Cellular Oncology最新文献

{"title":"IRF1 suppresses gastric tumorigenesis via dual PI3K/AKT-ERK pathway modulation and functional antagonism of oncogenic MX2.","authors":"Wenjing Chen, Neng Lou, Xietao Chen, Xianjing Hu, Chenchen Mao, Jiaqi Yang, Jun Cheng, Chenbin Chen, Xiangyang Xue, Xian Shen","doi":"10.1007/s13402-025-01134-w","DOIUrl":"10.1007/s13402-025-01134-w","url":null,"abstract":"<p><p>BACKGROUND: Interferon regulatory factor 1 (IRF1) plays a crucial role in the type I interferon (IFN) response. However, its functional role and underlying mechanisms in gastric cancer (GC) remain unclear. This study aims to investigate the biological significance of IRF1 in GC progression and its potential as a therapeutic target. METHODS: IRF1 expression was analyzed using The Cancer Genome Atlas (TCGA) and GTEx databases, validated by immunohistochemistry (IHC) in 366 GC patients. Functional experiments, including CCK-8, Transwell migration and invasion assays, and apoptosis analysis, were conducted in GC cell lines with IRF1 overexpression or knockdown. A subcutaneous xenograft model was established to evaluate the in vivo effects of IRF1 on tumor growth. Co-immunoprecipitation and western blotting were performed to explore the molecular interactions between IRF1 and Myxovirus resistance 2 (MX2), as well as its regulation of the PI3K signaling pathway. RESULTS: IRF1 expression was significantly higher in gastric cancer tissues than in adjacent normal tissues. Higher IRF1 levels were also associated with improved patient survival. Overexpression of IRF1 inhibited GC cell proliferation, migration, and invasion while promoting apoptosis, whereas IRF1 knockdown had the opposite effects. Mechanistically, IRF1 suppressed PI3K/p-AKT signaling while enhancing p-ERK1/2 activation. Moreover, IRF1 directly interacted with MX2, a protein involved in epithelial-mesenchymal transition (EMT), and this interaction was essential for suppressing MX2-mediated oncogenic activity. In vivo experiments confirmed that IRF1 overexpression significantly reduced tumor growth and metastasis. CONCLUSIONS: IRF1 functions as a tumor suppressor in GC by modulating the PI3K signaling pathway and interacting with MX2 to inhibit EMT. These findings highlight IRF1 as a potential therapeutic target for GC treatment. </p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 1","pages":"24"},"PeriodicalIF":4.8,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12799679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958930","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":"Development of an APC and TP53-based duplex sequencing assay to positively predict colorectal cancer response to anti-EGFR therapy.","authors":"Mingli Yang, Michael J Schell, Jesse J Salk, Jake Higgins, Michael Hipp, Lance Pflieger, Warren Jack Pledger, Timothy J Yeatman","doi":"10.1007/s13402-025-01140-y","DOIUrl":"10.1007/s13402-025-01140-y","url":null,"abstract":"<p><strong>Purpose: </strong>EGFR inhibitor (EGFRi) therapies have been FDA-approved for metastatic colorectal cancer (CRC). However, extended RAS/RAF testing required in the drug labels, identifies only non-responders, and only ~50% of selected patients respond to therapy, suggesting an unmet need to develop additional biomarkers.</p><p><strong>Methods: </strong>We previously reported combined mutations in APC and TP53 as a potential positive biomarker to identify EGFRi-sensitive patients. By leveraging the TwinStrand Duplex Sequencing (DS) technology, this study developed an ultrasensitive 6-gene panel DS assay that adds a positive filter for APC(A) and TP53(P) mutations in addition to the negative KRAS(K), BRAF(B), and NRAS(N) mutation filters for EGFRi therapy.</p><p><strong>Results: </strong>The 6-gene DS assay was analytically validated using reference cell lines (n = 9, individually sequenced to > 3,000x Duplex depth). The assay yielded exceptionally high assay performance on (1) accuracy, (2) sensitivity, (3) specificity and (4) precision. Application to fresh frozen (FF):FFPE paired tissues from 21 CRC patients demonstrates that the ultrasensitive DS assay can accurately detect additional \"new\" mutations at low allelic frequencies compared to a standard NGS method (13 of the 17 new mutations had < 10% VAF) that may ultimately be responsible for drug resistance. Furthermore, Kaplan-Meier analysis on Duplex-sequenced EGFRi FFPE samples showed that the third-line metastatic CRC patients harboring combined APC and TP53 mutations (AP/APK(N) versus others) tended to have longer TOT (6.65 versus 3.60 months, p = 0.048, n = 29).</p><p><strong>Conclusion: </strong>These data suggest the potential of the 6-gene Duplex Sequencing assay to improve EGFRi patient selection and therapeutic outcomes.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 1","pages":"23"},"PeriodicalIF":4.8,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12799675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958864","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":"The epigenetic regulator SETDB1 as a key component of cancer stem cells and drug resistance in primary liver cancer.","authors":"Maël Padelli, Christophe Desterke, Aurore Devocelle, Georges Uzan, Antoinette Lemoine, Julien Giron-Michel","doi":"10.1007/s13402-025-01157-3","DOIUrl":"10.1007/s13402-025-01157-3","url":null,"abstract":"<p><p>BACKGROUND: Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with a poor prognosis and limited response to current therapies. Cancer stem cells (CSCs) contribute to this heterogeneity, driving tumor progression, immune evasion, and therapeutic resistance. Epigenetic regulators have emerged as pivotal modulators of CSC phenotypes. The histone methyltransferase SETDB1, a key stemness factor in both embryonic and adult stem cells, catalyzes H3K9 trimethylation (H3K9me3) and acts as a major oncogenic driver in a wide range of solid and hematological malignancies. Yet, its specific role in maintaining stemness and contributing to therapeutic resistance in HCC remains poorly defined. METHODS: Integrative analyses of bulk and single-cell transcriptomic datasets from public HCC cohorts were performed. Tumors were stratified by SETDB1 expression, followed by pathway enrichment, immune deconvolution, and stemness scoring. Associations with clinical outcomes, immune phenotypes, drug resistance signatures, and chromatin-binding partners (DNMT3A, TRIM28, HDAC1) were also explored. The role of SETDB1 was then examined in vitro, where a stem-like phenotype was induced in HCC cell lines under hypoxic conditions, and patterns of SETDB1 expression and stemness marker levels were assessed following paclitaxel treatment. RESULTS: SETDB1-low tumors were enriched in well-differentiated, immunologically active subclasses and were associated with increased predicted responsiveness to immune checkpoint blockade (ICB), sorafenib, and transarterial chemoembolization. Conversely, SETDB1-high tumors exhibited transcriptional features of dedifferentiation, elevated stemness scores, and enrichment in aggressive molecular subtypes. These tumors also displayed higher TP53 mutation rates, reduced immune infiltration, immune exclusion signatures, and activation of pathways linked to ferroptosis and ABC transporter dysfunction, consistent with resistance to ICB and conventional therapies. SETDB1 expression was also associated with hypoxia-related pathways, suggesting a role in maintaining CSC niches. In vitro, hypoxia-induced stemness coincided with increased SETDB1 levels, whereas paclitaxel treatment decreased both SETDB1 expression and stemness markers. A chromatin risk score incorporating SETDB1 and its partners predicted poor disease-free survival independently of clinical parameters. CONCLUSIONS: SETDB1 defines a stemness-enriched, immune-resistant HCC subtype associated with poor outcomes and therapeutic failure. Correlations between SETDB1 expression and stem-like features in vitro suggest a potential role in maintaining CSC phenotypes, supporting its relevance as a biomarker and candidate for epigenetic- and CSC-directed therapeutic strategies. </p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 1","pages":"18"},"PeriodicalIF":4.8,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12775003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145910634","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":"Optimized patient-derived lung cancer organoids recapitulating the immune landscape for precision therapy evaluation.","authors":"Huayang Xing, Rui Liu, Yidan Chen, Xueqin Chen, Xianzhi Gao, Chongyang Shen, Shirong Zhang, Yi Tang, Longfeng Wu, Mingliang You, Pinglong Xu, Bing Xia","doi":"10.1007/s13402-025-01158-2","DOIUrl":"10.1007/s13402-025-01158-2","url":null,"abstract":"<p><p>PURPOSE: Current lung cancer organoid models often fail to replicate the complex tumor immune microenvironment, reducing their predictive value for immunotherapy and radiotherapy. Therefore, it is crucial to establish an optimized lung cancer organoid model which could recapitulate the tumor immune microenvironment, enabling more accurate evaluation of therapeutic responses. METHODS: We developed an optimized air-liquid interface (ALI) culture method to generate patient-derived lung cancer organoids (ALI-LUOs) from 19 lung cancer samples. The tumor microenvironment, including immune and stromal components, was characterized using immunofluorescence, flow cytometry, and single-cell RNA sequencing. The organoids were further used to assess responses to αPD-1 therapy and radiotherapy. RESULTS: The optimized method significantly improved organoid formation efficiency while preserving immune cell viability for up to 30 days. Immune and fibroblast populations were confirmed by immunofluorescence and flow cytometry. Single-cell RNA sequencing demonstrated that ALI-LUOs accurately replicate the tumor immune landscape. Key tumor immunity pathways such as cGAS-STING could be captured by ALI-LUOs. Importantly, ALI-LUOs modeled clinical responses to immune checkpoint inhibitors and radiotherapy with high fidelity. CONCLUSIONS: The ALI-LUOs, developed through an optimized culture method, faithfully capture the key characteristics of lung cancer, including its immunosuppressive tumor microenvironment. Our findings highlight this modified ALI-LUOs as a valuable preclinical platform for evaluating antitumor immunity and refining lung cancer treatments. </p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 1","pages":"15"},"PeriodicalIF":4.8,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12775054/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145910560","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":"STT3A-mediated FCN3 N-glycosylation promotes Treg cell activation to drive hepatocellular carcinoma progression via Wnt/β-catenin.","authors":"Hongli Zhang, Peng Zhang, Tian Gong, Chengsheng Zhang, Zhijian Wang, Yong Zhao","doi":"10.1007/s13402-025-01159-1","DOIUrl":"10.1007/s13402-025-01159-1","url":null,"abstract":"<p><p>BACKGROUND: Hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality worldwide. While regulatory T (Treg) cells are known to contribute to HCC progression, the molecular mechanisms regulating their activation, particularly those involving post-translational modifications, remain poorly understood. METHODS: This study employed a comprehensive approach combining clinical sample analysis, in vitro cell models (HepG2, Hep3B, HCC-LM3) and in vivo xenograft experiments. Genetic manipulation involved lentiviral-mediated knockdown or overexpression of FCN3 and STT3A. Techniques included immunofluorescence, co-immunoprecipitation, glycosylation validation, CCK-8, wound healing, Transwell and flow cytometry. RESULTS: Clinical data revealed significant downregulation of FCN3 in HCC tissues, correlating with poor patient survival. Mechanistically, FCN3 suppressed Treg activation and HCC progression by inhibiting Wnt/β-catenin signaling through APC upregulation. However, the glycosyltransferase STT3A mediated N-glycosylation of FCN3 at Asn189, thereby disrupting the tumor-suppressive function of FCN3 in HCC. In mouse models, STT3A knockdown reduced tumor growth and decreased Treg infiltration. Additionally, the Treg cell-depleting agent diphtheria toxin could reverse the promoting effect of STT3A overexpression on HCC tumor growth. CONCLUSION: This research unveiled a novel STT3A-FCN3-β-catenin axis that drove HCC progression through glycosylation-dependent Treg activation. These findings provided new insights into immune evasion mechanisms and highlighted potential therapeutic opportunities for HCC. </p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 1","pages":"16"},"PeriodicalIF":4.8,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12774965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145910501","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":"Correction to: Regulation of AUF1 alternative splicing by hnRNPA1 and SRSF2 modulate the sensitivity of ovarian cancer cells to cisplatin.","authors":"Jia-Mei Wang, Ning Liu, Xue-Jing Wei, Fu-Ying Zhao, Chao Li, Hua-Qin Wang, Chuan Liu","doi":"10.1007/s13402-025-01156-4","DOIUrl":"10.1007/s13402-025-01156-4","url":null,"abstract":"","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 1","pages":"17"},"PeriodicalIF":4.8,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12775065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145910481","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":"ACTG1 promotes breast cancer aggressiveness and confers ribociclib resistance by deubiquitinating HSPA8 through UCHL3.","authors":"Quhui Wang, Xiancheng Liu, Xiaobing Yang, Zhixian He, Yangfeng Chen","doi":"10.1007/s13402-025-01144-8","DOIUrl":"10.1007/s13402-025-01144-8","url":null,"abstract":"<p><p>In this study, we examined the biological significance of the actin gamma 1 (ACTG1)-UCHL3–HSPA8 axis in breast cancer. Through bioinformatic analysis, we recognized ACTG1 as a potential oncogenic factor in BRCA. By exploiting qRT-qPCR and Western blot analysis, we assessed the expression of ACTG1 and explored its impact on cellular proliferation, migration, and invasion. Our findings suggest that ACTG1 exerts its oncogenic effects in breast cancer cells through the EMT signaling pathway. By mining the BIOGRID database, we identified potential downstream regulatory genes; and co-immunoprecipitation assays confirmed protein interactions between ACTG1 and HSPA8. We also observed that ACTG1 promoted breast cancer cell proliferation, invasion, and migration via its interaction with HSPA8. Importantly, our study elucidated the facilitation by UCHL3 of HSPA8 deubiquitination by ACTG1. In conclusion, our study revealed a key role played by the ACTG1–UCHL3–HSPA8 axis in driving breast cancer progression as well as the role of ribociclib resistance. Our findings provide compelling evidence for the therapeutic potential of targeting this axis in breast cancer treatment strategies.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 1","pages":"14"},"PeriodicalIF":4.8,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12769674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145905778","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":"Multi-omics profiling reveals that Scissor⁺ epithelial cells regulate intrahepatic metastasis of HCC via remodeling the metastatic microenvironment.","authors":"Wenlong Zhu, Chang Fan, Jiali Yao, Linlin Ji, Yihai Shi, Jin Ding, Yugang Zhuang, Li Wang","doi":"10.1007/s13402-025-01147-5","DOIUrl":"10.1007/s13402-025-01147-5","url":null,"abstract":"<p><p>PURPOSE: Malignancy epithelial cells exhibit considerable heterogeneity in HCC. However, the mechanism of malignant epithelial cells in the early intrahepatic metastasis (IM) remains elusive. Our aim was to identify the specific malignant epithelial cells and uncover the underlying mechanism contributing to the HCC IM. METHODS: Multi-omics were utilized to perform a comprehensive analysis of HCC IM. The heterogeneity of malignant epithelial cells was elucidated through multiply analyses, including Ro/e, Slingshot and Monocle 3 pseudotime analyses. Next, “Scissor” was employed to identify malignant epithelial cell (Scissor+ epithelial cell). Furthermore, “MIME” was used to establish an IM-associated prognostic signature for calculating Scissor+ related epithelial score (SRES). Moreover, “CellChat” and “NicheNet” were utilized to identify significant crosstalk between Scissor+ epithelial cells and various immunosuppressive cells. Finally, Multiplex immunohistochemistry (mIHC), Western blotting and Transwell migration assays were conducted for validation. RESULTS: The heterogeneity landscape of malignant epithelial cells in HCC IM has been identified. Combined with Scissor+ epithelial cells were enriched in C3, C3 was defined as a high-risk epithelial cluster for metastasis. Notably, EMT-related genes were elevated in Scissor+ epithelial cells, indicating these cells facilitate HCC IM. Then, six critical high-risk metastasis genes exhibiting higher expression in Scissor+ epithelial cells were utilized for calculating SRES for HCC patients. HCC patients with higher SRES exhibited significantly unfavourable clinical outcomes compared to those with lower SRES. Meanwhile, our signature exhibited a marked superiority over 39 previously published signatures. Interestingly, Scissor+ epithelial cells can remodel the metastatic microenvironment by recruiting CD4+ Treg via CCL20–CCR6 and enriching BCAM+ Cancer-associated fibroblasts (CAFs) through MDK-SDC2 and MDK-NCL. The spatial position of above cells was revealed by mIHC to validate the potential of crosstalk. Finally, Scissor+ epithelial cells can recruit more normal fibroblasts and convert them to BCAM+ CAF via MDK-SDC2 and MDK-NCL. CONCLUSION: Scissor+ epithelial cells were defined as malignant epithelial cells, which facilitate HCC IM and deteriorate the tumor microenvironment (TME). Then, SRES was established to predict the prognosis of HCC patients. Finally, the mechanisms of Scissor+ epithelial cells in remodeling the TME have been further elucidated. </p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 1","pages":"12"},"PeriodicalIF":4.8,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12769604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145905694","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":"CDK12 and CDK13 in oncology: from RNA regulation to therapeutic targeting.","authors":"Julia Dudkiewicz-Garbicz, Paweł K Włodarski","doi":"10.1007/s13402-025-01131-z","DOIUrl":"10.1007/s13402-025-01131-z","url":null,"abstract":"<p><p>This review aims to synthesize current knowledge on Cyclin-dependent kinase 12 (CDK12) and Cyclin-dependent kinase 13 (CDK13), two transcriptional kinases with distinct and overlapping roles in gene regulation, genome stability, and cancer biology. These kinases control transcription elongation and co-transcriptional processing, including splicing and polyadenylation, thereby linking RNA polymerase II activity with DNA repair and replication stress response. CDK12 and CDK13 play context-specific roles across malignancies, where amplification, truncating mutations, fusions, and deletions variably alter their transcriptional output and downstream DNA repair programs. Their dysregulation contributes to oncogenesis, metastasis, and resistance to conventional therapies. There is growing therapeutic interest in CDK12/13 inhibition, especially as selective inhibitors of single DNA repair nodes have shown limited success. Selective CDK12/13-targeting agents have shown efficacy in preclinical models by inducing synthetic lethality, restoring sensitivity to PARP inhibitors, and are being explored to potentiate immune checkpoint blockade. This review highlights the biological rationale for targeting CDK12 and CDK13 in cancer, summarizes emerging therapeutic strategies, and identifies key opportunities for integrating these approaches into precision oncology.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 1","pages":"13"},"PeriodicalIF":4.8,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12769584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145905751","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":"SERPINA1 drives TACE resistance in hepatocellular carcinoma by competitively binding ITGB3 to block ITCH-mediated ubiquitination and degradation.","authors":"Liou Zhang, Xiaoxi Bai, Mingyang Du, Wenyue Dou, Ziwen Xie, Jie Liu, Yang Hou","doi":"10.1007/s13402-025-01155-5","DOIUrl":"10.1007/s13402-025-01155-5","url":null,"abstract":"<p><p>PURPOSE: Transarterial chemoembolization (TACE) is the first-line treatment for intermediate-to-advanced hepatocellular carcinoma (HCC), but post-TACE resistance remains a major clinical challenge. While SERPINA1, a serine protease inhibitor involved in tumor microenvironment regulation, is dysregulated in various cancers, its role in TACE resistance is unclear. This study investigates SERPINA1’s functional and mechanistic involvement in HCC resistance to TACE. METHODS: Serum SERPINA1 levels were measured by ELISA in TACE-treated HCC patients. Functional assays under hypoxic/chemotherapeutic conditions and xenograft models assessed tumor progression. Mechanistic studies integrated qRT-PCR, Western blot, co-immunoprecipitation (Co-IP), GST pull-down, molecular docking, and mass spectrometry to elucidate the SERPINA1-ITGB3 interaction. RESULTS: Elevated post-TACE serum SERPINA1 levels were significantly associated with poor treatment response and poor prognosis (P < 0.05). Functional experiments demonstrated that SERPINA1 promoted HCC cell proliferation, migration, and invasion under hypoxic and chemotherapeutic stress, while xenograft models confirmed its tumorigenic role. Mechanistically, SERPINA1 competitively bound to the EGF-like 2/3 domains of ITGB3 via its C-terminal region (amino acids 320–392), thereby shielding ITGB3 from ITCH-mediated polyubiquitination and proteasomal degradation, which consequently sustained oncogenic signaling pathways. CONCLUSION: Our study identifies the SERPINA1-ITGB3 axis as a critical mediator of TACE resistance in HCC, providing a promising therapeutic target to enhance clinical outcomes. </p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 1","pages":"11"},"PeriodicalIF":4.8,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12753576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145854657","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}