Cancer gene therapy最新文献_第8页

ALKBH5-mediated m6A regulates the alternative splicing events of SRSF10 in ovarian cancer alkbh5介导的m6A调控SRSF10在卵巢癌中的选择性剪接事件。

IF 5 3区医学

Cancer gene therapy Pub Date : 2025-04-02 DOI: 10.1038/s41417-025-00898-5

Kexin Li, Yuqing Pei, Xin Dong, Yue Wu, Xiaoying Lou, Yiling Li, Shuang Liang, Yuxin Wu, Danfei Xu, Bin Li, Wei Cui

{"title":"ALKBH5-mediated m6A regulates the alternative splicing events of SRSF10 in ovarian cancer","authors":"Kexin Li, Yuqing Pei, Xin Dong, Yue Wu, Xiaoying Lou, Yiling Li, Shuang Liang, Yuxin Wu, Danfei Xu, Bin Li, Wei Cui","doi":"10.1038/s41417-025-00898-5","DOIUrl":"10.1038/s41417-025-00898-5","url":null,"abstract":"N6-methyladenosine (m6A) methylation was found to be involved in the tumorigenesis and development of ovarian cancer. Until now, it is not clear to identify the mechanism by m6A demethylase ALKBH5 affects RNA splicing in ovarian cancer. In this study, we examined ALKBH5 protein expression and m6A levels by immunohistochemistry and analyzed their correlation with clinical features and prognosis in patients with ovarian cancer. We identified the elevated expression of ALKBH5 and a general reduction in the level of m6A in ovarian cancer patients. In the ovarian cancer cell line A2780, ALKBH5 depletion was found using the siRNA strategy or the CRISPR/Cas9 knockout (KO) method, which significantly reduced the level of m6A and inhibited cell viability, proliferation, and migration. The MeRIP-seq and RNA-seq showed that ALKBH5-regulated m6A RNA modification mainly affects RNA splicing function in ovarian cancer cells. SRSF10 is a key target gene involved in alternative splicing regulation through ALKBH5-m6A. ALKBH5 knockdown resulted in increased retention of SRSF10 exon 5 and decreased expression of transcript SRSF10-211. In conclusion, the alternative splicing regulation effect by ALKBH5-mediated m6A suggests a novel promising approach for m6A modification in OC and provides novel insights into the mechanisms involved in ovarian cancer therapy.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 5","pages":"584-594"},"PeriodicalIF":5.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771439","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

The FOXP1-ABCG2 axis promotes the proliferation of cancer stem cells and induces chemoresistance in pancreatic cancer FOXP1-ABCG2轴促进胰腺癌干细胞增殖并诱导化疗耐药。

IF 5 3区医学

Cancer gene therapy Pub Date : 2025-04-01 DOI: 10.1038/s41417-025-00896-7

Woosol Chris Hong, Minsoo Kim, Ju Hyun Kim, Hyeon Woong Kang, Sungsoon Fang, Hye-Sol Jung, Wooil Kwon, Jin-Young Jang, Hyo Jung Kim, Joon Seong Park

{"title":"The FOXP1-ABCG2 axis promotes the proliferation of cancer stem cells and induces chemoresistance in pancreatic cancer","authors":"Woosol Chris Hong, Minsoo Kim, Ju Hyun Kim, Hyeon Woong Kang, Sungsoon Fang, Hye-Sol Jung, Wooil Kwon, Jin-Young Jang, Hyo Jung Kim, Joon Seong Park","doi":"10.1038/s41417-025-00896-7","DOIUrl":"10.1038/s41417-025-00896-7","url":null,"abstract":"Pancreatic cancer is an aggressive disease with low survival and high recurrence rates. A major obstacle in treating pancreatic cancer is the frequent development of chemoresistance to the standard therapeutic drug, gemcitabine. One mechanism by which pancreatic cancer develops chemoresistance is through the proliferation of cancer stem cells (CSC). However, the mechanisms regulating stemness in chemoresistant tumors remain unclear. Here, we found that the expression of the transcription factor Forkhead Box P1 (FOXP1) was elevated in chemoresistant pancreatic cancer and crucial for establishing CSC characteristics. Silencing FOXP1 reduced the expressions of stemness-associated genes and diminished the formation of both spheroids and colonies, highlighting the crucial role of FOXP1 in regulating stemness in chemoresistant tumor cells. Mechanistically, we discovered that FOXP1 regulates the expression of ATP-binding cassette superfamily G member 2 (ABCG2), which induces the efflux of gemcitabine. Knockdown of FOXP1 reduced the expression of ABCG2, resulting in decreased proliferation and increased sensitivity to gemcitabine. Moreover, the inhibition of FOXP1 in orthotopic mouse models reduced tumor growth and proliferation, and enhanced sensitivity to gemcitabine. Together, our data reveal FOXP1 as a potent oncogene that promotes CSC growth in chemoresistant pancreatic cancer.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 5","pages":"563-572"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tob negatively regulates NF-κB activation in breast cancer through its association with the TNF receptor complex Tob通过其与TNF受体复合物的关联负性调节NF-κB在乳腺癌中的激活。

IF 5 3区医学

Cancer gene therapy Pub Date : 2025-04-01 DOI: 10.1038/s41417-025-00897-6

Miho Tokumasu, Atsuko Sato, Taku Ito-Kureha, Mizuki Yamamoto, Nao Ohmine, Kentaro Semba, Jun-ichiro Inoue, Tadashi Yamamoto

{"title":"Tob negatively regulates NF-κB activation in breast cancer through its association with the TNF receptor complex","authors":"Miho Tokumasu, Atsuko Sato, Taku Ito-Kureha, Mizuki Yamamoto, Nao Ohmine, Kentaro Semba, Jun-ichiro Inoue, Tadashi Yamamoto","doi":"10.1038/s41417-025-00897-6","DOIUrl":"10.1038/s41417-025-00897-6","url":null,"abstract":"NF-κB mediates transcriptional regulation crucial to many biological functions, and elevated NF-κB activity leads to autoimmune and inflammatory diseases, as well as cancer. Since highly aggressive breast cancers have few therapeutic molecular targets, clarification of key molecular mechanisms of NF-κB signaling would facilitate the development of more effective therapy. In this report, we show that Tob, a member of the Tob/BTG family of antiproliferative proteins, acts as a negative regulator of the NF-κB signal in breast cancer. Studies with 35 human breast cancer cell lines reveal that Tob expression is negatively correlated with NF-κB activity. Analysis of The Cancer Genome Atlas (TCGA) database of clinical samples reveals an inverse correlation between Tob expression and NF-κB activity. Tob knockdown in human breast cancer cells promoted overactivation of NF-κB upon TNF-α treatment, whereas overexpression of Tob inhibited TNF-α stimulation-dependent NF-κB activation. Mechanistically, Tob associates with the TNF receptor complex I and consequently inhibits RIPK1 polyubiquitylation, leading to possible prevention of overwhelming activation of NF-κB.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 5","pages":"573-583"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RRM1 O-GlcNAcylation inhibition suppresses pancreatic cancer via TK1-mediated replication stress RRM1 o - glcn酰化抑制通过tk1介导的复制应激抑制胰腺癌。

IF 5 3区医学

Cancer gene therapy Pub Date : 2025-03-28 DOI: 10.1038/s41417-025-00895-8

Sui-Chih Tien, Mei Shih, Chun-Mei Hu

{"title":"RRM1 O-GlcNAcylation inhibition suppresses pancreatic cancer via TK1-mediated replication stress","authors":"Sui-Chih Tien, Mei Shih, Chun-Mei Hu","doi":"10.1038/s41417-025-00895-8","DOIUrl":"10.1038/s41417-025-00895-8","url":null,"abstract":"O-GlcNAcylation of ribonucleotide reductase large subunit M1 (RRM1) at position 734 influences high glucose-induced genomic instability and cell transformation in normal pancreatic cells. By disrupting the ribonucleotide reductase complex, it reduces dNTPs. Although the impact of RRM1 O-GlcNAcylation on pancreatic cancer progression remains unexplored, our CRISPR knock-in technology created the RRM1-T734A mutation to minimize RRM1 O-GlcNAcylation. In pancreatic cancer PANC-1 cells with this mutation, we observed heightened replication stress-induced DNA damage, S-phase delays, and diminished in vitro tumor cell growth. Mechanistically, RRM1-T734A enhanced its interaction with RRM2 while impairing binding to RRM2B, leading to decreased NTPs and disrupted dNTP equilibrium. Notably, it doubled dTTP levels via TK1 stabilization mediated by thymidine, resulting in S-phase delay. TK1 silencing restored RRM1-T734A-induced effects on S-phase retardation and decreased colony formation. Our findings highlight the pivotal role of O-GlcNAcylation of RRM1 at T734 in maintaining genomic stability and promoting pancreatic cancer malignancy. Furthermore, reducing RRM1 O-GlcNAcylation increased pancreatic cancer cell sensitivity to gemcitabine, proposing a potential therapeutic strategy.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 5","pages":"550-562"},"PeriodicalIF":5.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Recent advances in the role of circRNA in cisplatin resistance in tumors circRNA在肿瘤顺铂耐药中的作用研究进展

IF 5 3区医学

Cancer gene therapy Pub Date : 2025-03-27 DOI: 10.1038/s41417-025-00899-4

Jiawen Zhang, Qiwen Yu, Weijin Zhu, Xiaochun Sun

引用次数: 0

Cardamom synergizes with cisplatin against human osteosarcoma cells by mTOR-mediated autophagy 豆蔻与顺铂协同作用，通过mtor介导的自噬作用对抗人骨肉瘤细胞。

IF 5 3区医学

Cancer gene therapy Pub Date : 2025-03-26 DOI: 10.1038/s41417-025-00894-9

Sheng Li, Ziyun Li, Jiayu Wang, Xueqian Han, Lulu Zhang

{"title":"Cardamom synergizes with cisplatin against human osteosarcoma cells by mTOR-mediated autophagy","authors":"Sheng Li, Ziyun Li, Jiayu Wang, Xueqian Han, Lulu Zhang","doi":"10.1038/s41417-025-00894-9","DOIUrl":"10.1038/s41417-025-00894-9","url":null,"abstract":"Cisplatin (DDP), a frontline chemotherapeutic agent in osteosarcoma (OS) treatment, is frequently paired with other compounds to enhance its therapeutic potency. Cardamom (CAR), a natural flavonoid, exhibits significant inhibitory effects on human OS cells while minimizing toxic side effects. In this study, we combined CAR and DDP to treat OS, revealing that the DDP/CAR combination synergistically inhibits the growth of human OS cells in vitro and in vivo. Network pharmacological analysis indicated that mammalian target of rapamycin (mTOR) may be an important cross-target for DDP/CAR combination. Notably, this combined treatment significantly reduced mTOR phosphorylation and elevated autophagy levels within OS cells. At the mechanistic level, the DDP/CAR regimen enhanced apoptosis and compromised the viability of OS cells by triggering autophagy. This impact was attenuated by the use of the mTOR activator MHY and the autophagy inhibitor hydroxychloroquine (HCQ). Furthermore, in DDP-resistant cell lines, CAR was able to mitigate DDP resistance by bolstering autophagy levels. In general, our results suggest that CAR bolstering autophagy levels DDP against OS cells through the induction of mTOR-mediated autophagy.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 5","pages":"538-549"},"PeriodicalIF":5.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MDSC checkpoint blockade therapy: a new breakthrough point overcoming immunosuppression in cancer immunotherapy MDSC检查点阻断疗法：癌症免疫治疗突破免疫抑制的新突破点。

IF 4.8 3区医学

Cancer gene therapy Pub Date : 2025-03-26 DOI: 10.1038/s41417-025-00886-9

Abdulrahman Ibrahim, Nada Mohamady Farouk Abdalsalam, Zihao Liang, Hafiza Kashaf Tariq, Rong Li, Lukman O. Afolabi, Lawan Rabiu, Xuechen Chen, Shu Xu, Zhiming Xu, Xiaochun Wan, Dehong Yan

{"title":"MDSC checkpoint blockade therapy: a new breakthrough point overcoming immunosuppression in cancer immunotherapy","authors":"Abdulrahman Ibrahim, Nada Mohamady Farouk Abdalsalam, Zihao Liang, Hafiza Kashaf Tariq, Rong Li, Lukman O. Afolabi, Lawan Rabiu, Xuechen Chen, Shu Xu, Zhiming Xu, Xiaochun Wan, Dehong Yan","doi":"10.1038/s41417-025-00886-9","DOIUrl":"10.1038/s41417-025-00886-9","url":null,"abstract":"Despite the success of cancer immunotherapy in treating hematologic malignancies, their efficacy in solid tumors remains limited due to the immunosuppressive tumor microenvironment (TME), which is mainly formed by myeloid-derived suppressor cells (MDSCs). MDSCs not only exert potent immunosuppressive effects that hinder the success of immune checkpoint inhibitors (ICIs) and adaptive cellular therapies, but they also promote tumor advancement through non-immunological pathways, including promoting angiogenesis, driving epithelial-mesenchymal transition (EMT), and contributing to the establishment of pre-metastatic environments. While targeting MDSCs alone or in combination with conventional therapies has shown limited success, emerging evidence suggests that MDSC checkpoint blockade in combination with other immunotherapies holds great promise in overcoming both immunological and non-immunological barriers. In this review, we discussed the dual roles of MDSCs, with a particular emphasis on their underexplored checkpoints blockade strategies. We discussed the rationale behind combination strategies, their potential advantages in overcoming MDSC-mediated immunosuppression, and the challenges associated with their development. Additionally, we highlight future research directions aimed at optimizing combination immunotherapies to enhance cancer therapeutic effectiveness, particularly in solid tumor therapies where MDSCs are highly prevalent.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 4","pages":"371-392"},"PeriodicalIF":4.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-025-00886-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genome-wide CRISPR activation screen identifies ARL11 as a sensitivity determinant of PARP inhibitor therapy 全基因组CRISPR激活筛选鉴定出ARL11是PARP抑制剂治疗的敏感性决定因素。

IF 5 3区医学

Cancer gene therapy Pub Date : 2025-03-23 DOI: 10.1038/s41417-025-00893-w

Tengjiang Zhang, Yuan Zhang, Xuxiang Wang, Haitian Hu, Christopher G. Lin, Yaru Xu, Hanqiu Zheng

{"title":"Genome-wide CRISPR activation screen identifies ARL11 as a sensitivity determinant of PARP inhibitor therapy","authors":"Tengjiang Zhang, Yuan Zhang, Xuxiang Wang, Haitian Hu, Christopher G. Lin, Yaru Xu, Hanqiu Zheng","doi":"10.1038/s41417-025-00893-w","DOIUrl":"10.1038/s41417-025-00893-w","url":null,"abstract":"Resistance to poly-(ADP)-ribose polymerase inhibitors (PARPi) remains a significant challenge in clinical practice, leading to treatment failure in many patients. It is crucial to better understand the molecular mechanisms that underlie PARPi resistance. In this study, utilizing a genome-wide CRISPR activation screen with olaparib, we identified ARL11 as a potential modulator of PARPi treatment response in BRCA-wild-type MDA-MB-231 cells. Mechanistically, ARL11 interacts with STING to enhance innate immunity and forms positive feedback with type I interferon (IFN) induction, which induces ARL11 up-regulation and contributes to resistance to PARPi therapy. Additionally, we observed that ARL11 interacts with the RUVBL1 and RUVBL2 (RUVBL1/2) complex, the key DNA double-strand repair proteins, facilitating DNA homologous recombination (HR) repair and significantly reducing PARPi-induced DNA double-strand damages. Clinical sample analysis reveals that the expression levels of ARL11 and RUVBL1/2 are significantly elevated in breast cancer patients compared to healthy controls. Collectively, our findings suggested that ARL11 and RUVBL1/2 may be promising therapeutic targets to sensitize breast cancer cells to PARPi therapy.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 5","pages":"521-537"},"PeriodicalIF":5.0,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691165","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

TOM1L1 mediated the sort of tumor suppressive miR-378a-3p into exosomes and the excretion out of cells to promote ESCC progression TOM1L1介导肿瘤抑制miR-378a-3p进入外泌体并分泌出细胞，从而促进ESCC的进展。

IF 5 3区医学

Cancer gene therapy Pub Date : 2025-03-23 DOI: 10.1038/s41417-025-00889-6

Lu Wang, Huijuan Liu, Guohui Chen, Qinglu Wu, Songrui Xu, Qichao Zhou, Yadong Zhao, Qiaorong Wang, Ting Yan, Xiaolong Cheng

引用次数: 0

Therapeutic potential of synthetic microRNA mimics based on the miR-15/107 consensus sequence 基于miR-15/107共识序列的合成microRNA模拟物的治疗潜力。

IF 4.8 3区医学

Cancer gene therapy Pub Date : 2025-03-22 DOI: 10.1038/s41417-025-00885-w

Glen Reid, Marissa Williams, Yuen Yee Cheng, Kadir Sarun, Patrick Winata, Michaela B. Kirschner, Nancy Mugridge, Jocelyn Weiss, Mark Molloy, Himanshu Brahmbhatt, Jennifer MacDiarmid, Nico van Zandwijk

{"title":"Therapeutic potential of synthetic microRNA mimics based on the miR-15/107 consensus sequence","authors":"Glen Reid, Marissa Williams, Yuen Yee Cheng, Kadir Sarun, Patrick Winata, Michaela B. Kirschner, Nancy Mugridge, Jocelyn Weiss, Mark Molloy, Himanshu Brahmbhatt, Jennifer MacDiarmid, Nico van Zandwijk","doi":"10.1038/s41417-025-00885-w","DOIUrl":"10.1038/s41417-025-00885-w","url":null,"abstract":"MicroRNA expression is frequently suppressed in cancer, and previously we demonstrated coordinate downregulation of multiple related microRNAs of the miR-15/107 group in malignant pleural mesothelioma (PM). From an alignment of the miR-15 family and the related miR-103/107, we derived a consensus sequence and used this to generate synthetic mimics. The synthetic mimics displayed tumour suppressor activity in PM cells in vitro, which was greater than that of a mimic based on the native miR-16 sequence. These mimics were also growth inhibitory in cells from non-small cell lung (NSCLC), prostate, breast and colorectal cancer, and sensitised all cell lines to the chemotherapeutic drug gemcitabine. The increased activity corresponded to enhanced inhibition of the expression of target genes and was associated with an increase in predicted binding to target sites, and proteomic analysis revealed a strong effect on proteins involved in RNA and DNA processes. Applying the novel consensus mimics to xenograft models of PM and NSCLC in vivo using EGFR-targeted nanocells loaded with mimic led to tumour growth inhibition. These results suggest that mimics based on the consensus sequence of the miR-15/107 group have therapeutic potential in a range of cancer types.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 4","pages":"486-496"},"PeriodicalIF":4.8,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-025-00885-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0