Tomas EJ, Davis J, Ramos Valdes Y
… +1 more, Shepherd TG
Cancer Biol Ther
· 2026 Dec · PMID 41520277
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BACKGROUND: PARP inhibitors (PARPis) are new targeted agents that exploit homologous recombination DNA repair deficiencies (HRDs), which are present in 50% of high-grade serous carcinoma (HGSC) cases. Currently, olaparib...BACKGROUND: PARP inhibitors (PARPis) are new targeted agents that exploit homologous recombination DNA repair deficiencies (HRDs), which are present in 50% of high-grade serous carcinoma (HGSC) cases. Currently, olaparib is approved as maintenance therapy for -mutated HGSC, and niraparib is approved for platinum-sensitive recurrent disease. However, research is currently expanding their potential as front-line agents or in combination with carboplatin, a standard HGSC chemotherapeutic. METHODS: Immortalized ovarian cancer (iOvCa) cell lines, developed from HGSC patient ascites, were treated with carboplatin, olaparib and niraparib to determine their sensitivity. Immunofluorescence analysis of RAD51 was conducted for HRD testing of all the cell lines. The cell lines were cultured as three-dimensional organoids and spheroids to mimic tumor growth and metastasis, respectively, and then treated to assess the effects of different drug combinations. RESULTS: The half-maximal inhibitory concentrations of olaparib and niraparib varied across our iOvCa cell lines, with iOvCa195 -mutant line exhibiting the expected high sensitivity to both PARPis. Direct combination of carboplatin with olaparib or niraparib enhanced cell killing, yet achieved cell viability levels to those of carboplatin alone. In sequential experiments, carboplatin followed by either PARPi or showed no significant difference in cell viability to carboplatin alone, except in iOvCa195 organoids when treated with a PARPi first. CONCLUSIONS: Overall, first-line carboplatin treatment remains ideal, yet there may be select utility for PARPi prior to chemotherapy. Using patient-derived tumor models such as spheroids and organoids may provide insights for on-going and future clinical trials to enhance therapeutic outcomes for HGSC patients.
Liu Y, Xiao L, Nie X
… +7 more, Lyu J, Tang C, Li L, Zhang X, Li T, Huang J, Zhang S
Cancer Biol Ther
· 2026 Dec · PMID 41481002
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BACKGROUND: The potential of Lenvatinib to synergize with combined radiotherapy and immunotherapy in LUAD remains incompletely characterized. METHODS: We investigated Lenvatinib's effects on radiation-induced PD-L1 in LU...BACKGROUND: The potential of Lenvatinib to synergize with combined radiotherapy and immunotherapy in LUAD remains incompletely characterized. METHODS: We investigated Lenvatinib's effects on radiation-induced PD-L1 in LUAD cells and VEGFR2 in HUVECs via Western blot, VEGFA expression via RT-qPCR/ELISA, and angiogenesis via immunofluorescence. LUAD-HUVEC crosstalk was modeled in vitro. In C57BL/6 mice bearing LUAD tumors, we evaluated the efficacy of RT and anti-PD-L1 with or without Lenvatinib, monitoring tumor growth, survival, and profiling the tumor microenvironment by mIHC and flow cytometry. RESULTS: Lenvatinib suppressed radiation-induced PD-L1 and VEGFR2 expression, inhibited angiogenesis, and disrupted HUVEC-facilitated LUAD proliferation. The triple-combination (RT + anti-PD-L1 + Lenvatinib) significantly suppressed tumor progression ( < 0.05) and extended median survival (34 vs. 29.5 days, < 0.05) versus dual therapy. It also enhanced intratumoral CD8 T-cell infiltration and cytotoxicity, promoted M1-like macrophage polarization, and reduced regulatory T cell frequency and microvessel density. CONCLUSIONS: Lenvatinib potentiates RT and anti-PD-L1 therapy in LUAD through dual immune-vascular modulation, supporting the clinical translation of this triple-combination strategy.
Wu Y, Jin J, Zhang Y
… +4 more, Huang X, Wang H, Huang Y, Xie H
Cancer Biol Ther
· 2026 Dec · PMID 41454916
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BACKGROUND: Accumulating evidence suggests that deregulated long non-coding RNAs (lncRNAs) drive breast cancer (BRCA) progression. This study investigated the expression profile and mechanism of PGM5P4 antisense RNA 1 (P...BACKGROUND: Accumulating evidence suggests that deregulated long non-coding RNAs (lncRNAs) drive breast cancer (BRCA) progression. This study investigated the expression profile and mechanism of PGM5P4 antisense RNA 1 (PGM5P4-AS1) in BRCA. MATERIALS: The differentially expressed lncRNAs in BRCA were identified using the GEO dataset. Cancer and adjacent tissues were obtained from BRCA patients. Real-time quantitative polymerase chain reaction was used to quantify the expression of PGM5P4-AS1, microRNA (miR)-3664-5p, and Krüppel-like factor 9 (KLF9). The Chi-squared test was used to assess the clinicopathological correlation of PGM5P4-AS1. Kaplan-Meier curves and Cox regression were used to evaluate their prognostic significance. Cell Counting Kit-8 kits, flow cytometry, and Transwell assays were used to assess cell proliferation, migration, invasion, and apoptosis. Dual-luciferase reporter and RNA immunoprecipitation assays were used to analyze the gene-target interactions. RESULTS: PGM5P4-AS1 downregulation in BRCA was consistently documented across three GEO datasets. In BRCA cancer tissues, both PGM5P4-AS1 and KLF9 were significantly downregulated, whereas miR-3664-5p was noticeably upregulated. A reduction in PGM5P4-AS1 was associated with tumor differentiation, tumor node metastasis staging, and lymph node metastasis. Low PGM5P4-AS1 expression independently predicts poor survival. Further, miR-3664-5p noticeably reverses the suppression of cell proliferation, migration, and invasion, as well as the promotion of apoptosis, induced by PGM5P4-AS1 overexpression. Mechanistically, miR-3664-5p targets PGM5P4-AS1/KLF9 directly, and KLF9 silencing reverses the cellular function inhibition caused by miR-3664-5p downregulation. CONCLUSION: This study first shows that decreased PGM5P4-AS1 in BRCA patients links to poor prognosis, promotes malignancy via miR-3664-5p/KLF9 axis, offering new therapy and prognosis in sight.
Arcos-Montoya D, García-López P, Wegman-Ostrosky T
… +14 more, Camacho-Arroyo I, Valdés-Rives SA, Bello-Alvarez C, Manjarrez-Marmolejo J, De La Fuente-Granada M, Ordaz-Ramos A, Ávila-González D, Díaz NF, Guadarrama-Rangel CF, Navarrete AMB, Aboud O, Cantú-de-León DF, Cacho-Díaz B, González-Arenas A
Cancer Biol Ther
· 2026 Dec · PMID 41439468
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BACKGROUND: Gliomas, including glioblastomas (GB) and high-grade astrocytomas (HGA), are the most common brain tumors in adults, with poor survival rates around 15 months. Hormonal factors, particularly progesterone rece...BACKGROUND: Gliomas, including glioblastomas (GB) and high-grade astrocytomas (HGA), are the most common brain tumors in adults, with poor survival rates around 15 months. Hormonal factors, particularly progesterone receptor (PR) activation, promote tumor growth. Current treatment involves surgery, radiotherapy and chemotherapy (temozolomide), but survival rates remain low. Repurposing mifepristone (MF), a contraceptive drug, shows promise for GB treatment, warranting further study. METHODS: PR expression in U87, U251 and C6 cell lines were assessed using immunofluorescence and Western Blot. PR isoforms were quantified by densitometry. Progesterone (P4) and 5α-dihydroprogesterone (5α-DHP) synthesis were evaluated using LC/MS. MF's effect on cell viability was determined by IC and IC values. Its impact on non-tumoral cells and 3D glioma sphere formation was also analyzed. The effects of administration of MF were assessed using a rat model with C6 glioma implants. Clinical outcomes were evaluated in GB patients receiving MF alongside standard treatment. RESULTS: PR was predominantly nuclear in all cell lines, with U87 showing the highest PR-B isoform levels. Only U251 synthesized 5α-DHP significantly. MF reduced viability in U251, U87 and C6 cells without affecting non-tumoral cells. Sphere formation efficiency decreased with MF treatment. In rats, MF reduced tumor volume dose-dependently. Clinically, MF improved patient survival from 165 to 588days and enhanced quality of life without severe adverse effects. CONCLUSION: MF effectively reduces GB cell viability, sphere formation efficacy and tumor volume. These findings support further investigation of MF as a therapeutic strategy in GB treatment. PRÉCIS (CONDENSED ABSTRACT): Our research highlights the critical role PR in GB progression using and models. MF, a PR modulator, effectively reduced cell viability and sphere formation in cellular assays and significantly decreased tumor volume in an study. The pilot trial demonstrated the pharmacological safety of using MF as an adjuvant in GB treatment. Patients treated with MF showed a significant increase in survival, with an 80% survival rate at 1 year compared to 0% in those who were treated with the standard treatment.
Yu JZ, Zou XP, Wu XB
… +5 more, Cui YY, Wei T, Di J, Feng XC, Li XM
Cancer Biol Ther
· 2026 Dec · PMID 41431399
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BACKGROUND: ZMIZ2, an androgen receptor (AR) transcriptional co-regulator, promotes prostate cancer (PCa) cell proliferation by interacting with AR to upregulate genes associated with cell proliferation; however, its spe...BACKGROUND: ZMIZ2, an androgen receptor (AR) transcriptional co-regulator, promotes prostate cancer (PCa) cell proliferation by interacting with AR to upregulate genes associated with cell proliferation; however, its specific cooperative mechanisms remain unclear. This study aims to elucidate these mechanisms. MATERIALS AND METHODS: We analyzed the expression level and prognostic significance of ZMIZ2 in PCa using bioinformatics methods. ZMIZ2 expression and its correlation with the Gleason score were analyzed using clinical samples. LNCaP cells with ZMIZ2 overexpression or AR knockdown were employed to evaluate cell proliferation. RNA-seq, qPCR, Western blot, and co-immunoprecipitation were used to explore the molecular mechanisms. In vivo xenograft models were utilized to validate the effects. RESULTS: ZMIZ2 expression was significantly higher in PCa tissues and positively correlated with the Gleason score. Overexpressing ZMIZ2 robustly promoted LNCaP cell growth, but this promoting effect was dramatically lessened in the absence of AR expression. Mechanistically, ZMIZ2 recruited multiple acetyltransferases and formed a transcriptional complex with the -terminal domain of AR, which bound to the promoters of cell cycle-related genes CDK1, CCNA2, and CCNE2, leading to upregulated transcription. Both in vitro cell culture experiments and in vivo models supported ZMIZ2's role in promoting proliferation. CONCLUSION: ZMIZ2 promotes PCa cell proliferation through the AR signaling pathway by regulating key cell-cycle genes, highlighting it as a potential therapeutic target.
Jordanides PP, Jagadeesha S, Upadhaya P
… +11 more, Ryan NM, Anderson K, Lamenza FF, Shrestha S, Siddiqui A, Bopp AR, Pracha SH, Roth P, Kehres R, Mo X, Oghumu S
Cancer Biol Ther
· 2026 Dec · PMID 41431358
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BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer globally with high mortality rates, highlighting the urgent need for novel therapeutic strategies. We investigated the efficacy of...BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer globally with high mortality rates, highlighting the urgent need for novel therapeutic strategies. We investigated the efficacy of combining phosphoinositide 3-kinase gamma (PI3Kγ) inhibition with programmed death-ligand 1 (PD-L1) blockade in a poorly immunogenic HNSCC model. MATERIALS AND METHODS: Mouse bone marrow-derived macrophages (BMDMs) were differentiated and polarized in the presence or absence of the PI3Kγ inhibitor IPI-549 or culture supernatants from MOC2 cells treated with or without IPI-549. MOC2 cells were orthotopically injected into C57BL/6 mice, and treated with anti-PD-L1, IPI-549, combined anti-PD-L1 and IPI-549 or vehicle control. Tumor burden, survival, and immunological responses were evaluated. RESULTS AND CONCLUSION: Dual inhibition of PI3Kγ (using IPI-549) and PD-L1 demonstrated nearly significant reduction in primary tumor burden and significantly increased survival compared to single or control treatments. PI3Kγ inhibition promoted macrophage differentiation toward an antitumoral M1 phenotype. In the bone marrow, dual therapy significantly increased MHC-II expression across various myeloid cell subsets and effectively normalized myelopoiesis. Notably, combination therapy increased CD8+ T-cell infiltration into tumors while decreasing T-cell exhaustion marker (LAG-3, CTLA-4, and TIM-3) and protumoral cytokine (IL-4). Combined PI3Kγ and PD-L1 inhibition offers a promising strategy for treating poorly immunogenic HNSCC by simultaneously targeting multiple immunosuppressive mechanisms. These findings provide a strong rationale for combining PI3Kγ and PD-L1 inhibitors as a therapeutic strategy for poorly immunogenic HNSCC, potentially improving clinical outcomes for patients.
Yue Z, Li L, Liu S
… +7 more, Gao C, He S, Xue T, Zhao W, Cui C, Duan C, Su Y
Cancer Biol Ther
· 2026 Dec · PMID 41423806
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BACKGROUND: Current risk stratification for neuroblastoma (NB) relies on limited markers like MYCN amplification. Coilin, a key Cajal body component, regulates cellular processes. This study investigates whether coilin e...BACKGROUND: Current risk stratification for neuroblastoma (NB) relies on limited markers like MYCN amplification. Coilin, a key Cajal body component, regulates cellular processes. This study investigates whether coilin expression in bone marrow (BM) serves as a predictive biomarker for NB progression and elucidate its function in this disease. METHODS: The functions and molecular mechanisms of coilin were investigated by employing cell lines and animal models. Coilin mRNA levels in patient samples were measured by RT-PCR, and their relationships with clinicobiological characteristics and outcomes were analyzed. RESULTS: Cisplatin induced dramatic changes of coilin distribution and expression. Databases showed that high expression of coilin exerted predictive values for poor outcome in NB. Coilin promoted proliferation and . Knockdown of coilin expression inhibited cell migration and invasion, promoted apoptosis and increased the Cisplatin drug sensitivity. Moreover, coilin activates p53/p21 signaling pathway and was a direct target of MYCN. Analysis of BM samples demonstrated that high expression of coilin was obviously associated with adverse clinical biological features. Importantly, the levels of coilin at diagnosis were markedly higher than those at the time before maintenance treatment in the exact paired patients. Survival analysis presented that high coilin expression in BM is associated with poor prognosis. CONCLUSIONS: A novel and accessible coilin-targeted liquid biopsy method was developed, capable of detecting minimal residual disease (MRD) in early-stage NB and predicting disease progression and recurrence. Coilin was transcriptionally regulated by MYCN, offering potential avenues for the development of novel drugs or intervention strategies.
Valuskova Z, Cholujova D, Beke G
… +10 more, Hucko M, Marinkovicova ME, Suroviakova K, Klucar L, Drgona L, Leiba M, Kastritis E, Dorfman DM, Anderson KC, Jakubikova J
Cancer Biol Ther
· 2025 Dec · PMID 41410549
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BACKGROUND: Multiple myeloma (MM) features plasma cell (PC) heterogeneity and alterations in B-cell differentiation and immune regulation. Although lenalidomide/bortezomib/dexamethasone (RVd) and cyclophosphamide/bortezo...BACKGROUND: Multiple myeloma (MM) features plasma cell (PC) heterogeneity and alterations in B-cell differentiation and immune regulation. Although lenalidomide/bortezomib/dexamethasone (RVd) and cyclophosphamide/bortezomib/dexamethasone (CyBorD) are clinically effective, their precise impacts on PC/B-cell maturation remain unclear. METHODS: We performed CyTOF profiling on bone marrow samples from RVd- ( = 47) and CyBorD-treated MM patients ( = 15), each compared to untreated cohort ( = 43). Within each therapeutic arm, responders (RVd, = 35; CyBorD, = 5) were compared to non-responders (RVd, = 12; CyBorD, = 10). RESULTS: RVd and CyBorD therapies exerted distinct immune modulation patterns, differentially affecting PC, early B-cell stages, and naive T cells. Evaluation of transcriptional B-cell regulators in B-cell lymphopoiesis revealed that both regimens decreased IRF4, CXCR4, and FGFR3 while upregulating Pax-5 across B-cell stages and PC. RVd uniquely upregulated MYD88 and c-Myc and decreased sXBP1; its responders further suppressed BLIMP-1 and FGFR3. In contrast, CyBorD elevated sXBP1, BLIMP-1, and Notch-1 while reducing c-Myc in the B and PC subsets. Both therapies increased the expression of the stemness factor KLF4 and variably modulated NANOG; CyBorD altered Nestin and RARα2 in responder PCs, whereas RVd suppressed OCT3/4. Shared immunophenotypic aberrations included decreased MMSET, CD200, and CD52, and increased CD47, CD81, and CD44 in B-cell compartments. In PC, both regimens elevated CD338 while reducing CD47, CD319, and CD138. RVd responders further downregulated CD56, CD269, and CD329, and increased CD243. CONCLUSIONS: These shared and divergent modulations elucidate the molecular underpinnings of RVd and CyBorD efficacy and inform precision regimen selection.
Yuan J, Zhang M, Liu Y
… +3 more, Qiu Y, Zhang M, Chen H
Cancer Biol Ther
· 2025 Dec · PMID 41410179
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BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype with a poor prognosis and limited treatment options. Elevated Kinesin Family Member 14 (KIF14) expression in breast cancer (BC) is correlated with...BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype with a poor prognosis and limited treatment options. Elevated Kinesin Family Member 14 (KIF14) expression in breast cancer (BC) is correlated with poor prognosis, but its role in TNBC remains unclear. METHODS: KIF14 expression was analyzed using TCGA, TIMER, and GEO databases, and its association with prognosis was assessed via Kaplan‒Meier plotter. Functional assays, including CCK-8, wound healing, and Transwell assays, were performed to evaluate KIF14's impact on TNBC cell proliferation, migration, and invasion. GO and KEGG analyses of transcriptome data were used to explore molecular mechanisms. The relationship between KIF14 expression and immune infiltration was assessed in the TIMER database. KIF14 expression in clinical samples was validated using qRT-PCR and immunohistochemistry, and its correlation with clinical features was examined. RESULTS: KIF14 was significantly upregulated in BC ( < 0.05), and elevated KIF14 expression was associated with poor prognosis. KIF14 knockdown reduced cell proliferation, migration, and invasion. Network analysis revealed its involvement in lipid metabolism, NF-κB, PI3K-AKT, and mTOR signaling pathways. Immune infiltration analysis showed a significant association between KIF14 and immune cell types. CONCLUSION: KIF14 promotes TNBC progression and serves as a potential diagnostic and prognostic biomarker for TNBC.
Cancer Biol Ther
· 2025 Dec · PMID 41410152
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Lactylation, a recently identified post-translational modification, has reshaped our understanding of lactate from a metabolic byproduct to a central regulator of tumor biology. Accumulating evidence reveals that lactate...Lactylation, a recently identified post-translational modification, has reshaped our understanding of lactate from a metabolic byproduct to a central regulator of tumor biology. Accumulating evidence reveals that lactate-driven lactylation orchestrates metabolic reprogramming, epigenetic remodeling, immune evasion, metastasis, and therapeutic resistance, thereby fueling malignant progression. Beyond histones, diverse non-histone substrates further expand its regulatory network across cancer signaling pathways. We highlight the crosstalk between lactylation and other modifications, its role in tumor heterogeneity, and the therapeutic opportunities arising from targeting this pathway. These insights establish lactylation as both a hallmark and a potential vulnerability of cancer, opening new avenues for precision oncology.
Wu Z, Fu X, Feng Y
… +3 more, Zeng R, Qin H, Yao K
Cancer Biol Ther
· 2025 Dec · PMID 41400642
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Mesothelin (MSLN) is a glycosylphosphatidylinositol (GPI)-anchored membrane protein that promotes malignant behaviors including tumor cell proliferation, migration and immune evasion through activation of multiple signal...Mesothelin (MSLN) is a glycosylphosphatidylinositol (GPI)-anchored membrane protein that promotes malignant behaviors including tumor cell proliferation, migration and immune evasion through activation of multiple signaling pathways, such as MAPK/ERK and PI3K/AKT. MSLN is widely overexpressed in malignant tumors but shows low expression levels in normal tissues. This differential expression pattern renders MSLN an important clinical therapeutic target. Currently, MSLN-based tumor-targeting approaches predominantly involve antibody-drug conjugates (ADC), cancer vaccines, oncolytic viruses and chimeric antigen receptor T-cell (CAR-T) therapies. These therapeutic modalities have demonstrated encouraging efficacy in preclinical studies and phase I/II clinical trials. However, challenges such as unclear molecular mechanisms of MSLN signaling pathways and extracellular domain shedding impose limitations on targeted therapeutic strategies. Therefore, this review comprehensively discusses the gene and protein structures of MSLN, its biological functions, and related targeted therapeutic strategies, providing new insights into MSLN-targeted cancer therapy.
Yu P, Wei W, Peng X
… +4 more, Ye J, Ji Y, Zhang B, Cai Y
Cancer Biol Ther
· 2025 Dec · PMID 41369154
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BACKGROUND: Aberrant N6-methyladenosine (m6A) modification is linked to cancer development and progression. However, the role of YTH N6-methyladenosine RNA binding protein F2 (YTHDF2), an m6A 'reader protein', in nasopha...BACKGROUND: Aberrant N6-methyladenosine (m6A) modification is linked to cancer development and progression. However, the role of YTH N6-methyladenosine RNA binding protein F2 (YTHDF2), an m6A 'reader protein', in nasopharyngeal carcinoma (NPC) is poorly understood. This study aimed to clarify the role and mechanism of YTHDF2 in NPC development. METHODS: Bioinformatics analysis was performed to identify the differential expression, prognostic value, and enriched pathways of YTHDF2 in patients with NPC. Quantitative PCR, western blotting, and immunohistochemistry were used to detect mRNA and protein expression. Biological function of YTHDF2 was investigated using experiments, including proliferation, wound healing, and invasion assays. RNA immunoprecipitation sequencing (RIP-seq), RIP-qPCR, and Methylated RNA immunoprecipitation sequencing (MeRIP-seq) were employed to determine if YTHDF2 modulates forkhead box O1 (FOXO1) expression through m6A modification. RESULTS: YTHDF2 mRNA and protein levels were significantly increased in the NPC tissues and cell lines. Higher expression of YTHDF2 was associated with a poorer prognosis. Overexpressing YTHDF2 enhanced the NPC cell proliferation, migration, and invasion. Conversely, YTHDF2 knockdown inhibited these phenomena. Gene set enrichment analysis revealed that FOXO1-related signaling pathways were enriched in the YTHDF2-activated group. Mechanistically, YTHDF2 overexpression inhibited FOXO1 expression in NPC cells. RIP-seq, RIP-qPCR, and MeRIP-seq assays confirmed that YTHDF2 was bound to FOXO1 mRNA, reducing its stability and accelerated degradation. CONCLUSION: YTHDF2 potentially functions as an oncogene in NPC by binding to the m6A site of FOXO1, reducing its expression, thereby promoting malignant behavior. It may also be a viable biomarker and therapeutic target for NPC.
Gao Y, Zhang Z, Song Y
… +5 more, Song W, Li H, Zhang L, Li Z, Zhang M
Cancer Biol Ther
· 2025 Dec · PMID 41362935
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BACKGROUND: Natural killer/T-cell lymphoma (NKTCL) presents highly aggressive clinical behaviour, and the outcomes for relapsed and refractory patients are still poor. Our previous study identified somatic mutations in G...BACKGROUND: Natural killer/T-cell lymphoma (NKTCL) presents highly aggressive clinical behaviour, and the outcomes for relapsed and refractory patients are still poor. Our previous study identified somatic mutations in GNAQ in 8.7% of cases through whole-exome sequencing, revealing the T96S mutation in the Gαq protein. MATERIALS: The proliferation, gemcitabine sensitivity and apoptosis of NKTCL cells were assessed by CCK-8 assays and flow cytometry. The downstream pathways of GNAQ were explored by mRNA sequencing, Western blotting and co‑immunoprecipitation. Additionally, we investigated the role of GNAQ in the activation of the RHOA pathway in NKTCL. RESULTS: We found that GNAQ significantly inhibited the aggressive function of NKTCL, whereas the T96S mutation abolished the ability of wild-type GNAQ to trigger cell apoptosis. Further investigation revealed that GNAQ modulated NKTCL cell functions through the activation of the RHOA pathway, which is regulated by the GNAQ-ARHGEF25 complex. Clinically, high expression of RHOA was associated with improved overall survival (HR = 0.317, 95% CI: 0.126-0.800, = 0.015), whereas low expression of RHOA was correlated with poorer survival outcomes. The application of an RHOA pathway inhibitor or reactivation of the RHOA pathway significantly affected the biological functions of NKTCL cells both in vitro and in vivo. CONCLUSION: In summary, RHOA is a critical downstream effector of GNAQ in NKTCL. GNAQ promotes RHOA activation through ARHGEF25, which in turn regulates cellular functions by modulating cell proliferation and apoptosis, thereby influencing the progression of NKTCL.
Wang S, Zhu Z, Zhu Y
… +9 more, Tan J, Shen X, Wen H, Wu J, Xu J, Zheng J, Chen Y, Yang W, Deng H
Cancer Biol Ther
· 2025 Dec · PMID 41355356
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BACKGROUND: The tumour microenvironment (TME) significantly influences intercellular communication, with several secreted factors activating both tumour cells and fibroblasts. Connexin43 (Cx43), a crucial gap junction pr...BACKGROUND: The tumour microenvironment (TME) significantly influences intercellular communication, with several secreted factors activating both tumour cells and fibroblasts. Connexin43 (Cx43), a crucial gap junction protein, exhibits a significant regulatory role in tumourigenesis; however, the underlying regulatory mechanisms in colorectal cancer (CRC) are not fully understood. METHODS: Transwell co-culture system was utilized to evaluate fibroblast-mediated effects on CRC cells. Immunohistochemical analysis was conducted on clinical specimens. Cell migration and invasion capabilities were measured using Transwell assays. Subcellular localization was assessed via immunofluorescence. Protein interactions were validated by co-immunoprecipitation. RESULTS: The Wnt signalling pathway was activated in the co-culture of CRC cells and fibroblasts. Nuclear Cx43 upregulation was detected and confirmed as a pro-oncogenic factor via prognostic analysis of patient samples. Therefore, although Cx43 on the cell membrane serves as a tumour suppressor, the nuclear translocation of Cx43 has an important influence on the Wnt signalling pathway and promotes CRC progression. Nuclear translocation of Cx43 during malignant progression has a significant effect on metastasis and is regulated by secreted TGF-. Distinct nuclear translocation patterns of Cx43 observed across CRC cell lines suggest potential regulation by S368 phosphorylation. Co-immunoprecipitation confirmed Cx43/β-catenin interaction, revealing its role in facilitating -catenin nuclear accumulation. CONCLUSION: We systematically identified nuclear Cx43 as a factor promoting CRC progression. These findings highlight the novel mechanism involving the nuclear translocation of Cx43 as a promoting factor in CRC progression, and enhance our understanding of the interplay between the TME and CRC progression.
Diao Y, Nan A, Li R
… +9 more, Ding T, Li Z, Wang J, Zhu B, Li J, Yang L, Zhou L, Liu J, Hao X
Cancer Biol Ther
· 2025 Dec · PMID 41340217
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BACKGROUND: Prostate cancer (PCa) is a major health concern, and current PSA screening is limited by low specificity and the risk of overdiagnosis. Extracellular vesicle (EV)-derived RNA biomarkers offer a promising non-...BACKGROUND: Prostate cancer (PCa) is a major health concern, and current PSA screening is limited by low specificity and the risk of overdiagnosis. Extracellular vesicle (EV)-derived RNA biomarkers offer a promising non-invasive alternative for early detection. METHODS: We utilized a tethered cationic lipoplex nanoparticle (TCLN) biochip for amplification-free EV RNA detection at the single-vesicle level. Eight candidate RNAs (four miRNAs, three mRNAs, and one lncRNA) were profiled in serum and urine samples from PCa patients, benign prostatic hyperplasia (BPH) patients, and healthy controls (HC). Diagnostic and risk stratification performance was evaluated in discovery and validation cohorts, with qRT-PCR used for validation. RESULTS: TCLN reliably detected the candidate RNA biomarkers from PCa cell lines and clinical samples, with strong concordance to qRT-PCR. Serum EV RNAs (miR-141, miR-375, Let-7c) and urine EV RNAs (miR-141, miR-375, PCA3 lncRNA, T1-E2) effectively distinguished PCa patients from controls. Combined EV RNA biomarkers in serum and urine achieved diagnostic area-under-the-curve (AUCs) of 0.824 and 0.741, respectively, surpassing those of prostate-specific antigen (PSA) alone. Serum miR-141, miR-375, and urine miR-141, miR-375, and PCA3 lncRNA, also showed remarkable correlations with PCa Gleason score (GS), tumor stage, and metastatic status. CONCLUSION: The TCLN biochip enables sensitive, amplification-free detection of EV RNA biomarkers from serum and urine. Key markers such as miR-141, miR-375, and PCA3 showed strong diagnostic and risk stratification value in PCa. This non-invasive approach holds promise for improving early detection and clinical risk assessment.
Haroun R, Rutihinda C, Diallo AH
… +10 more, Ordonez JP, Nassri S, Shams A, Pacheco MFM, Saidi NE, Bouchard L, Turgeon GA, Gris D, Tai LH, Oweida AJ
Cancer Biol Ther
· 2025 Dec · PMID 41332426
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UNLABELLED: Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Although radiotherapy (RT) is used to treat over half of NSCLC patients, about 30% have inherent or acquired radi...UNLABELLED: Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Although radiotherapy (RT) is used to treat over half of NSCLC patients, about 30% have inherent or acquired radioresistance leading to treatment failure. There's a clinically unmet need to investigate mechanisms of radioresistance that can be targeted in combination with RT. Among these, HMGB1 has been shown to play a key role in tumor progression. Our research investigates TLR4, a receptor for HMGB1, highly expressed in NSCLC tissues, as a mediator of radioresistance. METHODS: The TLR4 inhibitor, TAK242, was tested in NSCLC cell lines (murine: LLCI, KLN205; human: H1975, SW900). Cells were irradiated at 2 and 10 Gy. , KLN205 cells were implanted in DBA/2 mice and tumors were irradiated at 10Gy. Gene and protein expression of TLR4 and MyD88 were assessed and . HMGB1 secretion was quantified after RT. Clonogenic assays were performed to evaluate the effect of TAK242 on radiosensitivity . The combination of TAK242 and RT was investigated in mice bearing KLN205 tumors. RESULTS: TAK242 significantly decreased NSCLC cell proliferation and migration. Radiation at 2 and 10 Gy increased TLR4 gene expression and in a dose-dependent manner. , TLR4 and HMGB1 protein expression was upregulated following radiation. TAK242 in combination with radiation enhanced radiosensitivity . TAK242 decreased the percentage of cells in the G1 phase, coupled with an increase in late S and G2/M, suggesting radiosensitization via cell cycle modulation. , the combination of RT and TAK242 significantly reduced growth of KLN205 tumors. CONCLUSION: These findings show that TLR4 inhibition enhances RT sensitivity in NSCLC.
Ren M, Ai ZE, Zhang Y
… +6 more, Shi L, Liu Y, Liu H, Shen H, Yao X, Yan Z
Cancer Biol Ther
· 2025 Dec · PMID 41319226
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The cancer-immunity cycle is regulated by a series of stimulatory and inhibitory factors. The stimulator of interferon genes (STING) pathway, a key stimulator of type I interferon production, connects innate and adaptive...The cancer-immunity cycle is regulated by a series of stimulatory and inhibitory factors. The stimulator of interferon genes (STING) pathway, a key stimulator of type I interferon production, connects innate and adaptive immunity to promote antitumor responses. Using a syngeneic pancreatic tumor model, we characterized the single-cell landscape changes induced by STING stimulation. Our findings revealed that STING agonist treatment reprograms transcription across multiple cell lineages, enhances innate immune responses and activates lymphocytes, thereby promoting antitumor effects. Single-cell transcriptome sequencing identified significant increases in monocytes, neutrophils, macrophages, and CD8 T cells, indicating augmented tumor inflammation. Differential gene expression analysis highlighted upregulated genes related to immune cell effector mechanisms and antigen presentation. Functional assays confirmed the enhanced tumor killing effects induced by STING activation. These results underscore the potential of STING agonists in reprogramming the tumor microenvironment to potentiate antitumor immunity, although clinical translation remains challenging owing to pharmacokinetic limitations and potential systemic toxicity. Further research is needed to optimize STING agonist delivery and dosage for effective cancer immunotherapy.