Molecular Cancer最新文献

{"title":"Circulating tumor cells: mechanisms and clinical significance in colorectal cancer metastasis","authors":"Xuanyu Ren, Mei Song, Xianzhi Liu, Weiling He","doi":"10.1186/s12943-025-02465-w","DOIUrl":"https://doi.org/10.1186/s12943-025-02465-w","url":null,"abstract":"Tumors are a major global health problem. As economic development and material standards increase, the incidence and mortality of digestive system tumors have shown an overall rising trend. Among them, colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer death worldwide. Despite advances in molecular biology and therapeutic strategies, tumor metastasis remains the main driver of cancer-related deaths (about 90%). Especially in CRC, the progression of metastasis greatly limits clinical intervention options. Circulating tumor cells (CTCs), a key mediator of hematogenous metastasis, have emerged as a key target for unravelling metastatic mechanisms and developing therapeutic strategies, and are gradually gaining prominence in tumor biology and precision medicine. Therefore, a comprehensive understanding of CTC-mediated mechanisms, especially in the invasion-metastasis cascade of CRC and other cancers of the digestive system, is crucial for early metastasis detection, prevention and identification of new therapeutic targets.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"13 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145210017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-coding RNAs in gastric cancer: mechanisms and therapeutic prospects","authors":"Zhifei Han, Wenjuan Liu, Yigao Zhu, Yinggang Sun, Dong Sun, Ruyue Jia, Yanting Yang, Houbao Qi, Long Zhang, Yanfei Huo, Nasha Zhang, Jie Chai, Ming Yang","doi":"10.1186/s12943-025-02467-8","DOIUrl":"https://doi.org/10.1186/s12943-025-02467-8","url":null,"abstract":"Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. It is associated with high molecular and phenotypic heterogeneity. Early-stage gastric cancer can be treated with endoscopic resection and surgery, whereas at its advanced stage, sequential chemotherapy presents the only treatment option, which starts with first-line platinum and fluoropyrimidine-based dual drugs, supporting a median survival period of less than one year. Targeted monoclonal antibodies approved for the treatment of gastric cancer are effective for a limited subset of patients. Furthermore, painless and precise markers for the early detection of gastric cancer and new targets for its treatment are unavailable. Interestingly, many non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play key roles in the development of gastric cancer. Multiple pieces of evidence suggest that ncRNAs play a crucial role in the treatment of gastric cancer using chemotherapy and targeted therapy drugs. In this article, we systematically reviewed the important roles of ncRNAs in chemotherapy resistance, immune escape, metabolism, and angiogenesis of gastric cancer, and systematically elucidated the relevant molecular mechanisms. In addition, we also proposed the potential clinical significance of ncRNA as a new therapeutic target and prognostic biomarker for gastric cancer.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"19 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A circRNA promotes esophageal squamous cell carcinoma progression by inhibiting TRIM25-mediated degradation of IGF2BP family members","authors":"Shuangyan Tan, Yue Ming, Jiawei Guo, Wenrong Liu, Hulin Ma, Yu Liu, Zhijie Xu, A-Lai Gu-Ha, Lunzhi Dai, Yi-Dan Lin, Yong Peng","doi":"10.1186/s12943-025-02442-3","DOIUrl":"https://doi.org/10.1186/s12943-025-02442-3","url":null,"abstract":"Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with poor prognosis and limited treatment options. While circular RNAs (circRNAs) are frequently dysregulated in ESCC, their functional roles and molecular mechanisms in tumor progression remain largely unexplored. We characterized circRNA using RT-PCR, Sanger sequencing, and fluorescent in situ hybridization. Gain- and loss-of-function studies in vitro and in vivo were performed to assess circRNA function. Molecular interactions were investigated via RNA pull-down assays coupled with mass spectrometry, electrophoretic mobility shift assays, co-immunoprecipitation, and immunoblot analysis. Clinical relevance was evaluated by RT-qPCR and immunohistochemistry in patient specimens. We identified circLNF, a novel circRNA derived from the long non-coding RNA FIRRE gene, which is significantly upregulated in ESCC. Functional assays demonstrated that circLNF promotes proliferative and migratory capacities in cultured cells and accelerates tumor progression and metastasis in animal models. Mechanistically, circLNF directly interacts with IGF2BP family proteins through their “CAUC” motifs, protecting them from TRIM25-mediated ubiquitination and proteasomal degradation. Importantly, circLNF expression positively correlated with IGF2BP1 protein levels in ESCC patient tissues, underscoring the clinical relevance of the circLNF-IGF2BP axis in ESCC progression. Our findings reveal an oncogenic role of circLNF in ESCC by inhibiting TRIM25-mediated proteasomal degradation of IGF2BP proteins and highlight circLNF as a potential therapeutic target for ESCC.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"97 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BRD9-p53-E2F1 circuit orchestrates cell growth and DNA damage repair in gastric cancer","authors":"Qingqing Zhou, Qi Wang, Yantao Duan, Chi Zhang, Tengfei Liu, Hengrui Liu, Mindi Zhao, Zhihuang Hu","doi":"10.1186/s12943-025-02449-w","DOIUrl":"https://doi.org/10.1186/s12943-025-02449-w","url":null,"abstract":"BRD9 is involved in multiple physiological and pathological pathways, yet its functional role and molecular mechanisms in gastric cancer (GC) remain largely unexplored. Addressing this knowledge gap is critical given the persistent global mortality burden of GC and the limited efficacy of current therapeutic strategies. BRD9 expression in GC patients was systematically analyzed using immunohistochemical (IHC) assays and transcriptomic datasets. Comprehensive functional validation, employing cellular and murine tumor models, elucidated BRD9’s role in GC progression. Molecular pathways underlying BRD9-mediated gastric carcinogenesis were delineated through integrated approaches, including RNA sequencing, co-immunoprecipitation (co-IP), subcellular fractionation, and luciferase reporter assays. BRD9 was significantly overexpressed in GC and associated with poor patient prognosis. Functionally, BRD9 promoted GC cell proliferation and enhanced DNA damage repair capacity. Mechanistically, elevated BRD9 expression inhibited p53 nuclear translocation via direct binding, subsequently activating the E2F transcription factor family. Notably, we identified that E2F1 directly bound to and transactivated the BRD9 promoter, establishing a positive feedback loop that sustains BRD9 expression. Additionally, BRD9 knockdown sensitized GC cells to cisplatin and oxaliplatin treatment. These findings highlight the critical role of BRD9 in GC progression and its therapeutic potential. The BRD9-p53-E2F1 axis acts as a crucial regulator of GC cell proliferation and DNA damage response. Targeting BRD9 pharmacologically could be a novel therapeutic approach to enhance chemotherapy efficacy and improve treatment outcomes in GC patients.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"79 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"P23 acts as a negative regulator of ferroptosis in NSCLC by blocking GPX4 degradation via chaperone-mediated autophagy","authors":"Junlin Chen, Yulin Peng, Meirong Zhou, Yilin Che, Shilei Zhao, Chengjian He, Wen Zhang, Xiangge Tian, Wenhao Zhang, Zhe Liu, Minghao Zhou, Guobiao Liang, Xiaokui Huo, Yan Wang, Zhenlong Yu, Xiaochi Ma","doi":"10.1186/s12943-025-02439-y","DOIUrl":"https://doi.org/10.1186/s12943-025-02439-y","url":null,"abstract":"Ferroptosis has been identified as a tumor-inhibiting event in a variety of cancers; however, its molecular basis in non-small cell lung cancer (NSCLC) has not been completely elucidated. Notably, glutathione peroxidase 4 (GPX4) plays a crucial role in ferroptosis. Our previous research revealed that prostaglandin E synthase 3 (p23), a potential transcription factor, plays a crucial role in promoting cancer progression and metastasis through succinylation. Our study revealed a previously unknown antiferroptotic function of p23. Mechanistically, p23 stabilizes GPX4 by competitively binding heat shock cognate 71 kDa protein (HSC70) to suppress chaperone-mediated autophagy (CMA) activity, which subsequently inhibits ferroptosis and accelerates tumor growth. Notably, impairing p23 succinylation disrupts its interaction with HSC70, restoring CMA-mediated GPX4 degradation. Collectively, our findings suggest that targeting p23-regulated CMA pathways represents a potentially viable strategy to modulate ferroptosis in NSCLC. The role of p23 in competing with GPX4 for binding to HSC70, blocking CMA-mediated degradation of GPX4 and inhibiting ferroptosis ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"28 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"​​The immune microenvironment of pathogen-associated cancers and current clinical therapeutics","authors":"Xiao-Yu Wei, Hui-Jing Feng, Ying-Yin Zhu, Shi-Jing Guo, Hong Wang, Ming Li, Qi Mei","doi":"10.1186/s12943-025-02448-x","DOIUrl":"https://doi.org/10.1186/s12943-025-02448-x","url":null,"abstract":"Pathogen-associated cancers account roughly 15–20% of all malignancies worldwide and arise from chronic infections by oncogenic viruses, bacteria and parasites. Pathogens can alter the tumor microenvironment (TME) into an immune-suppressive niche using multiple mechanisms, including immune checkpoint manipulation, chronic inflammation, metabolic reprogramming, and direct epigenetic modifications. Immune dysfunctions related to infections linked to cancers can include M2-polarized macrophages, expansion of MDSCs, exhausted T/NK cells, and tolerogenic dendritic cells, all progressing immune evasion and resistance to cancer therapy. Advances in therapeutics exist in prophylactic vaccines, immune checkpoint inhibitors, and next-generation methods such as the engineered Salmonella to deliver to hypoxic tumors and the targeting the microbiome. The advancement of pathogen-, cancer-, and patient-specific therapeutics is not without its challenges, including heterogeneity of the pathogens, absence of clinically useful biomarkers, concerns about the safety of the restoring anti-pathogen immunity and challenges of scale for manifold interventions. This review will provide a synthesis of the mechanistic aspects of pathogen-mediated TME remodeling, contemporary clinical therapeutics, and ongoing investigations into using pathogen/host dynamics to enhance measurable precision immunotherapy strategies.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"99 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HPGD induces ferroptosis and autophagy to suppress esophageal squamous cell carcinoma through the LXA4–ERK1/2–U2AF2–TFRC axis","authors":"Tianyun Ma, Xiamei Guo, Jueying Zhao, Chenlong Wang, Xiaojuan Yu, Rongliang Mo, Zhuoying Han, Lulu Feng, Longfei Liu, Weiyong Yu, Fangyi Xu, Li Zhang, Qilong Wang, Chao Luo","doi":"10.1186/s12943-025-02464-x","DOIUrl":"https://doi.org/10.1186/s12943-025-02464-x","url":null,"abstract":"Although 15-hydroxyprostaglandin dehydrogenase (HPGD) is known to regulate the metabolism of prostaglandins and lipoxin A4, and its dysregulation has been implicated in various cancers, its role in esophageal squamous cell carcinoma (ESCC) has not been determined. This study is the first to comprehensively characterize HPGD expression in ESCC and establish its clinical relevance in predicting patient outcomes. Furthermore, we elucidated the previously unrecognized molecular mechanisms through which HPGD suppresses ESCC progression and its potential as a novel therapeutic target. Transcriptome sequencing was performed on paired tumor and adjacent normal tissues from deceased patients with ESCC to identify differentially expressed genes. The differential expression of the HPGD gene was subsequently validated in two independent, large-scale ESCC patient cohorts, and its prognostic significance was evaluated. To evaluate the functional role of HPGD in ESCC, the enzyme was overexpressed in ESCC cell lines, and a series of in vitro assays were conducted to assess its effects on proliferation, apoptosis, invasion, and migration. To elucidate the molecular mechanisms underlying the effects of HPGD, we performed transcriptomic sequencing to profile gene expression changes in ESCC cells. Through multiple analyses, including measurements of lipid peroxidation, intracellular ferrous ion and reactive oxygen species (ROS) levels, dual-fluorescence flow cytometry for autophagy, phosphoprotein microarrays, biotin pull-down assays, and chromatin immunoprecipitation (ChIP), we demonstrated that HPGD regulates the malignant phenotype of ESCC cells primarily by inducing ferroptosis and autophagy. Finally, the impact of HPGD on ESCC tumor growth was validated in vivo using a subcutaneous xenograft model in nude mice. HPGD expression was significantly lower in ESCC tissues than in normal tissues and was negatively correlated with tumor cell differentiation and patient outcomes. HPGD overexpression inhibited ESCC cell proliferation, invasion, and migration in vitro and in xenograft tumor growth in vivo. In vitro experiments demonstrated that HPGD suppresses ERK1/2 activation by facilitating lipoxin A4 (LXA4) degradation. This inhibition facilitates binding of the RNA-binding protein U2AF2 to the promoter region of the transferrin receptor (TFRC), thereby increasing TFRC expression. Consequently, these alterations lead to intracellular iron accumulation and initiate ferroptosis. Excessive generation of ROS during ferroptosis results in hyperactivation of autophagy via the AMPK/mTOR signaling pathway. Mitigating the HPGD-induced upregulation of TFRC or reducing ROS production effectively reverses ferroptosis, prevents excessive autophagy, and ameliorates malignant cell phenotypes. HPGD exerts its antitumor effects by promoting ferroptosis through the LXA4-ERK1/2-U2AF2 signaling axis, which in turn induces autophagy hyperactivation via the AMPK-mTOR pathway. These finding","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"28 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and safety of TAS-102 plus Surufatinib in third and later line metastatic pancreatic cancer: a prospective, single center and biomarker exploratory, phase II study","authors":"Yunxin Lu, Qingguang Lin, Yongxin Mo, Furong Liu, Mengwei Zhang, Runjie Huang, Yun Wang, Yinnan Wang, Zhiqiang Wang, Huiyan Luo, Guifang Guo, Jianwen Chen, Yu Liu, Mingming He, Fenghua Wang, Feng Wang, Dongsheng Zhang","doi":"10.1186/s12943-025-02437-0","DOIUrl":"https://doi.org/10.1186/s12943-025-02437-0","url":null,"abstract":"Metastatic pancreatic cancer (mPC) has a dismal prognosis, with first line systemic therapy relying primarily on FOLFIRINOX (5FU/irinotecan/oxaliplatin) or AG (Gemcitabine/Nab-Paclitaxel). Therapeutic options for mPC refractory to these regimens remain poorly defined, and data on later-line options are scarce. This prospective, single-arm study evaluated the safety and preliminary efficacy of combining the anti-angiogenic agent surufatinib with the cytotoxic drug TAS-102 (Trifluridine/Tipiracil) in mPC patients who had progressed on ≥ 2 prior lines of therapy. mPC patients who were refractory to at least 2 previous regimens were enrolled and received TAS-102 (35 mg/m2, po, bid, D1-D5, D8-D12) plus surufatinib (250 mg, po, qd) in a 4-week cycle. The tumor response was assessed by the researcher every 8 weeks and treatment continued until disease progression, unacceptable toxicity, investigator discretion, or patient withdrawal of informed consent. Primary and secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Between January 2023 and June 2024, 22 patients were enrolled into this study. Among 20 patients analyzed for efficacy, median PFS was 2.35 months (95% CI: 1.91–3.94) and median OS was 6.34 months (95% CI: 3.81–10.09). The ORR and DCR were 20% (4/20; all partial response) and 30% (6/20), respectively. All patients experienced treatment emergent adverse events (TEAEs), with anemia (59.1%), neutropenia (54.6%), leukocytopenia (50.0%), and lymphocytopenia (45.5%) as the most common any-grade events. Grade ≥ 3 TEAEs including neutropenia (31.8%), lymphocytopenia (13.6%), and anemia (9.1%), were observed in 50.0% (11/22) of patients. Subgroup analysis identified metastases involving > 2 organs or hepatic sites as potential predicative biomarkers for inferior efficacy. Proteomic screening revealed that overexpressed OCIAD2 correlated with poor prognosis, a finding validated in two publicly available external cohorts (CPTAC database and RuiJin cohort). Combination of TAS-102 and surufatinib demonstrates clinically meaningful efficacy and manageable toxicity as therapeutic option for later-line mPC. The biomarkers identified in this study may hold the potential to guide patient stratification and warrant further investigation to optimize precision application of this regimen. This study was prospectively registered at clinicaltrials.gov with the number NCT05481463 on August 1st 2022.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"92 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding the ubiquitin network: molecular mechanisms and therapeutic vulnerabilities for precision radio-sensitization in cancer","authors":"Fu-Ying Zhao, Li-Ye Shi, Lu-Jiao Yu, Si-Qi Wang, Chu-Yao Sun, Na Zhang, Hua-Qin Wang","doi":"10.1186/s12943-025-02433-4","DOIUrl":"https://doi.org/10.1186/s12943-025-02433-4","url":null,"abstract":"Radiotherapy resistance remains a major clinical challenge, largely driven by tumors’ ability to dynamically adapt through complex molecular networks. Critically, the ubiquitin system has emerged as a critical regulator of this resistance. This review examines how the ubiquitin system orchestrates radiotherapy resistance through spatiotemporal control of DNA repair fidelity, metabolic reprogramming, and immune evasion. We explore how the ubiquitin code, defined by its chain topology diversity (such as K48-linked proteolysis versus K63-mediated signaling) and crosstalk with phosphorylation, SUMOylation, and acetylation, generates diverse resistance mechanisms. These mechanisms, however, also present vulnerabilities exploitable for radio-sensitization. Notably, monoubiquitylation of both histone and non-histone protein collaboratively modulates chromatin dynamics and DNA damage responses to maintain genome integrity during radiation. Furthermore, ubiquitination critically regulates caner metabolism, reprogramming processes such as ferroptosis susceptibility, hypoxia adaptation, and nutrient flux, thereby creating targetable vulnerabilities for radio-sensitization. While targeting key E3 ligases and deubiquitinases (DUBs) shows preclinical promise, clinical translation faces obstacles including functional redundancy, unintended on-target toxicity, and adaptive tumor responses. Distinct from other post-translational modifications (PTMs), the ubiquitin system offers unique clinical advantages: its dynamic reversibility, chain topology diversity, and recent breakthroughs in targeted degradation (e.g., PROTACs) enable precise disruption of radioresistance networks. By integrating these mechanistic insights with biomarker-guided therapeutic strategies, ubiquitin-targeting agents are emerging as fundamental components of next-generation radiotherapy protocols.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"10 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hsa_circ_0038737 promotes PARPi resistance in castration-resistant prostate cancer via IGF2BP3-mediated DNPH1 mRNA stabilization","authors":"Zhongyuan Wang, Qintao Ge, Aihetaimujiang Anwaier, Shiwei Liu, Xi Tian, Zihao Zhang, Tao Feng, Zhe Hong, Dingwei Ye, Wenhao Xu, Xiaojian Qin","doi":"10.1186/s12943-025-02447-y","DOIUrl":"https://doi.org/10.1186/s12943-025-02447-y","url":null,"abstract":"Resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) poses a major challenge to therapeutic efficacy in castration-resistant prostate cancer (CRPC). Although circular RNAs (circRNAs) have emerged as critical regulators in cancer biology, their involvement in PARPi resistance remains largely uncharacterized. This study aims to elucidate the molecular mechanism by which hsa_circ_0038737 modulates PARPi resistance in CRPC through post-transcriptional regulatory pathways. We employed a comprehensive set of in vitro and in vivo approaches, including qRT-PCR, RNA sequencing, RNA-protein pull-down, RNA immunoprecipitation, functional assays, and xenograft/organoid models, to investigate the biological function and mechanistic role of hsa_circ_0038737 in CRPC progression and therapeutic response. We identified hsa_circ_0038737 as a nuclear-enriched circRNA significantly upregulated in CRPC, with expression levels correlating with poor prognosis and aggressive clinical features. Mechanistically, hsa_circ_0038737 interacts with RNA-binding protein (RBP) IGF2BP3, enhancing the stability of DNPH1 mRNA, a nucleotide sanitizer critical for DNA repair. The circRNA-RBP-mRNA regulatory axis promotes PARPi resistance by facilitating DNA damage repair capacity. Moreover, we revealed that reverse-complementary Alu elements mediate circRNA biogenesis, with HNRNPDL facilitating this process. Pharmacologic inhibition of DNPH1 effectively restored PARPi sensitivity both in vitro and in vivo. Our findings reveal a novel hsa_circ_0038737/IGF2BP3/DNPH1 axis driving PARPi resistance in CRPC, offering promising potential biomarkers and therapeutic targets to overcome resistance and improve treatment outcomes in advanced prostate cancer.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"43 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}