Cancer Cell International最新文献

{"title":"Understanding crosstalk between the gut and liver microbiome: pathogenesis to therapeutic approaches in liver cancer.","authors":"Himanshi Goyal, Kaneez Fatima, Jyotdeep Kaur","doi":"10.1186/s12935-025-03840-9","DOIUrl":"10.1186/s12935-025-03840-9","url":null,"abstract":"<p><p>HCC is the most common primary liver cancer, ranking as the sixth most prevalent cancer globally and the third leading cause of cancer-related deaths. Etiological factors include:chronic liver diseases driven by alcohol abuse, viral hepatitis, obesity, and metabolic disorders. Emerging evidence also suggests that gut microbiome alterations and subsequent immune and metabolic dysregulation contribute to the pathogenesis and progression of HCC. The gut-liver axis represents a dynamic interplay between the gastrointestinal tract and the liver, modulated by the gut microbiome, microbial metabolites, and immune responses. This bidirectional communication plays a pivotal role in maintaining metabolic homeostasis and immune surveillance, while its dysregulation is implicated in various pathologies, including hepatocellular carcinoma (HCC). The gut microbiome, through microbial dysbiosis and metabolite secretion, significantly influences the tumor microenvironment and immune evasion mechanisms in HCC. Perturbations in gut barrier function and Toll-like receptor 4 (TLR4) activation drive chronic inflammation, promoting tumor progression. Moreover, microbial metabolites such as short-chain fatty acids (SCFAs) and bile acids, modulate inflammatory and metabolic pathways, offering novel insights into disease pathogenesis and potential biomarkers. Therapeutic strategies, including probiotics, prebiotics, and immune checkpoint inhibitors demonstrate promise in reprogramming the gut microbiome and restoring immune balance in HCC management. This review explores the multifaceted roles of the gut-liver axis in pathogenesis, the contributions of the intra-tumoral microbiome, and the potential of microbial metabolites as therapeutic avenues. A deeper understanding of these interactions could pave the way for innovative, targeted interventions in liver cancer and other gut-liver axis-associated diseases.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"291"},"PeriodicalIF":6.0,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12305952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting DKC1/NF-κB axis suppresses tumorigenesis and enhances 5-FU sensitivity in gastric cancer.","authors":"Tengkai Wang, Hui Zhang, Yaoyao Feng, Yinrong Yang","doi":"10.1186/s12935-025-03926-4","DOIUrl":"10.1186/s12935-025-03926-4","url":null,"abstract":"<p><strong>Background: </strong>Gastric cancer (GC), an aggressive malignant tumor with poor overall survival worldwide, urgently requires novel diagnostic and therapeutic targets. The dyskeratosis congenita 1 (DKC1) gene has been reported to have diverse biological functions and prognostic values in several types of human cancers. However, the specific role and molecular mechanism of DKC1 in GC have received less attention.</p><p><strong>Methods: </strong>Multi-omics analysis integrated The Cancer Genome Atlas (TCGA) data with validation in GC specimens and GC cell lines. DKC1 expression was quantified via immunohistochemistry, real-time polymerase chain reaction (qRT-PCR), and western blotting. Functional impacts on proliferation (CCK-8/cell cycle analysis), migration (Transwell), apoptosis (Annexin V/PI staining), and chemosensitivity (5-fluorouracil [5-FU] IC50) were assessed. RNA sequencing of DKC1-silenced AGS cells informed pathway enrichment (Gene Set Enrichment Analysis [GSEA]/Kyoto Encyclopedia of Genes and Genomes [KEGG]) to predict the underlying mechanism.</p><p><strong>Results: </strong>DKC1 expression was increased and displayed a remarkable diagnostic value in GC. High DKC1 expression correlated with advanced histologic grade and diffuse-type Lauren classification in GC patients. Functional studies revealed that DKC1 effectively promoted GC cell proliferation and migration while suppressing apoptosis in vitro. RNA-seq analysis and rescue experiments confirmed that DKC1 regulated GC progression via the NF-κB signaling pathway. Critically, DKC1 knockdown synergistically enhanced 5-FU efficacy through cell cycle dysregulation.</p><p><strong>Conclusions: </strong>DKC1 was identified as a regulator of GC development through the NF-κB pathway. It displayed a dual role as a diagnostic biomarker and therapeutic target. Elevated DKC1 expression correlated with aggressive clinicopathological features and a good diagnostic value in GC. Furthermore, DKC1 knockdown synergistically enhanced 5-FU efficacy. These data suggested that DKC1 is a potential tumor diagnostic biomarker and a therapeutic target for GC.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"288"},"PeriodicalIF":6.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12302887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting cancer stem cells with CAR-based immunotherapy: biology, evidence, and future directions.","authors":"Kaveh Hadiloo, Parsa Mostanadi, Ali Asadzadeh, Siavash Taremi, Abdolreza Esmaeilzadeh","doi":"10.1186/s12935-025-03846-3","DOIUrl":"10.1186/s12935-025-03846-3","url":null,"abstract":"<p><p>Cancer stem cells (CSCs) are pivotal in tumor initiation, progression, and relapse, underscoring the need for targeted therapies to achieve lasting responses. This review delves into CSC biology, highlighting their tumor-initiating potential demonstrated through limiting dilution assays and their role in resistance to therapies. Although successful CAR therapies, such as anti-CD19 CAR T-cells, can induce complete responses without directly targeting CSCs, CAR strategies focusing on CSCs may offer promising avenues to prevent recurrence. We assess CAR therapies targeting CSC-specific antigens, including CD133 and GD2, in preclinical and clinical contexts, emphasizing their effectiveness against glioblastoma, breast cancer, and other malignancies. Nevertheless, challenges such as marker specificity and suppression by the tumor microenvironment (TME) persist. Future strategies, which may include dual-targeting and AI-driven marker discovery, aim to improve CSC elimination and advance personalized cancer immunotherapy.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"289"},"PeriodicalIF":6.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12302805/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting m6A methylation for early diagnosis and precision medicine in hepatocellular carcinoma.","authors":"Qing-Kang Zheng, Ya-Nan Shi, Ming-Yuan Yang, Yi-Yuan Xie, Kai Sun, Huan-Zhang Niu","doi":"10.1186/s12935-025-03923-7","DOIUrl":"10.1186/s12935-025-03923-7","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) ranks as a significant global malignancy, occupying the sixth position in incidence and the third in cancer-related mortality. Despite this, the mechanisms underlying HCC progression remain insufficiently understood. m6A modification is one of the most common post-transcriptional modifications in eukaryotic mRNA, regulated by methyltransferases, demethylases, and m⁶A-binding proteins. Proteins specialized in m6A recognition selectively bind to m6A-modified RNA, influencing processes such as splicing, maturation, nucleation, degradation, and translation. Current research, both domestic and international, primarily explores how m6A modification and its associated proteins affect malignant cell proliferation, migration, invasion, metastasis, and drug resistance. However, the role of m6A-related proteins in tumor progression in HCC remains poorly characterized. This review elucidates the composition, mechanisms, and biological functions of m6A methylation modification proteins in HCC progression, alongside recent advancements in m6A-related biomarker discovery and immunotherapeutic developments, aiming to enhance early clinical diagnosis and facilitate targeted drug development for HCC.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"286"},"PeriodicalIF":6.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12302885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"m⁶A-modified CTC-297N7.9 inhibits hepatocellular carcinoma metastasis via epigenetically downregulating CCL2 and CD47.","authors":"Huamei Wei, Changhong Pu, Min Zeng, Rongzhou Lu, Yunyu Wei, Yanyan Huang, Zheng Huang, Lizheng Huang, Zuoming Xu, Jianchu Wang, Rihai Ma, Jian Pu","doi":"10.1186/s12935-025-03857-0","DOIUrl":"10.1186/s12935-025-03857-0","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) is one of most common malignancies with poor prognosis, largely due to its high propensity for metastasis and recurrence. As the most common internal RNA modification, N⁶-methyladenosine (m⁶A) plays critical and diverse roles in HCC progression. However, the mechanisms by which m⁶A regulates HCC metastasis remain incompletely understood. Here, we aimed to identify key m⁶A modification events during HCC metastasis.</p><p><strong>Methods: </strong>The expression of CTC-297N7.9. was measured by qPCR. m⁶A modification level of CTC-297N7.9 was measured by methylated RNA immunoprecipitation (MeRIP) and single-base elongation- and ligation-based qPCR amplification method (SELECT). The roles of m⁶A-modified CTC-297N7.9 in HCC were investigated by in vitro cell viability, proliferation, migration and phagocytosis assays, and in vivo liver metastasis and lung metastasis assays. The underlying mechanisms of m⁶A-modified CTC-297N7.9 were dissected by chromatin isolation by RNA purification (ChIRP), assay for transposase accessible chromatin (ATAC) and cleavage under target & tagmentation (CUT&Tag) assays.</p><p><strong>Results: </strong>The m⁶A modification level of CTC-297N7.9 is decreased in HCC tissues and correlated with microvascular invasion and poor prognosis. CTC-297N7.9 suppresses HCC metastasis in an m⁶A-dependent manner. m⁶A-modified CTC-297N7.9 attenuates tumor-associated macrophages (TAMs) infiltration and M2 polarization through downregulating CCL2 expression and secretion. Additionally, m⁶A-modified CTC-297N7.9 promotes phagocytosis of HCC cells by macrophages through downregulating the phagocytosis checkpoint CD47. Mechanistic investigations revealed that m⁶A-modified CTC-297N7.9 binds the m⁶A reader YTHDC1, which further binds and recruits the histone H3K9me3 methyltransferase SETDB1 and H3K27me3 methyltransferase EZH2 to the promoters of CCL2 and CD47, leading to the upregulation of H3K9me3 and H3K27me3 modifications at CCL2 and CD47 promoters, and transcriptional silencing of CCL2 and CD47.</p><p><strong>Conclusions: </strong>Our study demonstrates that m⁶A-modified CTC-297N7.9 acts as a metastasis suppressor in HCC, and highlights its potential as a prognostic biomarker and therapeutic target for HCC.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"290"},"PeriodicalIF":6.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12306055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of CD4_Naive cells related gene FMO4 as a positive regulator of the poor prognosis of septic CRC patients.","authors":"Weiye Hou, Peiwen Fu, Zhenling Nie, Wanye Wang, Jingjing Li, Bangshun He, Qiao Tang, Tianyi Gao","doi":"10.1186/s12935-025-03917-5","DOIUrl":"10.1186/s12935-025-03917-5","url":null,"abstract":"<p><strong>Background: </strong>Septic disease usually results in delayed access to intensive care and poor outcomes in CRC patients. Studies have shown that T cells play important roles in CRC and sepsis immune systems. Hence, this study was performed to investigate the role of T cells and T-cell-related genes in CRC-related sepsis prognosis.</p><p><strong>Methods: </strong>Single-cell sequencing data from CRC and sepsis patients were first analysed to explore common T-cell signals, including those related to cellular communication and signalling pathways. Then, functional enrichment analysis and Mendelian randomization (MR) analysis were conducted on marker genes of T cells to identify the key genes and their effects on septic CRC. The expression of key genes and their associations with CRC prognosis were validated in 32 blood samples from CRC patients with sepsis.</p><p><strong>Results: </strong>Compared with that in the negative control group, CD4_Naive cells infiltration was significantly lower in the combined single-cell sequencing data analysis of CRC and sepsis patients (p < 0.05). Our MR analysis and clinical sample verification results revealed that a high FMO4 gene was negatively associated with CD4_Naive cells infiltration and related to poor prognosis in septic patients with CRC (p < 0.05). The functional enrichment analysis of FMO4 revealed that FMO4 participated mainly in xenobiotic catabolic processes and taurine and hypo-Taurine metabolism in septic CRC, which further inhibited the energy metabolic activity of CD4_Naive cells.</p><p><strong>Conclusion: </strong>The CD4_Naive cells related gene FMO4 appears to promote poor prognosis in septic CRC patients, suggesting that it is a promising candidate for therapeutic intervention.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"285"},"PeriodicalIF":6.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12302463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IGFBP1 orchestrates metabolic reprogramming to drive clear cell renal cell carcinoma progression through NR1H4-mediated lipid homeostasis disruption.","authors":"Yanning Sun, Yuhu Hao, Fan Peng, Hongju Ling, Kai Sun, Jiechuan Qiu, Tianmin Yang, Leizuo Zhao, Qinghua Xia","doi":"10.1186/s12935-025-03904-w","DOIUrl":"10.1186/s12935-025-03904-w","url":null,"abstract":"<p><p>The hallmark lipid accumulation phenotype observed in clear cell renal cell carcinoma (ccRCC) serves as a critical pathophysiological driver of tumor progression. Our investigation revealed that IGFBP1 expression was significantly elevated in ccRCC versus matched normal renal tissues, with increased levels correlating with poorer patient survival outcomes. IGFBP1 knockdown not only suppressed tumor proliferation and invasiveness in vitro but also provoked substantial lipidomic remodeling, as validated through comprehensive lipidomic profiling. Specifically, IGFBP1-deficient cells demonstrated marked reductions in triglycerides (TGs), diacylglycerols (DAGs), free fatty acids (FFA), and cholesterol esters (CEs), thereby establishing IGFBP1 as a key regulator of the metabolic derangements' characteristic of ccRCC pathogenesis. Mechanistic exploration identified NR1H4 as a potential transcriptional regulator operating downstream of IGFBP1-mediated signaling pathways. A thorough interrogation of these pathways established mechanistic links between IGFBP1 activity and endoplasmic reticulum stress, revealing an integrated network that coordinates lipid homeostasis within malignant renal epithelium. These findings substantiated the role of IGFBP1 as a central node in the metabolic reprogramming associated with ccRCC and propose actionable targets for therapeutic intervention through modulation of lipid metabolic pathways.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"284"},"PeriodicalIF":6.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12302755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Construction and validation of acetylation-related gene signatures for immune landscape analysis and prognostication risk prediction in luminal breast cancer.","authors":"Mengdi Zhu, Jinna Lin, Haohan Liu, Jingru Wang, Nianqiu Liu, Yudong Li, Hongna Lai, Qianfeng Shi","doi":"10.1186/s12935-025-03920-w","DOIUrl":"10.1186/s12935-025-03920-w","url":null,"abstract":"<p><strong>Background: </strong>Epigenetic acetylation plays an essential role in the development and drug resistance of luminal breast cancer. However, the acetylation regulatory network in luminal breast cancer remains underexplored.</p><p><strong>Methods: </strong>We used the TCGA-BRCA database to explore the acetylation regulatory network in luminal breast cancer. Spearman correlation coefficients, Cox proportional hazards, and the STRING database were used to identify genes that were correlated with acetylation regulatory molecules in luminal breast cancer and could predict patient outcomes. An acetylation regulatory risk model was constructed via Consensus Cluster Plus and the LASSO risk model. GSEA, K‒M survival analysis, and receiver operating characteristic (ROC) curve analysis were used to analyze survival and possible regulatory pathways of the risk model. TIDE, Microenvironment Cell Populations-counter, and CIBERSORT algorithms were used to analyze the immune landscape of the risk model population. Patients' tumor specimens were used to detect the expression of KAT2B and TAF1L. The luminal breast cancer cell lines MCF-7 and T47D were used in cell viability, Transwell, western blotting, and RT‒qPCR experiments to confirm the risk model. Mouse model was constructed for in vivo validation of KAT2B and TAF1L function.</p><p><strong>Results: </strong>In our study, we utilized the TCGA-BRCA database to conduct a comprehensive analysis of the acetylation regulatory pattern in luminal breast cancer. Using Consensus Cluster Plus and the LASSO risk model, we screened 6 acetylation-related genes (KAT2B, TAF1L, CDC37, CCDC107, C17orf106, and ASPSCR1) and constructed a 6-gene risk model of luminal breast cancer. Based on this model, luminal breast cancer patients were classified into high- and low-risk subgroups. The high-risk subgroup had a poor prognosis. Further analysis revealed that the high-risk subgroup was associated with lower CD8 + T-cell infiltration and greater responsiveness to immune checkpoint inhibitor therapy. In vitro and in vivo experiments revealed that knockdown of KAT2B and TAF1L dramatically inhibited tumor cell proliferation. In vitro experiments also showed knockdown of KAT2B and TAF1L dramatically inhibited tumor cell migration, increased lymphocyte infiltration, and significantly upregulated the expression of CD8 + T-cell-associated chemokines in luminal breast cancer cells.</p><p><strong>Conclusions: </strong>In this study, we successfully constructed a 6-gene acetylation-associated risk model for luminal breast cancer, providing a new direction and evidence for personalized treatment. Our results also suggested that KAT2B and TAF1L might serve as potential therapeutic targets in luminal breast cancer.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"287"},"PeriodicalIF":6.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12302894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plumbagin targets the GLUT1/MMP-2 axis to inhibit oral squamous cell carcinoma progression.","authors":"Fei He, Weiqi Wang, Sadam Ahmed Elayah, Linyang Xie, Ming Yu, Yuxin Gong, Hao Cui, Xiang Liang, Junbo Tu, Ying Han, Sijia Na","doi":"10.1186/s12935-025-03915-7","DOIUrl":"10.1186/s12935-025-03915-7","url":null,"abstract":"<p><strong>Aim: </strong>This study aimed to investigate the clinicopathological characteristics and prognostic value of GLUT1 in oral squamous cell carcinoma (OSCC) and the effect of plumbagin (PLB) on inhibiting OSCC invasion and metastasis through the GLUT1/Matrix Metalloproteinase 2 (MMP2) axis pathway.</p><p><strong>Materials and methods: </strong>One hundred and twenty human OSCC specimens were collected. Immunohistochemistry was performed to analyze the expression, clinicopathological characteristics, and prognostic value of GLUT1 in these specimens. Cal27 and SCC9 cell lines were used to investigate the role of PLB in cell proliferation, migration, invasion, and metastasis in vitro and in vivo.</p><p><strong>Results: </strong>Immunohistochemistry showed significant associations between GLUT1 expression and MMP2, tumor recurrence, lymphatic metastasis, and TNM stage. In vitro and in vivo experiments demonstrated that PLB inhibited OSCC cell proliferation, migration, and invasion by downregulating GLUT1 and MMP2. WZB117, a GLUT1 inhibitor, also reduced cell colony formation, migration, and invasion. However, univariate and multivariate analyses indicated that GLUT1 expression was not an independent prognostic marker for OSCC overall and disease-free survival.</p><p><strong>Conclusions: </strong>The findings demonstrated a novel anti-cancer mechanism of plumbagin, inhibiting OSCC invasion and migration by suppressing the GLUT1/MMP2 axis pathway, providing a theoretical basis for the future clinical use of plumbagin in the treatment of OSCC.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"283"},"PeriodicalIF":6.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12302832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cyclin dependent kinase 9 inhibitor induces transcription-replication conflicts and DNA damage accumulation in breast cancer.","authors":"Minyoung Lee, Kyung-Hun Lee, Ahrum Min, So Hyeon Kim, Sujin Ham, Hae Min Hwang, Youlim Noh, Yu-Jin Kim, Dae-Won Lee, Jiwon Koh, Seock-Ah Im","doi":"10.1186/s12935-025-03897-6","DOIUrl":"10.1186/s12935-025-03897-6","url":null,"abstract":"<p><strong>Background: </strong>Cyclin-dependent kinase 9 (CDK9) is a crucial regulator of transcriptional progression of RNA polymerase-II (RNAP2). RNA polymerases trapped in DNA can be a source of transcription-replication conflict (T-R conflict), which is a common source of replication stress. AZD4573, a highly selective CDK9 inhibitor, has been shown to induce apoptosis in leukemia cell lines, while its anti-tumor potential in breast cancer has yet to be elucidated.</p><p><strong>Methods: </strong>To evaluate the cytotoxicity of AZD4573 in vitro, MTT assays were performed. The expression of signal transduction molecules was determined using Western blotting, immunoprecipitation, and immunofluorescence. Apoptotic cell death was verified by the annexin-V assay. DNA strand breaks and repair efficacy were evaluated through the alkaline comet assay. The siRNA knock-down system was used to confirm the action mechanism.</p><p><strong>Results: </strong>AZD4573 induced T-R conflicts during S-phase, increasing replication stress and DNA strand breaks, resulting in apoptosis by induction of caspase-3. Furthermore, we identified Dead-box 25 (DDX25) helicase as a key mediator in resolving the T-R conflicts. Nuclear translocation of DDX25 correlated with reduced sensitivity to AZD4573 by the resolution of T-R conflicts.</p><p><strong>Conclusions: </strong>Inhibition of CDK9 by AZD4573 induces the accumulation of DNA damage through T-R conflicts. DDX25 helicases were identified as a key mediator in resolving T-R conflicts and the reduced sensitivity to AZD4573.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"282"},"PeriodicalIF":6.0,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12297744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}