Cancer Biology & Therapy最新文献

{"title":"Fractionated radiotherapy initiated at the early stage of bone metastasis is effective to prolong survival in mouse model.","authors":"Yun Zhang, Zhunyi Gao, Ziwei Qi, Jiahe Xu, Jiao Xue, Lujie Xiong, Junhui Wang, Yuhui Huang, Songbing Qin","doi":"10.1080/15384047.2025.2455756","DOIUrl":"https://doi.org/10.1080/15384047.2025.2455756","url":null,"abstract":"<p><strong>Background and purpose: </strong>Bone metastasis is common for breast cancer and associated with poor prognosis. Currently, radiotherapy (RT) serves as the standard treatment for patients exhibiting symptoms of bone metastasis to alleviate pain. Whether earlier application of RT will better control bone metastasis remains unclear.</p><p><strong>Methods: </strong>We utilized a mouse model of breast cancer bone metastasis by intra-femoral injection of 4T1-luc breast tumor cells. The bone metastasis was treated by RT using various doses, timings, and modalities. Tumor growth was assessed through bioluminescence imaging, and lung metastases was quantified following lung tissue fixation. Flow cytometry was employed to analyze alterations in immune cell populations.</p><p><strong>Results: </strong>Single high-dose RT suppressed tumor growth of bone metastases, but caused severe side effects. Conversely, fractionated RT mitigated tumor growth in bone metastases with fewer adverse effects. Fractioned RT initiated at the early stage of bone metastasis effectively inhibited tumor growth in the bone, suppressed secondary lung metastases, and prolonged mouse survival. In line with the known pro- and anti-metastatic effects of neutrophils and T cells in breast cancer, respectively, earlier fractioned RT consistently decreased the proportions of neutrophils while increased the proportions of T cells in both the bone and the lung tissues.</p><p><strong>Conclusion: </strong>The data suggest that fractionated RT can inhibit the progression of early stage of bone metastasis and reduce secondary lung metastasis, leading to favorable outcomes. Therefore, these findings provide preclinical evidence to support the application of fractionated RT to treat patients with bone metastasis as earlier as possible.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"26 1","pages":"2455756"},"PeriodicalIF":4.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Daurisoline inhibits glycolysis of lung cancer by targeting the AKT-HK2 axis.","authors":"Shi-Ming Tan, Lan Luo, Yi-Fu He, Wei Li, Xin-Xing Wan","doi":"10.1080/15384047.2024.2442556","DOIUrl":"10.1080/15384047.2024.2442556","url":null,"abstract":"<p><p>Lung cancer, one of the most prevalent tumors, remains a clinical challenge with a poor five-year survival rate. Daurisoline, a bis-benzylisoquinoline alkaloid derived from the traditional Chinese herb Menispermum dauricum, is known to suppress tumor growth effectively. However, its precise mechanism of action remains unclear. In this study, we demonstrate that Daurisoline targets glycolysis and reduces the protein level of HK2, thereby inhibiting lung cancer progression. Mechanistic investigations reveal that Daurisoline directly binds to AKT and antagonizes the AKT-GSK3β-c-Myc-HK2 signaling axis. Furthermore, in an animal model, we validate the in vivo anti-tumor effect of Daurisoline without any observable side effects. Overall, our findings suggest that Daurisoline holds potential as an anti-tumor agent through its targeting of glycolysis.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"26 1","pages":"2442556"},"PeriodicalIF":4.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11660295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term effects of neoadjuvant chemotherapy in variant histology locally advanced colon cancer: a propensity score-matched analysis.","authors":"Qiancheng Wang, Shiyang Jin, Zeshen Wang, Yuming Ju, Kuan Wang","doi":"10.1080/15384047.2024.2441511","DOIUrl":"https://doi.org/10.1080/15384047.2024.2441511","url":null,"abstract":"<p><strong>Purpose: </strong>Neoadjuvant chemotherapy (NAC) has proven valuable in treating locally advanced colon cancer (LACC) and is included as a treatment option for patients with clinical T4b colon cancer by the National Comprehensive Cancer Network. However, the long-term survival benefit of NAC in LACC remains debated, due to a lack of conclusive clinical trial results identifying the patients who would benefit most from NAC. This study aimed to assess the efficacy of NAC in patients with LACC based on histological subtype.</p><p><strong>Patients and methods: </strong>This retrospective study analyzed 3,709 patients with LACC who underwent curative resection at Harbin Medical University Cancer Hospital between 2014 and 2018. Patients were grouped into two groups: neoadjuvant chemotherapy (NAC) and adjuvant chemotherapy (AC) groups. Propensity score matching (PSM) was used to adjust for confounders, and survival outcomes of the two groups across different histological subtypes were evaluated using Kaplan-Meier (K-M) curves and log-rank tests.</p><p><strong>Results: </strong>Patients with non-mucinous adenocarcinoma (NMAC) treated with NAC had a significantly improved 5-year OS rate (76.3% vs. 69.2%, <i>p</i> = .039) and DFS rate (67.2% vs. 60.1%, <i>p</i> = .041) compared with patients treated with AC. However, there was no significant difference in OS and DFS between the two treatment groups among patients with mucinous adenocarcinoma (MAC) and signet ring cell carcinoma (SRCC).</p><p><strong>Conclusion: </strong>In patients with LACC, the prognostic value of NAC varied by histology. NMAC may serve as a predictor of improved long-term survival benefit from NAC in these patients.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"26 1","pages":"2441511"},"PeriodicalIF":4.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sigma1 inhibitor suppression of adaptive immune resistance mechanisms mediated by cancer cell derived extracellular vesicles.","authors":"Paola A Castagnino, Derick A Haas, Luca Musante, Nathalia A Tancler, Bach V Tran, Rhonda Kean, Alexandra R Steck, Luis A Martinez, Elahe A Mostaghel, D Craig Hooper, Felix J Kim","doi":"10.1080/15384047.2025.2455722","DOIUrl":"10.1080/15384047.2025.2455722","url":null,"abstract":"<p><p>Adaptive immune resistance in cancer describes the various mechanisms by which tumors adapt to evade anti-tumor immune responses. IFN-γ induction of programmed death-ligand 1 (PD-L1) was the first defined and validated adaptive immune resistance mechanism. The endoplasmic reticulum (ER) is central to adaptive immune resistance as immune modulatory secreted and integral membrane proteins are dependent on ER. Sigma1 is a unique ligand-regulated integral membrane scaffolding protein enriched in the ER of cancer cells. PD-L1 is an integral membrane glycoprotein that is translated into the ER and processed through the cellular secretory pathway. At the cell surface, PD-L1 is an immune checkpoint molecule that binds PD-1 on activated T-cells and blocks anti-tumor immunity. PD-L1 can also be incorporated into cancer cell-derived extracellular vesicles (EVs), and EV-associated PD-L1 can inactivate T-cells within the tumor microenvironment. Here, we demonstrate that a selective small molecule inhibitor of Sigma1 can block IFN-γ mediated adaptive immune resistance in part by altering the incorporation of PD-L1 into cancer cell-derived EVs. Sigma1 inhibition blocked post-translational maturation of PD-L1 downstream of IFN-γ/STAT1 signaling. Subsequently, EVs released in response to IFN-γ stimulation were significantly less potent suppressors of T-cell activation. These results suggest that by reducing tumor derived immune suppressive EVs, Sigma1 inhibition may promote antitumor immunity. Sigma1 modulation presents a novel approach to regulating the tumor immune microenvironment by altering the content and production of EVs. Altogether, these data support the notion that Sigma1 may play a role in adaptive immune resistance in the tumor microenvironment.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"26 1","pages":"2455722"},"PeriodicalIF":4.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11776462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"β-amino acid substitution in the SIINFEKL antigen alters immunological recognition.","authors":"Ichwaku Rastogi, John A Mannone, Ruslan Gibadullin, Jena E Moseman, John Sidney, Alessandro Sette, Douglas G McNeel, Samuel H Gellman","doi":"10.1080/15384047.2025.2486141","DOIUrl":"https://doi.org/10.1080/15384047.2025.2486141","url":null,"abstract":"<p><strong>Background: </strong>Peptide vaccines offer a direct way to initiate an immunogenic response to a defined antigen epitope. However, peptide vaccines are unstable <i>in vivo</i>, subject to rapid enzymatic proteolysis. Replacement of an α-amino acid residue with a homologous β-amino acid residue (native side chain, but backbone extended by a single CH₂ unit) impairs proteolysis at nearby amide bonds. Therefore, antigen analogues containing α-to-β replacements have been examined for functional mimicry of native all-α antigens. Another group previously took this approach in the ovalbumin (OVA) antigen model by evaluating single α-to-β analogues of the murine major histocompatibility complex (MHC) I-restricted peptide SIINFEKL.</p><p><strong>Methods: </strong>We re-examined this set of α/β SIINFEKL antigens. We tested the susceptibility to proteolysis in mouse serum and their ability to activate OVA-antigen-specific CD8 T cells <i>in vitro</i>. Additionally, we tested the α/β antigens <i>in vivo</i> for their ability to induce an antigen-specific immunogenic response in naïve mice and in OVA-expressing tumor-bearing mice.</p><p><strong>Results: </strong>The α/β antigens were comparable to the native antigen in their susceptibility to proteolysis in serum. Each α/β antigen was capable of activating antigen-specific CD8 T cells <i>in</i> <i>vitro</i>. However, antigen-specific CD8 T cells induced against α/β antigens <i>in</i> <i>vivo</i> were not cross-reactive to the native antigen. Moreover, immunization with α/β analogues did not elicit anti-tumor effects in tumor-bearing mice.</p><p><strong>Conclusions: </strong>We conclude that even though α/β analogues of the SIINFEKL antigen can elicit a T cell-based response, this class of backbone-modified peptides is not promising from the perspective of antitumor vaccine development.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"26 1","pages":"2486141"},"PeriodicalIF":4.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of extracellular vesicle ZNF280B derived from lung cancer stem cells on lung cancer progression.","authors":"Qixia Guo, Jiayan Lu, Hui Zhao, Ding Zhou, Hua Liu","doi":"10.1080/15384047.2025.2450849","DOIUrl":"https://doi.org/10.1080/15384047.2025.2450849","url":null,"abstract":"<p><strong>Objective: </strong>The purpose of this research was to investigate the role of extracellular vesicles derived from lung cancer stem cells (lung CSCs-EVs) in lung cancer and to explore their potential mechanisms.</p><p><strong>Methods: </strong>Lung CSCs were first isolated and verified using flow cytometry and RT-qPCR assays. Lung CSCs-EVs were extracted through ultracentrifugation and further characterized using transmission electron microscopy and Western blotting. The interaction between lung CSCs-EVs and lung cancer cells was observed through PKH67 staining. Subsequently, we analyzed the differentially expressed genes in lung CSCs using bioinformatics data analysis and evaluated the prognostic value of ZNF280B in lung cancer with the Kaplan-Meier Plotter. RT-qPCR was utilized to assess the mRNA expression levels of these genes, while Western blotting was used to evaluate the protein expression levels of ZNF280B and P53. Next, CCK-8 and colony formation assays were conducted to assess the effects of lung CSCs-EVs and ZNF280B on cancer cell proliferation, migration (via wound healing assay), and invasion (using transwell assay). Additionally, subcutaneous tumor-bearing experiments in nude mice were performed to evaluate the roles of lung CSCs-EVs in lung cancer progression <i>in vivo</i>.</p><p><strong>Results: </strong>The results indicated that lung CSCs-EVs accelerated the progression of lung cancer. Mechanistically, these lung CSCs-EVs transferred ZNF280B into cancer cells, leading to the inhibition of P53 expression.</p><p><strong>Conclusions: </strong>In summary, the manuscript first describes the molecular mechanism by which lung CSCs-EVs promote pro-cancer functions in lung cancer through the ZNF280B/P53 axis.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"26 1","pages":"2450849"},"PeriodicalIF":4.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MGAT4EP promotes tumor progression and serves as a prognostic marker for breast cancer.","authors":"Lin Zhong, Jianfeng Zhu, Jie Chen, Xuchu Jin, Liangquan Liu, Shufeng Ji, Jing Luo, Hong Wang","doi":"10.1080/15384047.2025.2475604","DOIUrl":"10.1080/15384047.2025.2475604","url":null,"abstract":"<p><p>Breast cancer remains a global health challenge with varied prognoses despite treatment advancements. Therefore, this study explores the pseudogene MGAT4EP as a potential biomarker and therapeutic target in breast cancer. Using TCGA data and bioinformatics, MGAT4EP was identified as significantly overexpressed in breast cancer tissues and associated with poor prognosis. Multivariate Cox regression confirmed MGAT4EP as important prognostic factor. A clinical prediction model based on MGAT4EP expression showed high accuracy for 1-, 3-, and 5-year survival rates and was translated into a nomogram for clinical application. Functional studies revealed that silencing MGAT4EP <i>via</i> siRNA promoted apoptosis, inhibited migration and invasion in breast cancer cells. RNA-seq, GSEA, and GO analyses linked MGAT4EP to apoptosis and focal adhesion pathways. Notably, knock down of MGAT4EP significantly suppressed tumor growth and metastasis in xenograft and lung metastasis models. Taken together, these findings establish MGAT4EP as an attractive target for metastatic breast cancer and provide a potential a promising therapeutic target for breast cancer treatment.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"26 1","pages":"2475604"},"PeriodicalIF":4.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11901376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NVP-2, in combination with Orlistat, represents a promising therapeutic strategy for acute myeloid leukemia.","authors":"Qing Zhu, Jia Cheng, Yuqing Gao, Zimu Zhang, Jian Pan, Xin Su, Danhong Fei, Linbo Cai, Juanjuan Yu, Yanling Chen, Wanyan Jiao, Di Wu, Xiaolu Li, Peifang Xiao","doi":"10.1080/15384047.2025.2450859","DOIUrl":"10.1080/15384047.2025.2450859","url":null,"abstract":"<p><p>Cell cycle dysregulation and the corresponding metabolic reprogramming play significant roles in tumor development and progression. CDK9, a kinase that regulates gene transcription and cell cycle, also induces oncogene transcription and abnormal cell cycle in AML cells. The function of CDK9 for gene regulation in AML cells requires further exploration. In this study, we knocked down the CDK9 to investigate its effects on the growth and survival of AML cells. Through RNA-seq analysis, we identified that in U937 cells CDK9 regulates numerous genes involved in proliferation and apoptosis, including mTOR, SREBF1, and Bcl-2. Furthermore, our results demonstrated that both CDK9 and FASN are crucial for the proliferation and survival of Kasumi-1 and U937 cells. Mechanistically, MCL1, c-Myc, and Akt/mTOR/SREBF1 may be critical factors and pathways in the combined therapy of NVP-2 and Orlistat. In summary, our study revealed that CDK9 and FASN are vital for maintaining AML cell survival and proliferation. Treatment with NVP-2 and Orlistat may be a promising clinical candidate for patients with AML.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"26 1","pages":"2450859"},"PeriodicalIF":4.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730633/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sulfatase 2 inhibition sensitizes triple-negative breast cancer cells to paclitaxel through augmentation of extracellular ATP.","authors":"Jasmine M Manouchehri, Jharna Datta, Lynn M Marcho, Daniel Stover, Ramesh K Ganju, Bhuvaneswari Ramaswamy, William E Carson, Arjun Mittra, Xiaoli Zhang, Patrick M Schnell, Yu Yue, Mark P Rubinstein, Mathew A Cherian","doi":"10.1080/15384047.2025.2483989","DOIUrl":"10.1080/15384047.2025.2483989","url":null,"abstract":"<p><p>The highest incidence and cancer-related mortality rate among women worldwide is due to breast cancer. Triple-negative breast cancers (TNBC) are associated with more inferior outcomes than other breast cancers because of their progressive nature and the deficit in available therapies. Therefore, there is a need for new therapeutic approaches. Our lab determined that chemotherapy induces the release of extracellular adenosine triphosphate (eATP), and, hence, augments TNBC cells' response to chemotherapy. Despite this, eATP concentrations are restricted by a variety of extracellular ATPases. We propose that, as an ATPase inhibitor, heparan sulfate (HS) would augment eATP concentrations and TNBC vulnerability induced by chemotherapy. Sulfatase 2 (SULF2) removes sulfate from HS, the functional group essential for ATPase inhibition. Consequently, we propose that TNBC cell death and eATP release induced by chemotherapy would be intensified by SULF2 inhibitors. We examined eATP and cell viability in paclitaxel-treated TNBC and nontumorigenic immortal mammary epithelial MCF-10A cells in the presence of OKN-007, a selective SULF2 inhibitor, and/or heparan sodium sulfate. Furthermore, sulfatase 1 (SULF1) and SULF2 protein expressions were ascertained. We found that the expression of SULF2 was greater in TNBC cell lines when compared to MCF-10A cells. The release of eATP and loss of TNBC cell viability induced by chemotherapy was enhanced by OKN-007. The co-treatment of chemotherapy and OKN-007 also attenuated cancer-initiating cells. This data implies that the combination of SULF2 inhibitors with chemotherapy augments eATP and decreases cell viability of TNBC greater than chemotherapy alone.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"26 1","pages":"2483989"},"PeriodicalIF":4.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>PCK2</i> promotes invasion and epithelial-to-mesenchymal transition in triple-negative breast cancer by promoting TGF-β/SMAD3 signaling through inhibiting TRIM67-mediated SMAD3 ubiquitination.","authors":"Tsung-Ming Chang, Wei-Yu Fang, Hui-Ping Hsu, Pei-Yi Chu, Shih Sheng Jiang, Kuo-Wei Huang, Wen-Chun Hung, Hui-You Lin, Hui-Jen Tsai","doi":"10.1080/15384047.2025.2478670","DOIUrl":"10.1080/15384047.2025.2478670","url":null,"abstract":"<p><p><i>PCK2</i>, which encodes mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M), is upregulated in various cancers. We demonstrated high expression of PEPCK-M in approximately half of triple-negative breast cancers (TNBCs) previously. TNBC is associated with an aggressive phenotype and a high metastasis rate. In this study, we investigated the role of <i>PCK2</i> in TNBC. <i>PCK2</i> knockdown suppressed proliferation and mTOR signaling in TNBC cells. In addition, cell invasion/migration ability and the expression of epithelial-to-mesenchymal transition (EMT) markers were positively correlated with <i>PCK2</i> expression in TNBC cells via regulation of transforming growth factor-β (TGF-β)/SMAD3 signaling. <i>SMAD3</i> was positively regulated by <i>PCK2</i> in TNBC cells. Knockdown of <i>SMAD3</i> in <i>PCK2</i>-overexpressing TNBC cells reduced the expression levels of EMT markers, Snail and Slug, and suppressed cell invasion/migration. In addition, <i>PCK2</i> knockdown attenuated the stimulatory effect of TGF-β on SMAD3 phosphorylation in TNBC cells. PEPCK-M promotes the protein and mRNA expression of SMAD3 via competitive binding to tripartite motif-containing 67 (TRIM67), an E3 ubiquitin ligase, to reduce SMAD3 ubiquitination, which leads to promoting nuclear translocation of SMAD3 and autoregulation of SMAD3 transcription. Moreover, high <i>PCK2</i> mRNA expression was significantly associated with poor survival in TNBC patients. In conclusion, our study revealed for the first time that <i>PCK2</i> activates TGF-β/SMAD3 signaling by regulating the expression and phosphorylation of SMAD3 by inhibiting TRIM67-mediated SMAD3 ubiquitination and promoting the stimulatory effect of TGF-β to promote TNBC invasion. The regulatory effect of <i>PCK2</i> on mTOR and TGF-β/SMAD3 signaling suggests that <i>PCK2</i> is a potential therapeutic target for suppressing TNBC progression.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"26 1","pages":"2478670"},"PeriodicalIF":4.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11913380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}