Cancer gene therapy最新文献

ATPase copper transporting beta contributes to cisplatin resistance as a regulatory factor of extracellular vesicles in head and neck squamous cell carcinoma. 作为头颈部鳞状细胞癌细胞外囊泡的调节因子，atp酶铜转运β有助于顺铂耐药。

IF 5 3区医学

Cancer gene therapy Pub Date : 2025-10-17 DOI: 10.1038/s41417-025-00975-9

Tatsuo Ogawa, Kisho Ono, Shoji Ryumon, Hotaka Kawai, Kohei Sato, Koki Umemori, Kunihiro Yoshida, Kyoichi Obata, Yuki Kunisada, Tatsuo Okui, Kuniaki Okamoto, Hitoshi Nagatsuka, Fatemeh Momen-Heravi, Soichiro Ibaragi

{"title":"ATPase copper transporting beta contributes to cisplatin resistance as a regulatory factor of extracellular vesicles in head and neck squamous cell carcinoma.","authors":"Tatsuo Ogawa, Kisho Ono, Shoji Ryumon, Hotaka Kawai, Kohei Sato, Koki Umemori, Kunihiro Yoshida, Kyoichi Obata, Yuki Kunisada, Tatsuo Okui, Kuniaki Okamoto, Hitoshi Nagatsuka, Fatemeh Momen-Heravi, Soichiro Ibaragi","doi":"10.1038/s41417-025-00975-9","DOIUrl":"https://doi.org/10.1038/s41417-025-00975-9","url":null,"abstract":"Cisplatin (CDDP) resistance remains a major clinical challenge in the treatment of head and neck squamous cell carcinoma (HNSC). Our group identified ATPase copper transporting beta (ATP7B) as a mediator of CDDP resistance through its role in drug efflux and small extracellular vesicle (sEV) secretion. Herein, we uncovered a novel mechanism by which ATP7B regulates sEV dynamics and the intercellular transmission of CDDP resistance. Using transcriptomic analyses of HNSC datasets, we demonstrate that ATP7B expression correlates with endocytosis- and epithelial-mesenchymal transition (EMT)-related gene sets and with elevated levels of EV-associated proteins. CDDP-resistant HNSC cells exhibited upregulated ATP7B, Rab5/Rab7, and preferentially secreted HSP90- and EpCAM-rich sEVs. These sEVs were leading to increased ATP7B expression and reduced CDDP sensitivity in recipient cells. A pharmacological inhibition of sEV biogenesis with GW4869 suppressed ATP7B and Atox1 expressions, inhibited late endosome maturation, and significantly enhanced CDDP-induced apoptosis in HNSC cells. In vivo, GW4869 reduced the sEV protein content and ATP7B expression in xenograft tumors. These findings establish that ATP7B is a critical modulator of sEV cargo and resistance propagation. Our results highlight a previously unrecognized ATP7B-sEV axis driving chemoresistance and identify sEV inhibition as a promising strategy to overcome therapeutic failure in HNSC.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Spleen tyrosine kinase (SYK) inhibition suppresses growth of gastrointestinal neuroendocrine tumor cells: a pilot study in two cell lines. 脾脏酪氨酸激酶（SYK）抑制胃肠道神经内分泌肿瘤细胞的生长：两种细胞系的初步研究。

IF 5 3区医学

Cancer gene therapy Pub Date : 2025-10-16 DOI: 10.1038/s41417-025-00979-5

Angeliki Ditsiou, Lara Toffoli, Viviana Vella, Francesca D'Este, Teresa Gagliano

{"title":"Spleen tyrosine kinase (SYK) inhibition suppresses growth of gastrointestinal neuroendocrine tumor cells: a pilot study in two cell lines.","authors":"Angeliki Ditsiou, Lara Toffoli, Viviana Vella, Francesca D'Este, Teresa Gagliano","doi":"10.1038/s41417-025-00979-5","DOIUrl":"https://doi.org/10.1038/s41417-025-00979-5","url":null,"abstract":"Gastrointestinal neuroendocrine tumors (GI-NETs) lack effective targeted options beyond somatostatin analogs and mTOR inhibitors. Spleen tyrosine kinase (SYK) is a non-receptor kinase with emerging roles in solid tumors and available small-molecule inhibitors. We explored whether SYK is a plausible therapeutic target in GI-NET using two human cell lines. SYK expression in GI-NET cells was confirmed by immunofluorescence. Cells were exposed to a selective SYK inhibitor (BI-1002494), and proliferation was quantified using both 2D and 3D models. Both GI-NET models expressed SYK and exhibited reduced growth upon SYK blockade, with dose-dependent suppression of viability and increased cytotoxicity relative to vehicle. In spheroid assays, morphologic changes and reduced size were observed. These pilot data suggest SYK as a targetable vulnerability in GI-NET and support formal dose-response studies, genetic validation, and combination strategies with standard-of-care agents. Given the clinical availability of SYK inhibitors, these findings provide a rationale for translational studies in GI-NET.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145306886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MC1R contributes to ferroptosis resistance and tumor aggressiveness in colorectal cancer by activating Notch signaling. MC1R通过激活Notch信号参与结直肠癌铁下垂抵抗和肿瘤侵袭。

IF 5 3区医学

Cancer gene therapy Pub Date : 2025-10-15 DOI: 10.1038/s41417-025-00942-4

Xiangwei Zeng, Lujian Jiang, Huili Li, Jiamou Wang, Xuan He

{"title":"MC1R contributes to ferroptosis resistance and tumor aggressiveness in colorectal cancer by activating Notch signaling.","authors":"Xiangwei Zeng, Lujian Jiang, Huili Li, Jiamou Wang, Xuan He","doi":"10.1038/s41417-025-00942-4","DOIUrl":"https://doi.org/10.1038/s41417-025-00942-4","url":null,"abstract":"Ferroptosis, a form of iron-dependent cell death, is emerging as a potential therapeutic target due to its ability to inhibit tumor growth and enhance immune responses. However, the mechanisms regulating ferroptosis and tumor metastasis, particularly in colorectal cancer (CRC), remain poorly understood. In this study, bioinformatics analysis identified MC1R as a key regulator of ferroptosis-related genes. In vitro experiments showed MC1R overexpression in CRC cell lines promotes cell proliferation and migration while inhibiting ferroptosis via downregulating ACSL4 expression, with opposite effects seen in MC1R knockdown. In vivo experiments also found MC1R-knockdown CRC cells resulted in xenograft tumors with lower volume and weight. Mechanistically, MC1R activates the Notch signaling pathway, leading to ACSL4 inhibition, which inhibits ferroptosis and, in turn, cell growth and migration. High MC1R expression in CRC correlates with poor prognosis and is negatively associated with ferroptosis levels. Targeting MC1R could offer a novel strategy to enhance ferroptosis in CRC, potentially improving patient outcomes. This study elucidates the complex interactions between MC1R, Notch signaling, and ferroptosis, providing insights for developing targeted therapies in CRC.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SMAD4-armed oncolytic adenovirus therapy potentiates the chemotherapy effects in NSCLC through suppression of the Wnt/β-catenin pathway. smad4武装的溶瘤腺病毒治疗通过抑制Wnt/β-catenin通路增强了NSCLC的化疗效果。

IF 5 3区医学

Cancer gene therapy Pub Date : 2025-10-14 DOI: 10.1038/s41417-025-00976-8

Chuanjing Dai, Yaru Zhao, Huili Zhang, Sultan Muhammad Haris, Biao Huang, Xiong Tian, Xiaoyuan Jia, Huaguang Li, Fang Huang, Yigang Wang

{"title":"SMAD4-armed oncolytic adenovirus therapy potentiates the chemotherapy effects in NSCLC through suppression of the Wnt/β-catenin pathway.","authors":"Chuanjing Dai, Yaru Zhao, Huili Zhang, Sultan Muhammad Haris, Biao Huang, Xiong Tian, Xiaoyuan Jia, Huaguang Li, Fang Huang, Yigang Wang","doi":"10.1038/s41417-025-00976-8","DOIUrl":"https://doi.org/10.1038/s41417-025-00976-8","url":null,"abstract":"Non-small cell lung cancer (NSCLC) represents between 80 and 90% of primary lung cancer cases. Despite progress targeting oncogenic drivers, there are no therapies targeting tumor-suppressor loss. This study confirmed a significant downregulation of SMAD4 expression in both NSCLC tissues and cell lines. Loss of SMAD4 was associated with advanced clinical stage, pathological T stage, and poor prognosis for chemotherapy in NSCLC patients. SMAD4 knockdown promoted proliferation, cell cycle progression, migration, and invasion in NSCLC cells, whereas SMAD4 overexpression suppressed these malignant phenotypes. The molecular mechanism underlying SMAD4 loss-driven NSCLC progression links to the abnormal activation of Wnt/β-catenin pathway. Subsequently, an oncolytic adenovirus encoding SMAD4 (OAd CS) was constructed and its efficiency in inhibiting NSCLC growth was assessed. OAd CS selectively replicated in and killed NSCLC cells without affecting the survival of normal lung cells. Mechanistically, CS inhibited NSCLC cell growth through suppressing the Wnt/β-catenin pathway and activating the caspase pathway. Furthermore, combining OAd CS with gemcitabine exhibited superior tumor suppression compared to monotherapy, with no significant toxicity observed in a NSCLC xenograft model. Overall, these findings provide a novel therapeutic target and an additional combination therapy strategy for NSCLC.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Activating NRF2^E79Q mutation alters the differentiation of human non-small cell lung cancer. 激活NRF2E79Q突变可改变人非小细胞肺癌的分化。

IF 5 3区医学

Cancer gene therapy Pub Date : 2025-10-11 DOI: 10.1038/s41417-025-00966-w

Samera H Hamad, Hansa Joshi, T Hess, Stuart R Jefferys, Zena Saleh, Nasrine Bendjilali, Rani S Sellers, Gord Zhu, Travis Shrank, Rayvon T Moore, David Corcoran, Jeremy M Simon, Francis R Spitz, David Shersher, Michael B Major, Bernard E Weissman

{"title":"Activating NRF2E79Q mutation alters the differentiation of human non-small cell lung cancer.","authors":"Samera H Hamad, Hansa Joshi, T Hess, Stuart R Jefferys, Zena Saleh, Nasrine Bendjilali, Rani S Sellers, Gord Zhu, Travis Shrank, Rayvon T Moore, David Corcoran, Jeremy M Simon, Francis R Spitz, David Shersher, Michael B Major, Bernard E Weissman","doi":"10.1038/s41417-025-00966-w","DOIUrl":"10.1038/s41417-025-00966-w","url":null,"abstract":"The NRF2 signaling pathway promotes tumor initiation, progression and resistance to chemotherapy, radiation therapy and immune checkpoint inhibitors. The mechanisms underlying the biology of NRF2-active tumors are varied and include altered cellular metabolism, a reductive shift in redox state, and immunosuppression. Here we determined the molecular and phenotypic impact of NRF2 activation on two human non-small cell lung cancer (NSCLC) cell models. Inducible expression of NRF2E79Q, a common activating NRF2 mutation, in H358 lung adenocarcinoma (LUAD) cells altered cellular morphology and increased xenograft tumor growth in mice but not in 2D cell culture. In contrast, NRF2E79Q expression in H596 lung adeno-squamous cell carcinoma altered cellular morphology, increased neuroendocrine marker gene expression, but did not impact tumor growth in 2D or in xenografts. Gene expression profiling revealed shared and unique NRF2 transcriptional programs between these models, some of which were shared in primary lung tumors. Collectively, our findings reveal context-dependent effects of NRF2 activation on the growth and differentiation state of two human NSCLC models, supporting a role for NRF2 activation in altering the differentiation of human NSCLC during tumor progression.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

GPR107: A key driver of breast cancer invasion and metastasis through collagen IV modulation. GPR107：通过胶原IV调节乳腺癌侵袭和转移的关键驱动因素。

IF 5 3区医学

Cancer gene therapy Pub Date : 2025-10-10 DOI: 10.1038/s41417-025-00977-7

Ruyue Xu, Jiahui Liang, Shuyuan Zhang, Puseletso Moru, Kainan Liao, Deping Xu, Guodong Cao, Chunlin Cai, Dandan Zang, Guoling Zhou, Min Ren, Haisheng Zhou

{"title":"GPR107: A key driver of breast cancer invasion and metastasis through collagen IV modulation.","authors":"Ruyue Xu, Jiahui Liang, Shuyuan Zhang, Puseletso Moru, Kainan Liao, Deping Xu, Guodong Cao, Chunlin Cai, Dandan Zang, Guoling Zhou, Min Ren, Haisheng Zhou","doi":"10.1038/s41417-025-00977-7","DOIUrl":"https://doi.org/10.1038/s41417-025-00977-7","url":null,"abstract":"Breast cancer is a leading cause of cancer-related death in women, and the development of effective treatments for advanced disease remains a critical challenge. Metastasis, the spread of cancer cells to distant sites, is the major cause of mortality in breast cancer. We identified a novel role for the G protein-coupled receptor 107 (GPR107) in promoting breast cancer invasion and metastasis. Furthermore, we found that GPR107 mediates a reduction in collagen Ⅳ (COL4), a key component of the extracellular matrix (ECM) that normally restricts tumor cell invasion. This reduction in COL4 levels was associated with GPR107 mediating the Clathrin-mediated endocytosis of COL4 from the ECM, an increase in matrix metalloproteinase 2 (MMP2) production to degrade COL4 in the ECM, and a decrease in COL4 production. Mechanistically, we identified GPR107 as a key mediator of the ERK/STAT3 pathway activation through β-arrestin, leading to increased expression of MMP2 and suppression of COL4 gene transcription, effectively promoting invasion and metastasis in breast cancer cells. These findings suggest that GPR107 could serve as a promising biomarker for predicting breast cancer malignancy and a potential therapeutic target for preventing and treating metastatic disease.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unveiling the role of the extracellular matrix in the osteosarcoma tumor microenvironment through integrated transcriptomics and experimental validation. 通过整合转录组学和实验验证揭示细胞外基质在骨肉瘤肿瘤微环境中的作用。

IF 5 3区医学

Cancer gene therapy Pub Date : 2025-10-07 DOI: 10.1038/s41417-025-00970-0

Yuyang Liu, Yuchen Han, Zixuan Guo, Yinglong Zhang, Xiuyuan Xu, Wenting Qi, Meng Xu, Jianxiong Li

{"title":"Unveiling the role of the extracellular matrix in the osteosarcoma tumor microenvironment through integrated transcriptomics and experimental validation.","authors":"Yuyang Liu, Yuchen Han, Zixuan Guo, Yinglong Zhang, Xiuyuan Xu, Wenting Qi, Meng Xu, Jianxiong Li","doi":"10.1038/s41417-025-00970-0","DOIUrl":"https://doi.org/10.1038/s41417-025-00970-0","url":null,"abstract":"Osteosarcoma (OS), the most common malignant bone tumor, is characterized by heterogeneous tumor cells and abundant microenvironmental components. The extracellular matrix (ECM)-a complex and dynamic network surrounding tumor cells-plays a pivotal role in OS malignancy (e.g., cell proliferation, metastasis), making insights into ECM involvement critical for advancing OS prognosis. This study conducted bioinformatic analyses on bulk RNA-sequencing and single-cell RNA sequencing data from public databases, initially identifying collagen type V alpha 2 (COL5A2) as a key gene in OS progression. It further validated biological functions and underlying mechanisms of COL5A2 via in vitro experiments, and constructed and validated prognostic models based on ECM signature cell clusters. Results identified osteoblastic cells (OCs) and endothelial cells (ECs) as core cellular components of OS. COL5A2 was highly expressed in OCs, and high COL5A2 expression correlated with significantly reduced overall survival in OS patients. Western blot, CCK-8, and colony formation assays demonstrated that COL5A2 promoted OS cell proliferation by activating the focal adhesion pathway and inducing phosphorylation of the FAK/Paxillin/Akt signaling axis. The prognostic model highlighted the C0 OCs cluster as clinically significant. CellChat analysis uncovered significant activation of the IGFBP pathway in both C0 OCs and C1 ECs, and identified the IGFBP3-TMEM219 axis as the key ligand-receptor pair mediating their crosstalk. This study establishes COL5A2 and the C0 OCs cluster as pivotal ECM-related signatures in OS, confirming COL5A2 drives OS proliferation through focal adhesion signaling and IGFBP3-TMEM219-mediated crosstalk-both representing promising therapeutic targets. Further investigation into ECM components is warranted to refine OS treatment strategies and improve clinical outcomes.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

pNaktide reverses metabolic reprogramming and disease progression of ATP1A1-deficiency clear cell renal cell carcinoma. pNaktide逆转atp1a1缺乏症透明细胞肾细胞癌的代谢重编程和疾病进展。

IF 5 3区医学

Cancer gene therapy Pub Date : 2025-10-07 DOI: 10.1038/s41417-025-00971-z

Yinghong Zhao, Jialing Lv, Wen Zhang, Ruoyu Deng, Chunyan Li, Lin Wang, Tengfei Zhang, Feineng Liu, Kaili Ma, Zhengcun Wu, Chao Zhang

{"title":"pNaktide reverses metabolic reprogramming and disease progression of ATP1A1-deficiency clear cell renal cell carcinoma.","authors":"Yinghong Zhao, Jialing Lv, Wen Zhang, Ruoyu Deng, Chunyan Li, Lin Wang, Tengfei Zhang, Feineng Liu, Kaili Ma, Zhengcun Wu, Chao Zhang","doi":"10.1038/s41417-025-00971-z","DOIUrl":"https://doi.org/10.1038/s41417-025-00971-z","url":null,"abstract":"ATP1A1 has been reported to exhibit differential expression across various tumors; however, its specific role in clear cell renal cell carcinoma (ccRCC) remains uncharted. This study investigates the role of ATP1A1 in ccRCC, assessing its potential as a prognostic marker and therapeutic target. Through database analysis and clinical sample evaluation, we found that ATP1A1 expression is significantly downregulated in ccRCC and closely correlates with poor patient prognosis. Both in vitro and in vivo experiments further confirmed that ATP1A1 exerts tumor-suppressive effects by inhibiting SRC kinase activity. Additionally, co-expression gene analysis suggests that ATP1A1 may regulate ccRCC development by targeting metabolic reprogramming. We also discovered that the overexpression of ATP1A1 induces a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS), resulting in increased levels of reactive oxygen species (ROS) and subsequent apoptosis. Moreover, we evaluated the therapeutic potential of pNaktide, a peptide that mimics ATP1A1 function. Our research indicates that pNaktide effectively inhibits ccRCC proliferation both in vitro and in vivo by suppressing the SRC signaling pathway and inducing metabolic changes akin to those observed with ATP1A1 overexpression. Studies utilizing nude mouse models further confirmed that pNaktide significantly reduces tumor volume and weight, supporting its potential as a therapeutic agent. In summary, this study demonstrates that low ATP1A1 expression is a critical factor in ccRCC progression and that pNaktide, by restoring ATP1A1-like functions, presents a promising therapeutic strategy for ccRCC.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Decoding BRCA1 promoter hypermethylation: a new frontier in understanding sporadic breast cancer. 解码BRCA1启动子超甲基化：了解散发性乳腺癌的新前沿。

IF 5 3区医学

Cancer gene therapy Pub Date : 2025-10-07 DOI: 10.1038/s41417-025-00969-7

Dipyaman Patra, Geetu Rose Varghese, Vishnu Sunil Jaikumar, Arathi Rajan, Neethu Krishnan, Krithiga Kuppuswamy, Rateeshkumar Thankappan, Priya Srinivas

{"title":"Decoding BRCA1 promoter hypermethylation: a new frontier in understanding sporadic breast cancer.","authors":"Dipyaman Patra, Geetu Rose Varghese, Vishnu Sunil Jaikumar, Arathi Rajan, Neethu Krishnan, Krithiga Kuppuswamy, Rateeshkumar Thankappan, Priya Srinivas","doi":"10.1038/s41417-025-00969-7","DOIUrl":"https://doi.org/10.1038/s41417-025-00969-7","url":null,"abstract":"The role of epimutations in sporadic oncogenesis has been a hot topic of debate and speculation, as hereditary mutations account for merely 5-10% of cancers. One such epimutation, BRCA1 promoter hypermethylation (BPM), is associated with BRCA1 inactivation at variable frequencies in sporadic breast cancers. Unlike hereditary BRCA1 mutations, the role of BPM in tumorigenesis remains obscure. To investigate this, we employed a modified CRISPR approach to induce site-specific methylations in the wild-type BRCA1 promoter, mimicking BPM under clinical conditions. Our research revealed complex pathways influenced by BPM that accelerate tumor formation and progression. We found that BPM downregulates BRCA1 by modulating ER-α expression, thus affecting the balance between BRCA1 isoforms β and α. BPM also regulates the lncRNA NBR2, which shares the BRCA1 promoter region. Remarkably, silencing NBR2 initiates a feedback loop that exacerbates BRCA1 downregulation and supports tumorigenesis. Shortly after BPM induction, tumor proliferation is enhanced by increased β-hCG and ER-α expression, alongside decreased PR levels. However, prolonged BPM maintenance leads to the remodulation of hormone receptors, resulting in a hormone receptor-negative status. Finally, we demonstrate the higher growth potential and invasiveness of BPM tumors through novel hypermethylation-based xenograft models. Comparative proteomic analysis of BPM cells at two different timepoints post-methylation induction identified diagnostic and prognostic markers. Key molecular biomarkers, including NBR2, β-hCG, ER-α, and associated proteins such as HSP90, STAT1, SPEN, and TFF1, have been identified as potential therapeutic targets for BRCA1-defective breast cancers.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Demethoxycurcumin suppresses HK2-mediated glycolysis by targeting PTEN/Akt signaling. 去甲氧基姜黄素通过靶向PTEN/Akt信号抑制hk2介导的糖酵解。

IF 5 3区医学

Cancer gene therapy Pub Date : 2025-10-02 DOI: 10.1038/s41417-025-00972-y

Jinzhuang Liao, Shiming Tan, Shuangze Han, Ruirui Wang, Pengfei Guo, Wei Zheng, Xinfang Yu, Wei Li

{"title":"Demethoxycurcumin suppresses HK2-mediated glycolysis by targeting PTEN/Akt signaling.","authors":"Jinzhuang Liao, Shiming Tan, Shuangze Han, Ruirui Wang, Pengfei Guo, Wei Zheng, Xinfang Yu, Wei Li","doi":"10.1038/s41417-025-00972-y","DOIUrl":"https://doi.org/10.1038/s41417-025-00972-y","url":null,"abstract":"Aerobic glycolysis is a hallmark of tumor cells, with the expression of glycolytic enzymes often being upregulated in many cancers, leading to enhanced metabolic activity. Among the key rate-limiting enzymes in this process, Hexokinase 2 (HK2) plays a crucial role in sustaining the biological activities of human cancers. Therefore, HK2 is considered a potential therapeutic target, although effective targeted drugs for oral squamous cell carcinoma (OSCC) treatment are currently lacking. To confirm potent anti-tumor agents that inhibit HK2 expression, we screened a library of 639 natural products and discovered that Demethoxycurcumin (Deme) was the most effective anti-tumor agent via inhibiting HK2-mediated glycolysis in OSCC cells, inducing intrinsic apoptosis. Mechanistically, Deme enhanced the interaction between USP13 and PTEN, leading to the stabilization of PTEN and consequent downregulation of HK2 via the PTEN/Akt/HK2 pathway. Notably, HK2 overexpression reversed the inhibitory effect of Deme on OSCC cells. Furthermore, at the tumor-inhibitory dose, Deme showed no effect on non-tumor HaCat cells. In vivo, Deme significantly suppressed tumor growth without apparent toxicity to vital organs. Together, these data suggest that Deme is a promising and safe anti-tumor compound that downregulates HK2 expression, providing a potential therapeutic strategy for OSCC treatment.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0