis induced by GPR107. In conclusion, our study highlights the importance of GPR107-EGFR crosstalk in OVCA metastasis by clarifying the function and molecular mechanism of GPR107-EGFR crosstalk, and provides a novel direction for developing new treatment strategies for OVCA.
Gloege HF, De Los Santos MAIC, Chakraborty A
… +15 more, Chadha M, Aguilar-Quintero A, Shen M, Heaslip CO, Finstuen-Magro S, McDannell B, Tanhaemami M, Meyer S, Klega K, Zhang YQ, Shulman DS, DuBois SG, Hall MD, Blandin AF, Crompton BD
Transl Oncol
· 2026 Jun · PMID 42314514
·
Full text
Ewing sarcoma is a highly aggressive solid malignancy affecting children and young adults. Ewing sarcoma is driven primarily by EWSR1::FLI1, a fusion oncoprotein that has been notoriously difficult to target with traditi...Ewing sarcoma is a highly aggressive solid malignancy affecting children and young adults. Ewing sarcoma is driven primarily by EWSR1::FLI1, a fusion oncoprotein that has been notoriously difficult to target with traditional pharmacologic agents. There are numerous examples of promising preclinical combinations of small molecules that are never tested in pediatric clinical trials because agents fail to reach the market due to limited efficacy for common adult cancers. Moreover, the effectiveness of single-agent therapies for cancer treatment is often limited. To address these limitations, we selected 28 compounds that were FDA approved at the time of the study or in late stages of clinical development and known to regulate important pathways in Ewing sarcoma. We performed a drug screen in Ewing sarcoma cell lines with 180 combinations of tyrosine kinase inhibitors, cell cycle inhibitors, and conventional chemotherapy. The results of the screen revealed that a PI3K inhibitor, copanlisib, combined with a CDK4/6 inhibitor, ribociclib, exhibited strong synergistic anti-Ewing sarcoma activity. Using proteomic methods such as a reverse-phase protein array and western immunoblotting, we demonstrated that this combination induced a downregulation of the PI3K/AKT pathway as well as proteins involved in cell cycle regulation. We further confirmed these in vitro data using bulk RNA-sequencing. To evaluate the phenotypic effect of the PI3K/CDK4/6 inhibition in Ewing sarcoma lines, we performed apoptosis and cell cycle analyses using flow cytometry and demonstrated that ribociclib primarily induced a G0/G1 arrest with minimal effect on Ewing cell viability but significantly enhanced the apoptotic effect of copanlisib treatment. In two xenograft models of Ewing sarcoma, we demonstrated that the combination significantly prolonged survival compared to treatment with either vehicle or single-agent therapy alone. Our findings identify a new candidate therapy combination for Ewing sarcoma and provide a resource of additional potential synergistic combinations for future validation.
Transl Oncol
· 2026 Jun · PMID 42314513
·
Full text
Head and neck squamous cell carcinoma (HNSCC) frequently exhibits metastatic progression and develops an immunosuppressive microenvironment. However, the tumor cell-intrinsic factors contributing to metastasis-associated...Head and neck squamous cell carcinoma (HNSCC) frequently exhibits metastatic progression and develops an immunosuppressive microenvironment. However, the tumor cell-intrinsic factors contributing to metastasis-associated immune remodeling remain incompletely understood. Here, we integrated two independent single-cell RNA-seq cohorts (GSE243933 and GSE181919) to compare primary and metastatic HNSCC ecosystems and identified vacuole membrane protein 1 (VMP1) as a malignant cell-intrinsic gene consistently upregulated across metastatic contexts. In TCGA-HNSCC and two GEO cohorts (GSE65858 and GSE117973), high VMP1 expression was associated with poor prognosis and enrichment of invasion-related programs, including epithelial-mesenchymal transition (EMT) and TNFα/NF-κB signaling, and was also associated with decreased CD8⁺ T-cell infiltration and impaired effector features. In an independent HNSCC tissue cohort, immunohistochemistry confirmed elevated VMP1 protein expression in tumors and its association with advanced clinicopathological features and unfavorable survival. Functionally, gain- and loss-of-function experiments in SCC25 and CAL27 cells showed that VMP1 enhances proliferation, migration, and invasion, accompanied by EMT-like marker switching, increased RelA/p65 phosphorylation, and elevated PD-L1 expression. Collectively, VMP1 identifies a metastasis-associated tumor-intrinsic factor associated with invasive progression and reduced CD8⁺ T-cell activity. The concomitant NF-κB activation and PD-L1 induction support a potential VMP1-associated NF-κB/PD-L1 link that may contribute to the association between invasion-related programs and immune modulation. These findings support the potential biomarker relevance of VMP1 and provide a rationale for further mechanistic and clinical investigation in HNSCC.
Xie J, Dong K, Wu J
… +3 more, Cheng X, Wang S, Zhang H
Transl Oncol
· 2026 Jun · PMID 42314512
·
Full text
Oxaliplatin resistance remains a significant therapeutic challenge in the treatment of colon adenocarcinoma (COAD). In this study, we identified the RNA-binding protein PUM2 as a key driver of oxaliplatin resistance. Bio...Oxaliplatin resistance remains a significant therapeutic challenge in the treatment of colon adenocarcinoma (COAD). In this study, we identified the RNA-binding protein PUM2 as a key driver of oxaliplatin resistance. Bioinformatics analysis revealed that PUM2 was upregulated in tumor tissues, which correlated with poor patient prognosis. Knockdown of PUM2 inhibited cell proliferation and migration and enhanced oxaliplatin sensitivity by promoting ferroptosis. These findings were validated in vivo, where PUM2 knockdown potentiated the anti-tumor efficacy of oxaliplatin in mouse xenograft models. Mechanistically, PUM2 was found to bind to the mRNA of the E3 ubiquitin ligase NEDD4L. Downregulation of NEDD4L reduced the ubiquitination and degradation of the transcription factor NRF2, leading to NRF2 accumulation and inhibiting ferroptosis. Furthermore, combining an NRF2 inhibitor (ML385) with oxaliplatin promoted ferroptosis and suppressed the growth of resistant tumors in vivo. In conclusion, our findings elucidate a novel PUM2/NEDD4L/NRF2 axis that promotes oxaliplatin resistance in COAD by inhibiting ferroptosis, thereby providing a preclinical rationale for future investigation into this pathway to overcome chemoresistance.
Wang W, Ye L, Sheng J
… +5 more, Wen L, Li H, Hong W, Ji Y, Xu X
Transl Oncol
· 2026 Jun · PMID 42302480
·
Full text
BACKGROUND: Previous studies have shown that tumor immune microenvironment related markers are associated with tumor prognosis. However, few studies have explored the prognostic value of tumor cell surface biomarkers (e....BACKGROUND: Previous studies have shown that tumor immune microenvironment related markers are associated with tumor prognosis. However, few studies have explored the prognostic value of tumor cell surface biomarkers (e.g., CD8, TIM3, PD-L1, LAG3, CD163, and TIGIT) in resectable ESCC. METHODS: We retrospectively analyzed 69 ESCC patients who underwent complete resection at Zhejiang Cancer Hospital. Using multiplex immunofluorescence histochemistry, we evaluated the expression of CD8, TIM3, PD-L1, LAG3, CD163, and TIGIT in tumor and immune microenvironments and their associations with clinical outcomes. Triple-color immunofluorescence confirmed TIGIT expression in ESCC tissues. Functional roles of TIGIT were further investigated via RNA-seq, real-time PCR, WB, CCK-8 assays, transwell assays, and flow cytometry. RESULTS: The median follow-up was 47.7 months. High expression was most frequent for CD8 (52.2%), followed by TIM3 (29.0%), PD-L1 (17.4%), LAG3 (24.6%), TIGIT (20.3%), and CD163 (14.5%). Median DFS was 17.4 months and OS was 26.8 months. Higher TIGIT expression correlated with shorter DFS and OS. Stratification by TIGIT-to-PAN-CK ratio confirmed that higher tumor-cell TIGIT was an unfavorable prognostic indicator. Functional analyses showed that TIGIT knockdown reduced ESCC cell migration, invasion, and proliferation, and altered cell cycle distribution with S-phase accumulation. RNA-sequencing implicated cytokine-receptor interactions and the JAK-STAT signaling axis in TIGIT-mediated functions. CONCLUSIONS: TIGIT, along with PD-L1 and CD163, is a potential prognostic marker for resectable ESCC. TIGIT is not only expressed in immune cells but also in ESCC tumor cells, suggesting its potential as a biomarker and therapeutic target. Further mechanistic studies are warranted to elucidate the downstream signaling pathways and validate the mechanisms of TIGIT in ESCC.
Xu M, Molina MA, Gómez-Martín C
… +6 more, Dekker MMHS, Ghasemi S, de Rooij J, Pegtel DM, van Trommel NE, Steenbergen RDM
Transl Oncol
· 2026 Jun · PMID 42302479
·
Full text
Cervical cancer is primarily caused by persistent infection with high-risk human papillomavirus (hrHPV), which alters host RNA expression, including regulatory microRNAs (miRNAs). Because urine is emerging as a convenien...Cervical cancer is primarily caused by persistent infection with high-risk human papillomavirus (hrHPV), which alters host RNA expression, including regulatory microRNAs (miRNAs). Because urine is emerging as a convenient biosource for cancer detection, we evaluated the feasibility of urinary miRNAs as non-invasive biomarkers for cervical cancer. We optimized miRNA isolation from whole urine and urine fractions using commercial RNA extraction kits, spike-in controls, and digital nanoplate PCR. Following identification of optimal conditions, IsoSeek small RNA sequencing was performed to profile miRNA expression in urine from women with cervical cancer (n = 20) and age-matched controls (n = 20). Differentially expressed candidates were then analytically confirmed by RT-qPCR. The Norgen RNA isolation kit applied to whole urine provided the most robust miRNA recovery. Sequencing identified significantly altered urinary levels of hsa-miR-143-3p and hsa-miR-204-3p in cervical cancer. The ratio of these miRNAs showed strong discriminatory performance for detecting cervical cancer using IsoSeek (AUC = 0.93) and remained robust after RT-qPCR analysis in the same cohort (AUC = 0.84). These findings support the feasibility of using urinary miRNA profiling for non-invasive biomarker discovery and highlight the hsa-miR-143-3p/hsa-miR-204-3p ratio as a promising candidate marker for cervical cancer detection.
Liu W, Wang Z, Li P
… +5 more, Liu Y, Chen J, Shi Z, Liu H, Ye J
Transl Oncol
· 2026 Jun · PMID 42302478
·
Full text
Circular RNAs (circRNAs) have emerged as key players in tumor progression, yet their role in head and neck squamous cell carcinoma (HNSCC) remains largely unexplored. The AURKA gene is frequently amplified and activated...Circular RNAs (circRNAs) have emerged as key players in tumor progression, yet their role in head and neck squamous cell carcinoma (HNSCC) remains largely unexplored. The AURKA gene is frequently amplified and activated in HNSCC. This study investigates the expression patterns and functions of circ_0008777, which is derived from AURKA exons 3-6, in HNSCC. The biological functions of circ_0008777 were evaluated in vitro and in vivo, along with its interactions with positive cofactor 4 (PC4) and miR-185-3p. Our data indicated that circ_0008777 expression levels are upregulated in HNSCC tissues and cell lines, and linked to aggressive clinical features. Knocking down circ_0008777 significantly inhibited HNSCC cell proliferation and migration in vitro, as well as restrained tumor growth in vivo, while overexpressing circ_0008777 had the opposite effects. Mechanistically, circ_0008777 can bind to PC4 to increase c-Myc transcription. Bioinformatics analysis showed that PC4 is highly expressed in HNSCC patients, with survival analysis revealing a negative correlation between PC4 expression and overall survival rates. PC4 knockout could hinder HNSCC cell proliferation and migration in vitro. Additionally, circ_0008777 can bind to miR-185-3p through a microRNA sponge mechanism, relieving miR-185-3p-mediated repression of c-Myc mRNA. Furthermore, the inhibitory effects of circ_0008777 knockdown on the cell migration and proliferation rates were rescued by c-Myc overexpression. In conclusion, circ_0008777 can promote HNSCC progression by upregulating c-Myc expression through both PC4- and miR-185-3p-related mechanisms, showing potential as a candidate therapeutic target in this cancer.