Cancer Cell International最新文献

{"title":"NCAPD3 contributes to lung cancer progression through modulated lactate-induced histone lactylation and MEK/ERK/LDHA axis.","authors":"Zhibo Chang","doi":"10.1186/s12935-025-03814-x","DOIUrl":"10.1186/s12935-025-03814-x","url":null,"abstract":"<p><p>Lung cancer (LC) is one of the most common malignant tumors globally. Non-SMC condensin II complex subunit D3 (NCAPD3) has been involved in the progression of many kinds of tumors. However, the effects of NCAPD3 in LC remain unclear. NCAPD3 expression was investigated by the Ualcan database and using Western blot. The effect of NCAPD3 on prognosis was explored via the Kaplan-Meier plotter database. Cell viability, colony formation, apoptosis, and Transwell assays, and in vivo tumorigenesis were performed to reveal the biological roles of NCAPD3. Glycolysis was assessed via measurement of glucose consumption, extracellular acidification rate (ECAR), lactate production, and ATP levels. The deeper mechanisms of NCAPD3 were investigated by Western blot and rescue experiments. Upregulation of NCAPD3 levels in LC tissues was found in Ualcan and significantly associated with poor prognosis. The expression of NCAPD3 was up-regulated in LC cell lines compared to BEAS-2B cells. Knockdown and overexpression experiments suggested that proliferation, apoptosis, migration, invasion, and glycolysis were regulated by NCAPD3 via the MEK/ERK/LDHA pathway. Additionally, NCAPD3 knockdown inhibited tumor growth in vivo. Mechanistically, NCAPD3 overexpression-mediated activation of the MEK/ERK/LDHA pathway and proliferation, Glucose uptake, and glycolysis were attenuated by MEK inhibitor U0126. Also, histone lactylation helps in tumorigenesis by promoting NCAPD3 expression. Taken together, our results revealed that histone lactylation of NCAPD3 promoted proliferation, migration, invasion, and glycolysis through modulating the MEK/ERK/LDHA signaling pathway in LC, which highlights a novel understanding of NCAPD3 in LC.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"189"},"PeriodicalIF":5.3,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12102810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132066","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":"Emerging roles of non-coding RNA derived from extracellular vesicles in regulating PD-1/PD-L1 pathway: insights into cancer immunotherapy and clinical applications.","authors":"Haixia Zhang, Lianfeng Gong, Li Yu, Chenge Xian, Zhaowu Ma, Xianwang Wang, Ruohan Xia","doi":"10.1186/s12935-025-03809-8","DOIUrl":"10.1186/s12935-025-03809-8","url":null,"abstract":"<p><p>Numerous studies have demonstrated that extracellular vesicles (EVs) carry a variety of noncoding RNAs (ncRNAs), which can be taken up by neighboring cells or transported to distant sites via bodily fluids, thereby facilitating intercellular communication and regulating multiple cellular functions. Within the tumor microenvironment, EV-ncRNA, on the one hand, regulate the expression of PD-L1, thereby influencing tumor immune evasion, promoting tumor cell proliferation, and enhancing tumor growth, invasion, and metastasis in vivo. On the other hand, these specific EV-ncRNAs can also modulate the functions of immune cells (such as CD8 + T cells, macrophages, and NK cells) through various molecular mechanisms, inducing an immunosuppressive microenvironment and promoting resistance to anti-PD-1 therapy. Therefore, delving into the molecular mechanisms underlying EV-ncRNA regulation of immune checkpoints presents compelling therapeutic prospects for strategies that selectively target EV-ncRNAs. In this review, we elaborate on the cutting-edge research progress related to EV-ncRNAs in the context of cancer and dissect their pivotal roles in the PD-1/PD-L1 immune checkpoint pathway. We also highlight the promising clinical applications of EV-ncRNAs in anti-PD-1/PD-L1 immunotherapy, bridging basic research with practical clinical applications.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"188"},"PeriodicalIF":5.3,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12103061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132065","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":"Role of hesperidin/hesperetin against chemotherapy-induced cardiotoxicity: a systematic review of non-clinical studies.","authors":"Sina Shaernejad, Ali Nosrat, Maryam Baeeri, Nasser Hashemi Goradel, Mirsalim SeyedSadeghi, Mostafa Akbariani, AmirAhmad Arabzadeh, Mahban Rahimifard, Hamed Haghi-Aminjan","doi":"10.1186/s12935-025-03828-5","DOIUrl":"10.1186/s12935-025-03828-5","url":null,"abstract":"<p><p>Despite the undeniable role of chemotherapeutics in cancer treatment, their administration may be associated with various side effects. Cardiac injury is among the most crucial side effects related to the induction of chemotherapeutic agents. Since the heart is a vital organ, cardiotoxicity often prevents clinicians from continuing chemotherapy. Hesperidin and hesperetin, flavonoids derived from citrus fruits, possess several pharmaceutical properties. This study firstly explores the cardioprotective effects of hesperidin and hesperetin against chemotherapy-induced cardiotoxicity mechanisms, emphasizing their potential as adjunctive therapies. Key literature gaps are identified, and further mechanistic studies will be proposed. The findings underscore the translational potential of these flavonoids, advocating for rigorous preclinical optimization and clinical trials to validate their efficacy and safety. This review lays a foundation for integrating natural compounds into cardioprotective strategies in oncology. A systematic search was conducted in databases (PubMed, Scopus, ISI) until May 2025, according to PRISMA principles. The search terms were chosen according to our research objective and queried in the title and abstract. Following the screening of 82 papers, twelve articles were selected based on our inclusion and exclusion criteria. Based on the evaluated results, chemotherapy adversely affects cardiac tissue, leading to elevated risks of morbidity and mortality. Co-administration of hesperidin and hesperetin with chemotherapy prevents heart injury and preserves cardiac function, maintaining it almost like a normal heart. The protective role of hesperidin and hesperetin is based on their ability to fight free radicals, reduce inflammation, and stop cell death. Nonclinical investigations indicate that hesperidin and hesperetin ameliorate chemotherapy-induced cardiotoxicity. Nonetheless, they may influence the efficacy of anticancer medications, which primarily function by elevating oxidants, inflammation, and apoptosis. This indicates that meticulously designed trials are necessary to evaluate the efficacy and safety of this combination along with the synergistic potential of them in preventing chemotherapy-induced cardiotoxicity while maintaining anticancer effectiveness.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"186"},"PeriodicalIF":5.3,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12100833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126370","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":"N-phenylmaleimide induces bioenergetic switch and suppresses tumor growth in glioblastoma tumorspheres by inhibiting SLC25A11.","authors":"Hye Joung Cho, Jihwan Yoo, Ran Joo Choi, Jae-Seon Lee, Ryong Nam Kim, Junseong Park, Ju Hyung Moon, Eui Hyun Kim, Wan-Yee Teo, Jong Hee Chang, Soo-Youl Kim, Seok-Gu Kang","doi":"10.1186/s12935-025-03813-y","DOIUrl":"10.1186/s12935-025-03813-y","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma (GBM) is a highly resistant tumor, and targeting its bioenergetics could be a potential treatment strategy. GBM cells depend on cytosolic nicotinamide adenine dinucleotide (NADH), which is transported into the mitochondria via the malate-aspartate shuttle (MAS) for ATP production. N-phenylmaleimide (KN612) is a MAS inhibitor that targets SLC25A11, an antiporter protein of the MAS. Therefore, this study investigated the effects of KN612 in GBM treatment using in vitro and in vivo models.</p><p><strong>Methods: </strong>We examined the biological effects of KN612 in GBM tumorspheres (TSs), including its effects on cell viability, ATP level, cell cycle, stemness, invasive properties, energy metabolic pathways, and transcriptomes. Additionally, we investigated the in vivo efficacy of KN612 in a mouse orthotopic xenograft model.</p><p><strong>Results: </strong>Transcriptomic analysis showed that SLC25A11 mRNA expression was significantly higher in GBM TSs than in normal human astrocytes. Additionally, siRNA-mediated SLC25A11 knockdown and KN612-mediated MAS inhibition decreased the oxygen consumption rate, ATP levels, mitochondrial activity, and cell viability in GBM TSs and decreased the stemness and invasion ability of GBM cells. Moreover, gene ontology functional annotation indicated that KN612 treatment inhibited cell-cycle and mitotic processes. Furthermore, KN612 treatment reduced tumor size and prolonged survival in an orthotopic xenograft model.</p><p><strong>Conclusions: </strong>Targeting GBM bioenergetics using KN612 may represent a novel and effective approach for GBM treatment.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"184"},"PeriodicalIF":5.3,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126265","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":"FAM111B and FANCD2, a dual expression signature, defines a distinct phenotype of pancreatic cancer.","authors":"Fang Wei, Wanying Li, Ting Zhou, Lijuan Feng, Xianglin Yuan, Lihong Zhang","doi":"10.1186/s12935-025-03819-6","DOIUrl":"10.1186/s12935-025-03819-6","url":null,"abstract":"<p><strong>Background: </strong>Despite various treatment strategies, the incidence and mortality of pancreatic cancer (PC) are among the highest for malignant tumors. Furthermore, there is a lack of effective molecular typing and targeted therapy to treat PC subtypes.</p><p><strong>Methods: </strong>Multiplex immunofluorescence experiments were performed to explore the roles of FAM111B, FANCD2, KRAS and TP53 in human PC tissues. Kaplan-Meier survival curves were generated and a nomogram was prepared for prognostic prediction. Protein correlations were analyzed using human PC tissues and TCGA and GEO data. Pathways analysis, immunoanalysis, and drug susceptibility analysis were performed based on information in the TCGA database.</p><p><strong>Results: </strong>Our results indicate that expression of FAM111B and FANCD2 is correlated in human PC tissues and comprises a dual expression signature with predictive value for the prognosis of PC. Using information in public databases, we confirmed the oncogenic relevance of FAM111B and FANCD2 in PC and identified a positive correlation between FAM111B, FANCD2, TP53 and KRAS.FAM111B and FANCD2 jointly regulate ferroptosis, mitotic nuclear division, and nuclear division pathways. Both proteins were demonstrated to be positively correlated with markers of CD4 + Th2 cells and PD-L1 in the tumor microenvironment. Furthermore, drug sensitivity analysis suggested that patients with high FAM111B or FANCD2 expression were highly sensitive to chemotherapeutic and targeted drugs, indicating that these proteins may serve as predictors of treatment efficacy.</p><p><strong>Conclusion: </strong>Elevated dual expression of FAM111B and FANCD2 is indicative of poor prognosis, alters the immune microenvironment, and exhibits sensitivity to certain therapeutic agents. Consequently, the high FAM111B/FANCD2 expression subtype may represent a novel and distinct phenotype of PC.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"185"},"PeriodicalIF":5.3,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12101032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126907","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":"CCDC110 promotes the progression of hepatocellular carcinoma by activating the TGF-β/SMAD signaling pathway through targeted regulation of TGFBR1.","authors":"Hao Shen, Haifeng Li, Haodong Tang","doi":"10.1186/s12935-025-03803-0","DOIUrl":"10.1186/s12935-025-03803-0","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) is recognized for its high growth rate, high degree of invasiveness, and tendency to spread, leading to a significant number of deaths. In the course of studying the transcriptome of HCC tissues, the protein coiled-coil domain-containing 110 (CCDC110) was identified. By employing tandem mass tag (TMT) quantitative proteomics, this research identified transforming growth factor beta receptor 1 (TGFBR1) as a potential target influenced by CCDC110. The purpose of this study was to examine the role of CCDC110 in the growth and invasion of HCC and to identify new potential targets for the treatment of HCC.</p><p><strong>Methods: </strong>In vitro and in vivo experiments were conducted to investigate the role and mechanism of CCDC110 in promoting the malignant behaviors of hepatocellular carcinoma through the regulation of TGFBR1.</p><p><strong>Results: </strong>We determined that the mRNA and protein levels of CCDC110 are elevated in hepatocellular carcinoma tissues and cell lines, which is correlated with a worse patient prognosis. CCDC110 enhances the proliferation of hepatocellular carcinoma cells, reduces their apoptosis, and increases their migration and invasion capabilities. In the cytoplasm, CCDC110 interacts with TGFBR1, enhancing stability of TGFBR1, promoting proliferation, and reducing the apoptosis, migration, and invasion of hepatocellular carcinoma cells through TGFBR1 both in vivo and in vitro. The CCDC110-TGFBR1 axis stimulates EMT, thereby enhancing the malignant biological behavior of hepatocellular carcinoma by activating the TGF-β/SMAD signaling pathway. The protein levels of CCDC110/TGFBR1 in hepatocellular carcinoma tissues are highly expressed and positively correlated. A combined analysis of CCDC110 and TGFBR1 provides improved guidance for the prognosis of patients with hepatocellular carcinoma.</p><p><strong>Conclusion: </strong>CCDC110 is highly expressed in hepatocellular carcinoma tissues and cell lines, and the CCDC110-TGFBR1 axis facilitates EMT and the malignant biological behavior of hepatocellular carcinoma through the activation of the TGF-β/SMAD signaling pathway.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"183"},"PeriodicalIF":5.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12093845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109669","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 regulation of LRPs by miRNAs in cancer: influencing cancer characteristics and responses to treatment.","authors":"Lianyue Qu, Fan Wang, Yuxiang Wang, Zixuan Li","doi":"10.1186/s12935-025-03804-z","DOIUrl":"10.1186/s12935-025-03804-z","url":null,"abstract":"<p><p>The low-density lipoprotein receptor-related protein (LRP) family is a group of cell surface receptors that participate in a variety of biological processes, including lipid metabolism, Wnt signaling, and bone metabolism. miRNAs are small non-coding RNA molecules that regulate gene expression and play a role in many biological processes, including the occurrence and development of tumors. Accumulating evidence demonstrates that LRP members are modulated by miRNAs across multiple cancer types, influencing key oncogenic processes-including tumor cell proliferation, apoptosis suppression, extracellular matrix remodeling, cell adhesion, and angiogenesis. The LRPs, miRNAs, their upstream lncRNAs, and downstream signaling molecules often form complex signaling pathways to regulate the activity of tumor cells. However, the tissue-specific roles and mechanistic underpinnings of these pathways remain incompletely understood. When examining the emerging concept of the interaction between miRNAs and LRPs, we emphasize the significance of these complex regulatory layers in the initiation and progression of cancer. Collectively, these findings are critical for advancing our understanding of the role of the LRPs family in the occurrence and development of tumors, as well as for the development of new strategies for cancer treatment.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"182"},"PeriodicalIF":5.3,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12085831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092785","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":"FBXL18 promotes endometrial carcinoma progression via destabilizing DUSP16 and thus activating JNK signaling pathway.","authors":"Jie Pi, Yong Wang, Yuzi Zhao, Jing Yang","doi":"10.1186/s12935-025-03808-9","DOIUrl":"10.1186/s12935-025-03808-9","url":null,"abstract":"<p><strong>Objective: </strong>The therapeutic options for patients with advanced endometrial carcinoma (EC) were still limited and the prognosis remained unfavorable. F-box and leucine-rich repeat protein 18 (FBXL18), belonging to the F-box protein family, was frequently altered in human cancer, while its functional role and underlying mechanisms in EC were largely unexplored.</p><p><strong>Methods: </strong>The expression of FBXL18 in EC tissues and cells were explored using data mining strategies and further experiments. Multiple in vitro assays, including CCK-8, colony formation, wound healing, and Transwell invasion assays, were performed to assess the function of FBXL18 on cell proliferation, migration, and invasion. Bioinformatic analyses, western blot, qRT-PCR, Co-immunoprecipitation and ubiquitination assays were employed to identify the downstream pathway and direct substrate of FBXL18.</p><p><strong>Results: </strong>FBXL18 was highly expressed in EC tissues and cell lines, and EC patients with high FBXL18 expression had poor clinical outcome. Loss- and gain-of-function assays showed that silencing FBXL18 suppressed EC cell proliferation, migration, and invasion, while overexpressing FBXL18 caused the opposite effects. Mechanistically, FBXL18 could physically interacted with DUSP16, a dual specificity phosphatase, leading to its ubiquitination and degradation, and thus activating JNK signaling pathway. Upregulation of DUSP16 in EC cells alleviated FBXL18 overexpression-induced activation of JNK signaling pathway, and reversed FBXL18 overexpression-mediated enhanced cell capacities of proliferation, migration, and invasion.</p><p><strong>Conclusion: </strong>In summary, our study had showcased the elevated expression, prognostic prediction performance, and the malignant tumor-promoting role of FBXL18 in EC. The novel mechanisms underlying this phenotype are that FBXL18 promotes the ubiquitination and degradation of DUSP16, and thus activates JNK/c-JUN signaling to facilitate EC progression.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"180"},"PeriodicalIF":5.3,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12085810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092835","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":"OTUD3 inhibits breast cancer cell metastasis by regulating TGF-β pathway through deubiquitinating SMAD7.","authors":"Chenchen Geng, Ke Dong, Junhua An, Ziqian Liu, Qianqian Zhao, Yanrong Lv","doi":"10.1186/s12935-025-03822-x","DOIUrl":"10.1186/s12935-025-03822-x","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer (BRCA) is the most common malignant tumor in women, and distant metastasis is an important cause of death. Epithelial mesenchymal transition (EMT) is an important factor in tumor cell metastasis, in which TGF-β signaling pathway plays an important role. SMAD7 can inhibit TGF-β pathway. Previously, we found that ovarian tumor domain-containing protein 3(OTUD3) could maintain the stability of multiple molecules through deubiquitination. In this study, multiple experiments were conducted to verify whether OTUD3 can inhibit TGF-β pathway by deubiquitinating SMAD7.</p><p><strong>Methods: </strong>Firstly, bioinformatics was used to search the expression of OTUD3 in breast cancer and its correlation with SMAD7 in the TCGA database. The correlation between the protein and mRNA expression levels of OTUD3 and SMAD7 in multiple BRCA cell lines was verified. Also, the OTUD3 and SMAD7 expression in human BRCA samples and its influence on prognosis were verified by immunohistochemical experiments. Then, the CO-IP experiment was performed by transfecting OTUD3 and SMAD7 in HEK293T cells to confirm whether OTUD3 could maintain SMAD7 protein stability through deubiquitination. Furthermore, luciferase reporting assay, in vitro protein interaction, and transwell assay were used to verify whether OTUD3 could inhibit TGF-β pathway by deubiquitinating SMAD7 and affect cell invasion. Western blot and RT-qPCR were used to detect the correlation between OTUD3 and molecules regulated by the TGF-β pathway. Finally, the effect of OTUD3 on tumor cells was determined by 3D matrigel cell culture.</p><p><strong>Results: </strong>The expression of OTUD3 was low in BRCA and positively correlated with SMAD7. Cytological experiments and immunohistochemistry confirmed that OTUD3 was positively correlated with the expression of SMAD7, and the patients with a low expression of OTUD3 had a short recurrence-free survival (RFS). Cell experiments confirmed that OTUD3 could regulate the TGF-β pathway by deubiquitinating SMAD7, which affected EMT and inhibited cell invasion. OTUD3 was found to inhibit the stemness of tumor cells by 3D matrigel cell culture.</p><p><strong>Conclusions: </strong>Our findings indicated OTUD3 inhibited BRCA metastasis associated with TGF-β signaling by deubiquitination to stabilize SMAD7 protein levels.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"181"},"PeriodicalIF":5.3,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12085847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092854","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":"Fibrogenesis-driven tumor progression in clear cell renal cell carcinoma: prognostic, therapeutic implications and the dual role of neuropilin-1.","authors":"Kai Wang, Xihao Shen, Jiyue Wu, Qing Bi, Zihao Gao, Zejia Sun, Wei Wang","doi":"10.1186/s12935-025-03801-2","DOIUrl":"10.1186/s12935-025-03801-2","url":null,"abstract":"<p><strong>Background: </strong>Clear cell renal cell carcinoma (ccRCC) is the predominant subtype of renal cancer, with a poor prognosis driven by therapy resistance and a propensity for recurrence. Tumor microenvironment (TME)-associated fibrosis accelerates disease progression by fostering immune evasion. Neuropilin-1 (NRP1), a key mediator in fibrotic signaling and cancer biology, has been implicated in these processes. However, the genetic correlation between fibrogenesis and ccRCC remains largely unexplored, necessitating a focused analysis of fibrogenesis-related genes (FRGs) to identify novel prognostic markers and therapeutic strategies.</p><p><strong>Methods: </strong>This study utilized an integrative bioinformatics framework to identify prognosis-associated fibrogenesis-related genes (pFRGs) and applied non-negative matrix factorization (NMF) to stratify ccRCC patients based on fibrotic signatures. A machine learning-derived prognostic model was developed to categorize patients into high-risk and low-risk groups, with tumor microenvironment (TME) features analyzed across these subgroups. The pro-tumorigenic role of NRP1 via the TGF-β/SMAD signaling pathway was validated in vitro and in vivo.</p><p><strong>Results: </strong>Twelve pFRGs were identified, with elevated expression correlating with reduced survival. NMF revealed two ccRCC subtypes with different fibrotic and immune profiles. The high-fibrosis subtype showed worse survival and a pro-tumorigenic TME. The risk model demonstrated robust predictive performance (AUCs: 0.738, 0.731, 0.711 for 1-, 2-, and 3-year survival). High-risk patients, marked by immune dysfunction, exhibited worse survival but greater immunotherapy sensitivity. Among the pFRGs, NRP1 was upregulated in ccRCC, and paradoxically associated with favorable prognosis in TCGA, primarily due to stromal enrichment. In vitro and in vivo experiments confirmed that NRP1 promotes ccRCC proliferation, migration, and invasion by enhancing TGF-β/SMAD-driven epithelial-mesenchymal transition (EMT).</p><p><strong>Conclusion: </strong>Fibrosis is a critical driver of ccRCC progression, linking fibrogenesis-related genes to poor prognosis, immune suppression, and tumor aggressiveness. NRP1 was identified as a central regulator of fibrosis-induced tumor progression through the TGF-β/SMAD signaling pathway. Combining NRP1 inhibition with anti-fibrotic therapies presents a potential strategy for enhancing therapeutic outcomes in ccRCC.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"179"},"PeriodicalIF":5.3,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12082889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086083","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}