Cancer Biol. Ther. [JOURNAL]
Sun
200 papers
NCAPD2 promotes the progression of lung adenocarcinoma through an AKT/MDM2/E2F1 positive feedback loop.
Wu Y, Li X, Lin Y … +9 more , Chen Y, Xin N, Hong D, Wei J, Li H, Guo T, Lin F, Chen Y, Lin Y
Cancer Biol Ther · 2025 Dec · PMID 41319185 · Full text
INTRODUCTION: Lung adenocarcinoma (LUAD) is one of the leading causes of cancer-related deaths worldwide. While NCAPD2 has been implicated in promoting tumorigenesis across various cancer types, its specific role in LUAD...
INTRODUCTION: Lung adenocarcinoma (LUAD) is one of the leading causes of cancer-related deaths worldwide. While NCAPD2 has been implicated in promoting tumorigenesis across various cancer types, its specific role in LUAD remains underexplored. This study aims to elucidate the molecular mechanisms by which NCAPD2 contributes to LUAD progression, with a focus on its involvement in the AKTMDM2/E2F1 positive feedback loop. MATERIALS AND METHODS: NCAPD2 expression in LUAD and normal tissues was analyzed using Western blotting and immunohistochemistry (IHC). Functional assays, including colony formation, wound healing, Transwell assays, and in vivo mouse models were conducted to evaluate the impact of NCAPD2 on LUAD cell proliferation, invasion, and metastasis. RNA sequencing and protein interaction experiments were used to investigate the role of NCAPD2 in the PI3K/AKT/MDM2 pathway and its interaction with E2F1. RESULTS: This study first identified that NCAPD2 expression is significantly upregulated in LUAD tissues, particularly in higher pathological stages. NCAPD2 overexpression promoted LUAD cell proliferation and metastasis, while its knockdown inhibited tumor growth and invasion. Mechanistically, NCAPD2 activated the PI3K/Akt pathway, facilitating the interaction between MDM2 and E2F1, reducing E2F1 ubiquitination, and increasing its expression. Furthermore, E2F1 enhanced NCAPD2 transcription, forming a positive feedback loop that drives LUAD progression. CONCLUSION: This study reveals a novel role of NCAPD2 in promoting LUAD progression through the AKT/MDM2/E2F1 positive feedback loop. These findings provide new insights into the molecular pathogenesis of LUAD and suggest NCAPD2 as a potential therapeutic target for improving patient outcomes.
High-throughput screening identifies the activity of histone deacetylase inhibitors in patient-derived models of soft tissue sarcoma.
Danks MR, Manasterski PJ, Beetham H … +13 more , Dawson JC, Elliott RJR, Culley J, Krishna R, Muir M, Thomson JP, Oswald AJ, Ewing A, Kerrison WGJ, Huang PH, Nixon I, Carragher NO, Brunton VG
Cancer Biol Ther · 2025 Dec · PMID 41319167 · Full text
BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is a rare and aggressive soft tissue sarcoma with limited treatment options and a poor prognosis. As a complex karyotype tumor, UPS lacks recurrent targetable mutati...
BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is a rare and aggressive soft tissue sarcoma with limited treatment options and a poor prognosis. As a complex karyotype tumor, UPS lacks recurrent targetable mutations, and response rates to standard first-line doxorubicin therapy are low. Phenotypic drug screening offers an alternative approach to identify new therapeutic targets without requiring prior knowledge of molecular mechanisms. METHODS: A library of FDA-approved compounds and a custom histone deacetylase (HDAC) inhibitor library were screened using well-annotated patient-derived cell lines. Hit compounds were further characterized using apoptosis assays and xenograft studies. Biomarkers of activity were evaluated using gene expression and western blot analyses. Synergy with doxorubicin was evaluated in combination assays. RESULTS: HDAC inhibitors emerged as a promising therapeutic class, demonstrating low IC values across cell lines (14.8-26.89 nM), with quisinostat taken forward for further evaluation. Gene expression changes in and were observed as potential biomarkers of activity. Combination assays revealed synergy between quisinostat and doxorubicin (average ZIP score: 1.02-15.65; ZIP: 3.98-33.71), increasing apoptotic cell death . , quisinostat alone and in combination with doxorubicin significantly reduced the tumor volume (vehicle 160.0 ± 63.2 mm, doxorubicin 78.0 ± 35.2 mm, quisinostat 84.3 ± 13.1 mm, and combination 49.2 ± 10.2 mm). Quisinostat also showed potent activity in leiomyosarcoma (LMS) cell lines (5.82-31.32 nM), which represent an additional complex karyotype soft tissue sarcoma. CONCLUSIONS: Quisinostat demonstrated strong preclinical activity and synergy with standard-of-care doxorubicin in models of UPS and LMS.
CD44v5 enhances the IL-4/IL-4Rα/STAT6/SAM68 aix inducing M2 polarization and promoting triple-negative breast cancer progression.
Ji Z, Wang L, Bao X … +5 more , Dai Y, Jiang M, Ma H, Li N, Yang C
Cancer Biol Ther · 2025 Dec · PMID 41319154 · Full text
BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype with a poor prognosis and limited treatment options. Tumor-associated macrophages (TAMs), the predominant and abundant immune cells in the tumor i...
BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype with a poor prognosis and limited treatment options. Tumor-associated macrophages (TAMs), the predominant and abundant immune cells in the tumor immune microenvironment (TIME), critically drive TNBC progression. Consequently, TAM reprogramming has emerged as a promising therapeutic approach. However, a major barrier remains the incomplete understanding of the molecular mechanisms governing TAM reprogramming. METHODS: The role of CD44v5 in TAM polarization was evaluated with a CD44v5 monoclonal antibody and CD44v5-knockdown cell lines. Subsequently, cell functional assays, including wound healing, invasion, and colony formation assays, were performed to assess changes in the MDA-MB-468 cell line. Cytokine secretion levels (IL-4 and IL-6) were measured by electrochemiluminescence immunoassay (ECLIA). RESULTS: We found that M2 macrophages and tumor-associated macrophages (TAMs) polarized through the IL4/IL4R signaling pathway and exerted similar protumorigenic functions, and that IL4 is the key protumorigenic factor secreted by M2 macrophages. Interestingly, CD44v5 blockade effectively inhibited M2 polarization and promoted the phenotypic shift to M1 macrophages, which was supported by increased CD86 expression and decreased IL-4 secretion. Furthermore, molecular docking analysis and colocalization microscopy confirmed that CD44v5 colocalized with IL-4Rα, preventing its internalization. CONCLUSION: CD44v5 promotes M2 macrophage polarization by stabilizing and enhancing the IL-4Rα/STAT6/IL-4 signaling pathway, thereby facilitating the progression of triple-negative breast cancer. CD44v5 serves as an important therapeutic target for the reprogramming of both TAMs and M2 macrophages, thereby providing a novel strategy for the treatment of TNBC.
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Qin Y, Ci H, Wang Z … +3 more , Zhang Y, Xu X, Wu Q
Cancer Biol Ther · 2025 Dec · PMID 41243277 · Full text
OBJECTIVE: Aryl hydrocarbon receptor nuclear transporter-like 2 (ARNTL2) can bind to clock circadian regulator (CLOCK) to regulate gene expression and is abnormally expressed in various cancers. Nevertheless, its effects...
OBJECTIVE: Aryl hydrocarbon receptor nuclear transporter-like 2 (ARNTL2) can bind to clock circadian regulator (CLOCK) to regulate gene expression and is abnormally expressed in various cancers. Nevertheless, its effects on esophageal cancer (ESCC) are unclear. This work can uncover the intriguing mechanism of ARNTL2 in ESCC. METHODS: Malignant phenotypes including cell proliferation, invasion, migration, and epithelial mesenchymal transition (EMT), were investigated. We established a BALB/c nude mouse (5-6 weeks) model with ESCC to verify the influence of ARNTL2/ANXA2/C-MYC axis. ESCC tissues ( = 100) and paired adjacent normal tissues ( = 100) from patients with ESCC were collected. The recruitment of ARNTL2 and CLOCK in promoter was studied by ChIP and dual-luciferase reporter assay. RIP and RNA pulldown were used to explore the relationship between ANXA2 and mRNA. RESULTS: Compared to adjacent normal tissues, ESCC tissues developed the significant increase , and . ARNTL2, which interacts with CLOCK, was recruited in promoter and elevated ANXA2. ARNTL2 silence reduced cell proliferation, migration and invasion and inhibited EMT, which was reversed by ANXA2 overexpression. ANXA2 can bind to the 3'UTR of transcript; further assays confirmed that ANXA2 increased the protein abundance of C-MYC. ANXA2 knockdown resulted in a decrease in malignant phenotypes, whereas C-MYC overexpression reversed these changes. ARNTL2 silence inhibited the formation, growth and EMT of subcutaneous tumors and suppressed C-MYC; ANXA2 overexpression reversed these alterations. CONCLUSION: ARNTL2 activated the transcription of , which interacts with transcript, promoting the development of malignant behaviors of ESCC cells.
Potential therapeutic GSK-3β inhibitor 9-ING-41 is active in combination with venetoclax in double-hit lymphoma (DHL).
Lei H, Zhang Y, Zheng H … +3 more , Shi P, Wei X, Guo X
Cancer Biol Ther · 2025 Dec · PMID 41220107 · Full text
BACKGROUND: Double-hit lymphoma (DHL) exhibits aggressive behavior due to dysregulated proliferation and resistance to apoptosis. Current therapies, including R-CHOP, show limited efficacy, necessitating novel strategies...
BACKGROUND: Double-hit lymphoma (DHL) exhibits aggressive behavior due to dysregulated proliferation and resistance to apoptosis. Current therapies, including R-CHOP, show limited efficacy, necessitating novel strategies. 9-ING-41, a novel ATP-competitive small-molecule inhibitor that targets glycogen synthase kinase-3β (GSK-3β), has emerged as a promising therapeutic agent because of its ability to disrupt oncogenic signaling pathways associated with tumor progression and treatment resistance. However, the antitumor effects of 9-ING-41 in DHL remain unclear. MATERIALS AND METHODS: DHL cell lines (Karpas-422 and SuDHL2) were treated with venetoclax and 9-ING-41, either alone or in combination. Cell viability in cytotoxicity assays was assessed using the CCK-8 assay, while apoptosis and cell cycle changes were analyzed via flow cytometry. Western blotting was employed to evaluate alterations in the levels of GSK-3β and WNT/β-catenin pathway proteins following treatment. RESULTS: In preclinical studies utilizing DHL cell models, the single agent 9-ING-41 demonstrated robust biological activity through inducing significant G1/S phase cell cycle arrest and triggering apoptosis. When coadministered with venetoclax, a clinically approved BCL-2 inhibitor, the combination exhibited marked synergistic cytotoxicity in DHL cells, achieving superior inhibitory effects compared to either agent alone. The combined treatment enhanced cell cycle arrest, significantly reducing the number of S-phase cells and reinforcing G0/G1 arrest. Further mechanistic studies revealed that the combination modulated key proteins in the GSK-3 pathway and downstream WNT/β-catenin pathway, revealing a potential synergistic mechanism. CONCLUSION: The demonstrated single-agent efficacy and combination synergy with venetoclax support the potential of 9-ING-41 as a novel therapeutic strategy for DHL. These findings provide a proof-of-concept that may serve as a basis for future preclinical investigations in DHL.
Progress in the study of molecular markers in the prognosis assessment and recurrence patterns of glioblastoma.
Hu Y, Ge X, Xie Q … +2 more , Ma R, Tao Q
Cancer Biol Ther · 2025 Dec · PMID 41201287 · Full text
Glioblastoma multiforme (GBM), the most invasive primary malignant tumor of the central nervous system, is characterized by an extremely poor prognosis and a high recurrence rate. Its significant molecular heterogeneity...
Glioblastoma multiforme (GBM), the most invasive primary malignant tumor of the central nervous system, is characterized by an extremely poor prognosis and a high recurrence rate. Its significant molecular heterogeneity challenges precise diagnosis and treatment. Recently, with the rapid development of molecular pathology, the combination of histological and molecular typing has become the mainstream method for GBM diagnosis. Here, we review the impact of classic molecular markers on patient prognosis in GBM, as well as the different values of traditional and novel molecular markers in prognosis assessment. We initially discuss the correlation between molecular markers and recurrence, as well as the research progress of molecular markers in emerging technological fields. Moreover, we propose the challenges currently faced by molecular markers in glioblastoma and discuss future research directions in this field.
The roles of the small nucleolar RNA host gene family in ovarian cancer.
Zhang T, Wu D, Li Z … +4 more , Han W, Shi J, Chen A, Zhu W
Cancer Biol Ther · 2025 Dec · PMID 41200835 · Full text
Ovarian cancer is one of the most malignant tumors in women. Long noncoding RNAs have been demonstrated to regulate multiple biological processes, including cell proliferation, migration, apoptosis, and drug resistance,...
Ovarian cancer is one of the most malignant tumors in women. Long noncoding RNAs have been demonstrated to regulate multiple biological processes, including cell proliferation, migration, apoptosis, and drug resistance, in various cancers. Small nucleolar RNA (snoRNA) host genes (SNHGs) are a group of long noncoding RNAs. Studies have reported that SNHGs are aberrantly expressed in many kinds of cancers and are associated with poor patient prognosis. In ovarian cancer, SNHGs play critical roles in the development and progression of ovarian cancer via different pathways. However, there is a lack of systematic reports on the research progress of SNHGs in ovarian cancer. Therefore, we reviewed the studies on the roles of SNHGs in the early diagnosis, development, and treatment of ovarian cancer and explored the underlying mechanisms to provide new insights into the treatment of ovarian cancer.
Correction.
Cancer Biol Ther · 2025 Dec · PMID 41195645 · Full text
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Challenges and caveats in manipulating extracellular vesicle secretion from pancreatic cancer cells.
Finan JM, Brody JR
Cancer Biol Ther · 2025 Dec · PMID 41137505 · Full text
BACKGROUND: Extracellular vesicle (EV) signaling is important in multiple malignancies, including pancreatic ductal adenocarcinoma (PDAC). In this coordinated cell‒cell signaling mechanism, genetically altered tumor cell...
BACKGROUND: Extracellular vesicle (EV) signaling is important in multiple malignancies, including pancreatic ductal adenocarcinoma (PDAC). In this coordinated cell‒cell signaling mechanism, genetically altered tumor cells signal to surrounding normal cells to promote tumor progression. Many efforts have been made to mechanistically interrogate this signaling axis by inhibiting EV secretion from cells. These techniques leverage our understanding of how EV biogenesis interferes with ceramide production or GTPase activity, which aids in membrane fusion with the plasma membrane. MATERIAL AND METHODS: Our group leveraged these methods in our orthotopic PDAC mouse model to investigate the importance of PDAC EV secretion. We interfered with the GTPases Rab27a and Rab35 and utilized an inhibitor of ceramide production (GW4869) to ablate EV secretion. RESULTS AND CONCLUSION: Overall, we found that these models did not perform as anticipated, and we could not consistently inhibit KPC cell EV secretion. These results emphasize the challenges of interfering with EV secretion, as several parallel pathways, such as direct membrane budding, can compensate. Further studies are needed to develop models for studying the role of EVs .
Patient-derived organoids (PDOs) as a promising platform for personalized treatment of colorectal cancer: current applications and future challenges.
Liu Y, Zhang Y, Zhang R … +2 more , Zhang C, Liu X
Cancer Biol Ther · 2025 Dec · PMID 41084366 · Full text
Colorectal cancer is a heterogeneous and molecularly complex cancer that often leads to poor prognosis. The standard treatment includes surgical resection and adjuvant therapies such as chemotherapy, radiotherapy, target...
Colorectal cancer is a heterogeneous and molecularly complex cancer that often leads to poor prognosis. The standard treatment includes surgical resection and adjuvant therapies such as chemotherapy, radiotherapy, targeted therapy, and immunotherapy. However, owing to the individual heterogeneity of patients, the effectiveness of these treatments is difficult to achieve consistently and efficiently. Patient-derived organoids (PDOs), by mimicking key genes, physical, and mechanical cues from the tumor microenvironment, simulates tumor heterogeneity, tissue structure, and molecular characteristics, as well as the cellular interactions within the tumor microenvironment. Additionally, it provides a more physiological and relevant environment for anticancer drug screening and predicting patient responses to personalized approaches, bridging the gap between simplified 2D models and animal models. Here, we review the roles of PDOs in customizing CRC treatment, discussing its roles in predicting drug sensitivity, drug screening, studying drug resistance mechanisms, simulating cell-to-cell interactions, and exploring immunotherapy targets to develop personalized therapies.
Unveiling the oncogenic role of lncRNA PIG13-DT in hepatocellular carcinoma progression.
Cai H, Chen S, Tang S … +7 more , Shi F, Zeng D, Wu Z, Wang F, Huang S, Li D, Guo W
Cancer Biol Ther · 2025 Dec · PMID 41065761 · Full text
BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality due to delayed diagnosis and poor prognosis. Long non-coding RNAs (lncRNAs) are key cancer regulators, yet the role of C1orf21-DT...
BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality due to delayed diagnosis and poor prognosis. Long non-coding RNAs (lncRNAs) are key cancer regulators, yet the role of C1orf21-DT (PIG13-DT) in HCC remains unclear. METHODS: We evaluated PIG13-DT expression in HCC and paired adjacent non-tumorous tissues. Functional studies were conducted using cell culture, cell-derived xenotransplantation (CDX) models, and molecular techniques including RNA pull-down, mass spectrometry, RIP-qPCR, and RNA sequencing. We explored the interplay between PIG13-DT, RNA-binding protein YBX3, and USP15 mRNA. RESULTS: PIG13-DT was highly expressed in HCC tissues compared with normal tissues and associated with poor prognosis. Functionally, PIG13-DT enhanced cancer stem cell (CSC) function, reduced reactive oxygen species (ROS) levels, and promoted HCC cell proliferation and migration. Mechanistically, PIG13-DT interacted with YBX3, stabilizing YBX3 and promoting USP15 mRNA translation and stability, thus driving HCC progression. Clinical data from lenvatinib-treated HCC patients showed that PIG13-DT expression was correlated with poor treatment response. CONCLUSION: Our study identifies a novel PIG13-DT/YBX3/USP15 axis driving HCC progression, suggesting PIG13-DT as a potential biomarker and therapeutic target. This work provides new insights into HCC molecular mechanisms and offers potential diagnostic and therapeutic implications.
Loss of ACSL1 fuels ferroptosis resistance in clear cell renal carcinoma.
Wang S, Wang Y, Liu B … +11 more , Zhang D, Zhang Z, Yang H, Li G, Zhao X, Liu J, Li Q, Song Y, Zhang Y, Wang Y, Zhou H
Cancer Biol Ther · 2025 Dec · PMID 41054261 · Full text
BACKGROUND: Clear cell renal cell carcinoma (ccRCC), the most common kidney cancer subtype, is marked by lipid metabolism reprogramming and therapy resistance. Ferroptosis-an iron-dependent, lipid peroxidation-driven cel...
BACKGROUND: Clear cell renal cell carcinoma (ccRCC), the most common kidney cancer subtype, is marked by lipid metabolism reprogramming and therapy resistance. Ferroptosis-an iron-dependent, lipid peroxidation-driven cell death-has gained attention as a therapeutic strategy. This study investigates the role of ACSL1, a key lipid metabolism enzyme, in ccRCC. METHODS: Using TCGA/GEO datasets, qPCR, immunohistochemistry, and immunofluorescence, ACSL1 expression and clinical significance were analyzed. Functional assays with ACSL1-overexpressing ccRCC cells and a xenograft mouse model evaluated its impact on tumor behavior. Transcriptomics and lipidomics, alongside ROS, ferroptosis, and p53 inhibitors, were applied to uncover mechanisms. RESULTS: ACSL1 is markedly downregulated in ccRCC and predicts poor prognosis. Overexpression suppressed proliferation and migration, induced cell death, and slowed tumor growth. Mechanistically, ACSL1 elevated ROS, activated p53, downregulated SLC7A11/GPX4, and triggered ferroptosis. Blocking ROS or p53 reversed these effects, confirming a ROS-p53-SLC7A11/GPX4 feedback loop. CONCLUSION: ACSL1 functions as a tumor suppressor in ccRCC by inducing ferroptosis via the ROS-p53-SLC7A11/GPX4 axis. It holds promise as a prognostic biomarker and therapeutic target in ccRCC.
Yes-associated protein 1 in cancer: bridging mechanical transduction and epigenetic regulation.
Liu T, Yu S, Zhang L … +6 more , Ji W, Wang G, Wang N, Li M, Hu T, Shi Z
Cancer Biol Ther · 2025 Dec · PMID 40977060 · Full text
Yes-associated protein 1 (YAP1) and its paralog TAZ serve as central mechanotransductive transcription coactivators that integrate mechanical cues from the extracellular matrix, such as stiffness and fluid shear stress,...
Yes-associated protein 1 (YAP1) and its paralog TAZ serve as central mechanotransductive transcription coactivators that integrate mechanical cues from the extracellular matrix, such as stiffness and fluid shear stress, with epigenetic modifications to drive oncogenic processes. They regulate diverse biological functions, including proliferation, metastasis, immune evasion, autophagy, ferroptosis, and metabolism. This review highlights how YAP1/TAZ signaling is modulated by mechanosensitive pathways (Integrin/FAK, Rho GTPases) and epigenetic mechanisms (m6A methylation, DNA methylation), contributing to therapy resistance and disease progression. Targeting the mechano-epigenetic axis of YAP1/TAZ offers promising therapeutic strategies for cancer treatment.
USP7 overexpression prevents the progression of clear cell renal cell carcinoma by enhancing pyroptosis via TRIP12 deubiquitination.
Li H, Ning Y, Yu J … +3 more , Chen Y, He Q, Jin J
Cancer Biol Ther · 2025 Dec · PMID 40947978 · Full text
Ubiquitin-specific protease 7 (USP7) involves in various human cancers due to its capacity for binding and stabilizing specific target proteins through deubiquitylation, but its roles in clear cell renal cell carcinoma (...
Ubiquitin-specific protease 7 (USP7) involves in various human cancers due to its capacity for binding and stabilizing specific target proteins through deubiquitylation, but its roles in clear cell renal cell carcinoma (ccRCC) development remains unknown. This study aimed to determine the role of USP7 in the pyroptosis mechanism in ccRCC, thereby providing novel anti-ccRCC strategies. Bioinformatics analysis was conducted to explore the expression of USP7 and TRIP12 in ccRCC patients and their association with patient overall survival. qRT-PCR, western blotting, and ELISA were used to determine the levels of USP7, TRIP12, pyroptosis-related factors. Cell viability, invasion, pyroptosis, and proliferation were evaluated using CCK-8, Transwell, flow cytometry, and immunohistochemistry assays. The direct interaction between USP7 and TRIP12 was validated by co-immunoprecipitation (CO-IP). We found downregulated USP7 in ccRCC tissues, which was related to the shorter patient overall survival (OS). Significantly, USP7 was also decreased in ccRCC cells. oe-USP7 (USP7 overexpression) inhibited ccRCC cell viability, migration, invasion, and enhanced pyroptosis. The caspase-1 specific inhibitor, VX-765, partially abolished the anti-viability, and pro-pyroptosis effects of oe-USP7, indicating USP7 overexpression prevented the malignant phenotype of ccRCC cells by enhancing caspase-1 dependent pyroptosis. Similarly, the shorter patient OS was indicated to be associated with reduced TRIP12 in ccRCC tissues. Besides, oe-USP7 increased TRIP12 expression in ccRCC cells by deubiquitinating TRIP12, while sh-TRIP12 eliminated the biological functions of oe-USP7. The similar effects of oe-USP7 on ccRCC development were found in ccRCC mice. USP7 mediated TRIP12 deubiquitination inhibited ccRCC progression by enhancing pyroptosis.
MiR-135a-3p inhibits the progression of prostate cancer by targeting TLR4.
Li L, Zhang X
Cancer Biol Ther · 2025 Dec · PMID 40843910 · Full text
To explore the expression of miR-135a-3p in prostate cancer，analyze its effects on tumor development and the involved mechanisms. A total of 125 specimens of cancer tissues and corresponding adjacent normal tissues from...
To explore the expression of miR-135a-3p in prostate cancer，analyze its effects on tumor development and the involved mechanisms. A total of 125 specimens of cancer tissues and corresponding adjacent normal tissues from prostate cancer patients were collected. Real - Time quantitative PCR was employed to quantify the expression levels of miR-135a-3p in prostate cancer tissues and cell lines. Kaplan-Meier survival curve analysis and Cox regression were performed to evaluate the prognostic significance of miR-135a-3p in prostate cancer. The CCK-8 assay was used to detect cell proliferation. A dual-luciferase reporter assay was employed to validate the targeting interaction between miR-135a-3p and Toll-like receptor 4 (TLR4). miR-135a-3p is lowly expressed in prostate cancer tissues and cells, and its low expression is associated with poor prognosis of patients. The low expression state of miR-135a-3p showed a significant correlation with TNM stage, clinical stage, Gleason score, and lymph node metastasis. In addition, miR-135a-3p inhibits the proliferation of prostate cancer cells and cancer progression by negatively regulating the expression of TLR4. miR-135a-3p is downregulated in prostate cancer and is associated with poor prognosis of patients. It exerts an inhibitory effect on the progression of prostate cancer by targeting TLR4.
Adipose-Derived Exosomes: mediators of crosstalk between Adipose tissue and cancer.
Wang C, Zheng Z, Wu C … +5 more , Zhang D, Wang Y, Zhang S, Wang G, Zhou R
Cancer Biol Ther · 2025 Dec · PMID 40817844 · Full text
Adipose-derived exosomes (ADEs), a subtype of extracellular vesicles, are critical mediators of communication between adipose tissue and tumors, playing pivotal roles in cancer progression and therapeutic response. These...
Adipose-derived exosomes (ADEs), a subtype of extracellular vesicles, are critical mediators of communication between adipose tissue and tumors, playing pivotal roles in cancer progression and therapeutic response. These nanoscale vesicles carry microRNAs, proteins, and lipids that influence tumor cell proliferation, migration, metastasis, and immune modulation. The dual functions of ADEs - both in promoting and suppressing tumorigenesis - are largely dependent on their cellular origin, molecular cargo, and the characteristics of the tumor microenvironment. Recent studies have identified ADEs as potential diagnostic biomarkers, therapeutic targets, and drug delivery platforms, offering promising avenues for precision oncology. However, significant challenges - such as biological heterogeneity, lack of standardization in production, concerns regarding efficacy and safety, and regulatory constraints - continue to hinder their clinical translation. This review aimed to explore the multifaceted roles of ADEs in cancer pathogenesis, their therapeutic potential, and current limitations, providing insights to guide future research and clinical applications.
Hypoxia-induced PYCR1 regulates glycolysis and histone lactylation to promote bladder cancer progression and metastasis via SLC6A14/Glutamine metabolism.
Li Z, Jiang Q, Yang Q … +2 more , Zhou Y, Wang J
Cancer Biol Ther · 2025 Dec · PMID 40808274 · Full text
Hypoxia-induced Pyrroline-5-Carboxylate Reductase 1 (PYCR1) is implicated in bladder cancer (BC), but its specific role remains elusive. This study investigated how PYCR1 promotes BC progression through glycolysis, histo...
Hypoxia-induced Pyrroline-5-Carboxylate Reductase 1 (PYCR1) is implicated in bladder cancer (BC), but its specific role remains elusive. This study investigated how PYCR1 promotes BC progression through glycolysis, histone H3 Lysine 18 Lactylation (H3K18la), and Solute Carrier Family 6 Member 14 (SLC6A14)-driven glutamine catabolism. Here, BC cell lines were cultured under hypoxia to evaluate changes in PYCR1 expression, glycolysis, and lactate production. The xenograft and metastasis models in nude mice were used to validate the role of the PYCR1/H3K18la/SLC6A14 axis in BC progression. GEPIA Bioinformatics database data showed that PYCR1 was upregulated in BC and was associated with poor prognosis. The PYCR1 positive expression rate in BC tissues was increased. Hypoxia induced PYCR1 expression in BC cells, enhancing glycolysis and lactate production, which increased H3K18la levels. Upregulated SLC6A14 expression promoted glutamine catabolism and enhanced BC cell proliferation, migration, and invasion. PYCR1 knockdown inhibited H3K18la levels, SLC6A14 expression, and BC cell aggressiveness; SLC6A14 overexpression reversed these effects. experiments confirmed that the PYCR1/H3K18la/SLC6A14 axis is critical for hypoxia-driven BC growth and metastasis. In summary, Hypoxia-induced PYCR1 enhances glycolysis, leading to increased lactate production and elevated H3K18la levels, which upregulates SLC6A14 transcription and glutamine catabolism, thereby promoting BC growth and metastasis.
Establishing a pediatric solid tumor PDX biobank for precision oncology research.
Akemi Kido L, Rodrigues Marusco M, Aparecida da Silva E … +12 more , Do Carmo L, Beatriz Teodoro Borges A, Luz Torres Silva F, Silveira Ruas J, Giomo de Lima D, de Abreu Fernandes L, Maia Martin Daiggi C, Aparecida Cardinalli I, Ferreira Euzébio M, Yoshioka Jotta P, Maschietto M, Pini Zenatti P
Cancer Biol Ther · 2025 Dec · PMID 40801203 · Full text
Developing advanced preclinical models and targeted therapies is essential for reducing cancer-related deaths in children with solid tumors. Patient-derived xenografts (PDX) have the potential to replicate key elements o...
Developing advanced preclinical models and targeted therapies is essential for reducing cancer-related deaths in children with solid tumors. Patient-derived xenografts (PDX) have the potential to replicate key elements of the original tumor, including morphology, genetic alterations, and microenvironment, making them valuable tools for studying tumor biology and drug response. We implanted 124 pediatric solid tumor samples, collected for 1 y, into NOD/SCID/IL2Rg (NSG) mice. Tumor fragments were placed subcutaneously, and the animals were monitored for up to 1 y. Histopathology, Short Tandem Repeat (STR) profiling, RT-PCR and/or RNA-sequencing were performed to confirm tumor identity and detect driver fusions. Fifty-five xenografts were successfully established (44.35% of implanted samples), representing 19 tumor types. Sarcomas, notably osteosarcoma, Ewing sarcoma, synovial sarcoma, and rhabdomyosarcoma, displayed first-generation engraftment rates above 55%. Central nervous system tumors had lower success, reflecting unique microenvironmental requirements. Histopathology and STR concordances were 85.45% and 81.1%, respectively, while 92.6% of sarcoma PDXs retained original fusion genes. Second-generation xenografts showed faster growth, suggesting adaptation to the murine host. Sporadic discrepancies, such as new fusions or lymphoproliferative expansions, indicated the need for ongoing molecular validation parallel to other techniques. A pediatric PDX biobank can effectively capture key tumor features while facilitating the study of therapeutic responses and tumor evolution. Our models confirm the feasibility of achieving stable histological and molecular profiles, offering a valuable resource for precision oncology research. Ultimately, these pediatric PDXs could accelerate the discovery of targeted therapy and significantly improve treatment outcomes.
SLX1 silencing overcomes Olaparib resistance in metastatic castration-resistant prostate cancer by disrupting SLX4-mediated DNA repair complexes.
Zhao X, Feng S, Nitie X … +2 more , Muluo S, Lei Y
Cancer Biol Ther · 2025 Dec · PMID 40789692 · Full text
PURPOSE: Metastatic castration-resistant prostate cancer (mCRPC) remains a significant therapeutic challenge and a leading cause of cancer-related mortality in men. PARP inhibitors like Olaparib are effective in homologo...
PURPOSE: Metastatic castration-resistant prostate cancer (mCRPC) remains a significant therapeutic challenge and a leading cause of cancer-related mortality in men. PARP inhibitors like Olaparib are effective in homologous recombination repair (HRR)-deficient tumors, but resistance often arises through DNA repair restoration. This study explores the role of the structure-specific endonuclease subunit SLX1, a catalytic subunit of the SLX1-SLX4 endonuclease complex, in Olaparib resistance. METHODS: Data from The Cancer Genome Atlas (TCGA) were used for expression and survival analyses. The CRPC cell line DU145, which harbors BRCA1 and BRCA2 mutations, was used as a cell model for both in vitro and in vivo studies. RESULTS: Elevated SLX1A expression in prostate cancer tissues was associated with significantly reduced progression-free and overall survival. SLX1 protein was upregulated in androgen-resistant prostate cancer cell lines (DU145, 22RV1, PC3) and further increased in Olaparib-resistant DU145 (DU145-OR) cells. Silencing SLX1 via shRNA enhanced Olaparib sensitivity, reducing colony formation and increasing DNA damage and apoptosis in DU145 and DU145-OR cells. Mechanistically, SLX1 knockdown disrupted SLX4 interactions with critical DNA repair proteins (ERCC1-XPF, PLK1, and TOPBP1), impairing DNA repair complex stability. In vivo, SLX1-silenced DU145 xenografts treated with Olaparib showed significantly reduced tumor growth with decreased Ki-67 expression and increased apoptosis/necrosis compared to controls. CONCLUSION: This study highlights SLX1 as both a prognostic marker and potential therapeutic target to enhance PARPi efficacy in advanced prostate cancer. Targeting SLX1 may be a promising strategy to overcome Olaparib resistance in mCRPC patients with homologous recombination deficiency.
Functional validation of somatic variability in and for prediction of platinum sensitivity and prognosis in epithelial ovarian carcinoma patients.
Mohammad AOA, Esraa A, Ivona K … +12 more , Petr H, Vojtěch H, Filip A, Lukáš R, Martin H, Marcela M, Kateřina K, Alena B, Jiří B, Alžběta S, Pavel S, Radka V
Cancer Biol Ther · 2025 Dec · PMID 40785058 · Full text
Concerning the dismal prognosis of chemoresistant patients with epithelial ovarian carcinoma (EOC), we aimed to follow up the findings of a previous whole-exome sequencing study using an orthogonal Sanger sequencing on t...
Concerning the dismal prognosis of chemoresistant patients with epithelial ovarian carcinoma (EOC), we aimed to follow up the findings of a previous whole-exome sequencing study using an orthogonal Sanger sequencing on the same patients and a separate set of 127 EOC patients ( = 177, all fresh frozen tumor samples). We focused on TP53 as a frequently mutated gene relevant for chemosensitivity, included KRAS as an additional therapeutically relevant target, complemented the study with transcript levels of both genes, and compared results with clinical parameters. All variants in TP53 and KRAS detected by exome sequencing were confirmed. KRAS mutated patients had significantly more frequent FIGO stages I or II ( = .002) and other than high-grade serous tumor subtypes (nonHGSCs) ( < .001), which was connected with lower KRAS transcript levels ( = .004). Patients with nonHGSC subtypes had less frequent TP53 mutations ( = .002). Carriers of TP53 variants disrupting the DNA binding loop had significantly longer platinum-free intervals than the rest ( = .037). Tumors bearing nonsense, frameshift, or splice site TP53 variants had a significantly lower TP53 transcript level, while those with missense variants had significantly higher levels than wild types ( < .001). The normalized intratumoral TP53 and KRAS transcript levels were correlated, and patients with co-mutated genes had poorer overall survival than others ( = .015). Protein levels of both genes significantly correlated with their respective transcripts ( = .028 and = .001, respectively). Our study points to as a target for future therapy of nonHGSCs and reveals the prognostic value of variants in the DNA binding loop.
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