Cancer gene therapy最新文献_第7页

Switching anti-EGFR antibody re-sensitizes head and neck cancer patient following acquired resistance to cetuximab 转换抗表皮生长因子受体（EGFR）抗体可使对西妥昔单抗产生耐药性的头颈癌患者重新获得敏感性。

IF 4.8 3区医学

Cancer gene therapy Pub Date : 2024-07-31 DOI: 10.1038/s41417-024-00812-5

Arun Khattri, Sheikh Nizamuddin, Nikhil Agrawal, Sandeep Kaushik, Sara Kochanny, Daniel Ginat, Mark W. Lingen, Elizabeth Blair, Tanguy Y. Seiwert

{"title":"Switching anti-EGFR antibody re-sensitizes head and neck cancer patient following acquired resistance to cetuximab","authors":"Arun Khattri, Sheikh Nizamuddin, Nikhil Agrawal, Sandeep Kaushik, Sara Kochanny, Daniel Ginat, Mark W. Lingen, Elizabeth Blair, Tanguy Y. Seiwert","doi":"10.1038/s41417-024-00812-5","DOIUrl":"10.1038/s41417-024-00812-5","url":null,"abstract":"Cetuximab induces responses in about 13% of head and neck squamous cell carcinomas (HNSCC). We describe the molecular mechanism of acquired resistance to cetuximab, which could be overcome by switching to a different anti-EGFR antibody. Biopsies were collected at three different time points: before the start of cetuximab (PRE-cetux), at acquired resistance to cetuximab (AR-cetux), and at acquired resistance to duligotuzumab (AR-duligo). Biopsies were analyzed using tumor and normal whole-exome sequencing, RNASeq, and targeted panel sequencing with ultra-deep coverage to generate differential mutation and expression profiles. WES and targeted sequencing analysis identified an EGFR p.G465R extracellular domain mutation in AR-cetux biopsy. Furthermore, RNASeq confirmed the expression of this mutation in the tumor tissue. This mutation prevented the binding of cetuximab to EGFR and was not present in PRE-cetux and AR-duligo biopsies, suggesting a potential mechanism of acquired resistance to cetuximab. Molecular dynamic simulations confirmed that duligotuzumab effectively binds EGFR with a p.G465R mutation. Interestingly, the p.G465R mutation improved the stability of the duligotuzumab-EGFR complex as compared to the wild-type EGFR. This is the first report of an EGFR ECD mutation associated with acquired resistance to cetuximab, posing a need for further validation. We suggest appropriate serial mutational profiling to identify ECD mutations should be considered for select patients with initial cetuximab benefit.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"31 10","pages":"1477-1485"},"PeriodicalIF":4.8,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-024-00812-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859083","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

Rabenosyn-5 suppresses non-small cell lung cancer metastasis via inhibiting CDC42 activity Rabenosyn-5 通过抑制 CDC42 的活性抑制非小细胞肺癌的转移。

IF 4.8 3区医学

Cancer gene therapy Pub Date : 2024-07-29 DOI: 10.1038/s41417-024-00813-4

Xiong Guo, Bin Mu, Lin Zhu, Yanli Zhuo, Ping Mu, Fu Ren, Fangjin Lu

{"title":"Rabenosyn-5 suppresses non-small cell lung cancer metastasis via inhibiting CDC42 activity","authors":"Xiong Guo, Bin Mu, Lin Zhu, Yanli Zhuo, Ping Mu, Fu Ren, Fangjin Lu","doi":"10.1038/s41417-024-00813-4","DOIUrl":"10.1038/s41417-024-00813-4","url":null,"abstract":"Metastasis, the primary cause of death in lung cancer patients, is facilitated by cytoskeleton remodeling, which plays a crucial role in cancer cell migration and invasion. However, the precise regulatory mechanisms of intracellular trafficking proteins involved in cytoskeleton remodeling remain unclear. In this study, we have identified Rabenosyn-5 (Rbsn) as an inhibitor of filopodia formation and lung cancer metastasis. Mechanistically, Rbsn interacts with CDC42 and functions as a GTPase activating protein (GAP), thereby inhibiting CDC42 activity and subsequent filopodia formation. Furthermore, we have discovered that Akt phosphorylates Rbsn at the Thr253 site, and this phosphorylation negates the inhibitory effect of Rbsn on CDC42 activity. Additionally, our analysis reveals that Rbsn expression is significantly downregulated in lung cancer, and this decrease is associated with a worse prognosis. These findings provide strong evidence supporting the role of Rbsn in suppressing lung cancer progression through the inhibition of metastasis.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"31 10","pages":"1465-1476"},"PeriodicalIF":4.8,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-024-00813-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792024","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

ZDHHC1 downregulates LIPG and inhibits colorectal cancer growth via IGF2BP1 Palmitoylation ZDHHC1 通过 IGF2BP1 棕榈酰化作用下调 LIPG 并抑制结直肠癌生长

IF 4.8 3区医学

Cancer gene therapy Pub Date : 2024-07-28 DOI: 10.1038/s41417-024-00808-1

Qun Zhang, Zhouyuan Du, Wei Zhou, Wei Li, Qinglin Yang, Haixin Yu, Tao Liu

{"title":"ZDHHC1 downregulates LIPG and inhibits colorectal cancer growth via IGF2BP1 Palmitoylation","authors":"Qun Zhang, Zhouyuan Du, Wei Zhou, Wei Li, Qinglin Yang, Haixin Yu, Tao Liu","doi":"10.1038/s41417-024-00808-1","DOIUrl":"10.1038/s41417-024-00808-1","url":null,"abstract":"Alteration in lipid metabolism is recognized as a hallmark feature of colorectal cancer (CRC). Protein S-palmitoylation plays a critical role in many different cellular processes including protein-lipid interaction. Zinc Finger DHHC-Type Containing 1 (ZDHHC1, also known as ZNF377) belongs to the palmitoyl-transferase ZDHHC family, and is a potential tumor suppressor. However, our knowledge of the functional roles of ZDHHC1 in CRC is limited. We discovered that ZDHHC1 expression was downregulated in CRC tissues and that low levels of ZDHHC1 were associated with unfavorable prognosis. Functional studies showed that ZDHHC1 inhibited CRC cell proliferation and invasion in vitro and in vivo. We also found that lipase G (LIPG) is negatively regulated by ZDHHC1 and plays a key role in CRC cell growth through lipid storage. Additionally, we demonstrated that ZDHHC1 functions as a IGF2BP1-palmitoylating enzyme that induces S-palmitoylation at IGF2BP1-C337, which results in downregulated LIPG expression via m6A modification. Mechanistic investigations revealed that the ZDHHC1/IGF2BP1/LIPG signaling axis is associated with inhibition of CRC cell growth. Our study uncovers the potential role of ZDHHC1 in CRC, including inhibition of CRC growth by reducing the stability of LIPG mRNA in an m6A dependent-manner by palmitoylation of IGF2BP1.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"31 9","pages":"1427-1437"},"PeriodicalIF":4.8,"publicationDate":"2024-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-024-00808-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141771063","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

The long-term effectiveness and mechanism of oncolytic virotherapy combined with anti-PD-L1 antibody in colorectal cancer patient 溶瘤病毒疗法联合抗PD-L1抗体对结直肠癌患者的长期疗效及机制研究

IF 4.8 3区医学

Cancer gene therapy Pub Date : 2024-07-27 DOI: 10.1038/s41417-024-00807-2

Hangyu Zhang, Yiqing Ren, Feiyu Wang, Xiaoxuan Tu, Zhou Tong, Lulu Liu, Yi Zheng, Peng Zhao, Jinlin Cheng, Jianwen Li, Weijia Fang, Xia Liu

{"title":"The long-term effectiveness and mechanism of oncolytic virotherapy combined with anti-PD-L1 antibody in colorectal cancer patient","authors":"Hangyu Zhang, Yiqing Ren, Feiyu Wang, Xiaoxuan Tu, Zhou Tong, Lulu Liu, Yi Zheng, Peng Zhao, Jinlin Cheng, Jianwen Li, Weijia Fang, Xia Liu","doi":"10.1038/s41417-024-00807-2","DOIUrl":"10.1038/s41417-024-00807-2","url":null,"abstract":"Colorectal cancer (CRC) is known to be resistant to immunotherapy. In our phase-I clinical trial, one patient achieved a 313-day prolonged response during the combined treatment of oncolytic virotherapy and immunotherapy. To gain a deeper understanding of the potential molecular mechanisms, we performed a comprehensive multi-omics analysis on this patient and three non-responders. Our investigation unveiled that, initially, the tumor microenvironment (TME) of this responder presented minimal infiltration of T cells and natural killer cells, along with a relatively higher presence of macrophages compared to non-responders. Remarkably, during treatment, there was a progressive increase in CD4+ T cells, CD8+ T cells, and B cells in the responder’s tumor tissue. This was accompanied by a significant upregulation of transcription factors associated with T-cell activation and cytotoxicity, including GATA3, EOMES, and RUNX3. Furthermore, dynamic monitoring of peripheral blood samples from the responder revealed a rapid decrease in circulating tumor DNA (ctDNA), suggesting its potential as an early blood biomarker of treatment efficacy. Collectively, our findings demonstrate the effectiveness of combined oncolytic virotherapy and immunotherapy in certain CRC patients and provide molecular evidence that virotherapy can potentially transform a “cold” TME into a “hot” one, thereby improving sensitivity to immunotherapy.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"31 9","pages":"1412-1426"},"PeriodicalIF":4.8,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-024-00807-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141771065","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

Pathophysiological role of ion channels and transporters in hepatocellular carcinoma 离子通道和转运体在肝细胞癌中的病理生理学作用。

IF 4.8 3区医学

Cancer gene therapy Pub Date : 2024-07-24 DOI: 10.1038/s41417-024-00782-8

Li Zhang, Hong Gu, Xin Li, Yongfeng Wang, Shun Yao, Xingyue Chen, Liming Zheng, Xingyue Yang, Qian Du, Jiaxing An, Guorong Wen, Jiaxing Zhu, Hai Jin, Biguang Tuo

{"title":"Pathophysiological role of ion channels and transporters in hepatocellular carcinoma","authors":"Li Zhang, Hong Gu, Xin Li, Yongfeng Wang, Shun Yao, Xingyue Chen, Liming Zheng, Xingyue Yang, Qian Du, Jiaxing An, Guorong Wen, Jiaxing Zhu, Hai Jin, Biguang Tuo","doi":"10.1038/s41417-024-00782-8","DOIUrl":"10.1038/s41417-024-00782-8","url":null,"abstract":"The incidence of hepatocellular carcinoma (HCC) has continued to increase annually worldwide, and HCC has become a common cause of cancer-related death. Despite great progress in understanding the molecular mechanisms underlying HCC development, the treatment of HCC remains a considerable challenge. Thus, the survival and prognosis of HCC patients remain extremely poor. In recent years, the role of ion channels in the pathogenesis of diseases has become a hot topic. In normal liver tissue, ion channels and transporters maintain water and electrolyte balance and acid‒base homeostasis. However, dysfunction of these ion channels and transporters can lead to the development and progression of HCC, and thus these ion channels and transporters are expected to become new therapeutic targets. In this review, ion channels and transporters associated with HCC are reviewed, and potential targets for new and effective therapies are proposed.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"31 11","pages":"1611-1618"},"PeriodicalIF":4.8,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-024-00782-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757304","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

Atypical phosphatase DUSP11 inhibition promotes nc886 expression and potentiates gemcitabine-mediated cell death through NF-kB modulation 抑制非典型磷酸酶DUSP11可促进nc886的表达，并通过NF-kB调节增强吉西他滨介导的细胞死亡。

IF 4.8 3区医学

Cancer gene therapy Pub Date : 2024-07-24 DOI: 10.1038/s41417-024-00804-5

Verena Silva Santos, Gabriela Maciel Vieira, Mariana Tannús Ruckert, Pamela Viani de Andrade, Luis Fernando Nagano, Mariângela Ottoboni Brunaldi, José Sebastião Dos Santos, Vanessa Silva Silveira

{"title":"Atypical phosphatase DUSP11 inhibition promotes nc886 expression and potentiates gemcitabine-mediated cell death through NF-kB modulation","authors":"Verena Silva Santos, Gabriela Maciel Vieira, Mariana Tannús Ruckert, Pamela Viani de Andrade, Luis Fernando Nagano, Mariângela Ottoboni Brunaldi, José Sebastião Dos Santos, Vanessa Silva Silveira","doi":"10.1038/s41417-024-00804-5","DOIUrl":"10.1038/s41417-024-00804-5","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers among all solid tumors. First-line treatment relies on gemcitabine (Gem) and despite treatment improvements, refractoriness remains a universal challenge. Attempts to decipher how feedback-loops control signaling pathways towards drug resistance have gained attention in recent years, particularly focused on the role of phosphatases. In this study, a CRISPR/Cas9-based phenotypic screen was performed to identify members from the dual-specificity phosphatases (DUSP) family potentially acting on Gem response in PDAC cells. The approach revealed the atypical RNA phosphatase DUSP11 as a potential target, whose inhibition creates vulnerability of PDAC cells to Gem. DUSP11 genetic inhibition impaired cell survival and promoted apoptosis, synergistically enhancing Gem cytotoxicity. In silico transcriptome analysis of RNA-seq data from PDAC human samples identified NF-ĸB signaling pathway highly correlated with DUSP11 upregulation. Consistently, Gem-induced NF-ĸB phosphorylation was blocked upon DUSP11 inhibition in vitro. Mechanistically, we found that DUSP11 directly impacts nc886 expression and modulates PKR-NF-ĸB signaling cascade after Gem exposure in PDAC cells resulting in resistance to Gem-induced cell death. In conclusion, this study provides new insights on DUSP11 role in RNA biology and Gem response in PDAC cells.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"31 9","pages":"1402-1411"},"PeriodicalIF":4.8,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757303","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

Therapeutic activity of retroviral replicating vector-mediated gene therapy in combination with anti-PD-1 antibody in a murine pancreatic cancer model 逆转录病毒复制载体介导的基因疗法与抗-PD-1 抗体相结合在小鼠胰腺癌模型中的治疗活性。

IF 4.8 3区医学

Cancer gene therapy Pub Date : 2024-07-23 DOI: 10.1038/s41417-024-00810-7

Hiroki Niwa, Toru Nakamura, Hiroki Kushiya, Tomotaka Kuraya, Kazuho Inoko, Akihito Inagaki, Tomohiro Suzuki, Katsunori Sasaki, Takahiro Tsuchikawa, Kei Hiraoka, Toshiaki Shichinohe, Yutaka Hatanaka, Douglas J. Jolly, Noriyuki Kasahara, Satoshi Hirano

{"title":"Therapeutic activity of retroviral replicating vector-mediated gene therapy in combination with anti-PD-1 antibody in a murine pancreatic cancer model","authors":"Hiroki Niwa, Toru Nakamura, Hiroki Kushiya, Tomotaka Kuraya, Kazuho Inoko, Akihito Inagaki, Tomohiro Suzuki, Katsunori Sasaki, Takahiro Tsuchikawa, Kei Hiraoka, Toshiaki Shichinohe, Yutaka Hatanaka, Douglas J. Jolly, Noriyuki Kasahara, Satoshi Hirano","doi":"10.1038/s41417-024-00810-7","DOIUrl":"10.1038/s41417-024-00810-7","url":null,"abstract":"Toca 511, a tumor-selective retroviral replicating vector encoding the yeast cytosine deaminase (yCD) gene, exerts direct antitumor effects through intratumoral prodrug 5-fluorocytosine (5-FC) conversion to active drug 5-fluorouracil by yCD, and has demonstrated therapeutic efficacy in preclinical and clinical trials of various cancers. Toca 511/5-FC treatment may also induce antitumor immunity. Here, we first examined antitumor immune responses activated by Toca 511/5-FC treatment in an immunocompetent murine pancreatic cancer model. We then evaluated the therapeutic effects achieved in combination with anti-programmed cell death protein 1 antibody. In the bilateral subcutaneous tumor model, as compared with the control group, enhanced CD8+ T-cell-mediated cytotoxicity and increased T-cell infiltration in Toca 511-untransduced contralateral tumors were observed. Furthermore, the expression levels of T-cell co-inhibitory receptors on CD8+ T-cells increased during treatment. In the bilateral subcutaneous tumor model, combination therapy showed significantly stronger tumor growth inhibition than that achieved with either monotherapy. In an orthotopic tumor and peritoneal dissemination model, the combination therapy resulted in complete regression in both transduced orthotopic tumors and untransduced peritoneal dissemination. Thus, Toca 511/5-FC treatment induced a systemic antitumor immune response, and the combination therapy could be a promising clinical strategy for treating metastatic pancreatic cancer.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"31 9","pages":"1390-1401"},"PeriodicalIF":4.8,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747535","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

Atypical cellular responses mediated by intracellular constitutive active TrkB (NTRK2) kinase domains and a solely intracellular NTRK2-fusion oncogene 由细胞内组成型活性TrkB（NTRK2）激酶结构域和单纯细胞内NTRK2融合型癌基因介导的非典型细胞反应

IF 4.8 3区医学

Cancer gene therapy Pub Date : 2024-07-22 DOI: 10.1038/s41417-024-00809-0

Rohini Gupta, Melanie Dittmeier, Gisela Wohlleben, Vera Nickl, Thorsten Bischler, Vanessa Luzak, Vanessa Wegat, Dennis Doll, Annemarie Sodmann, Elena Bady, Georg Langlhofer, Britta Wachter, Steven Havlicek, Jahnve Gupta, Evi Horn, Patrick Lüningschrör, Carmen Villmann, Bülent Polat, Jörg Wischhusen, Camelia M. Monoranu, Jochen Kuper, Robert Blum

{"title":"Atypical cellular responses mediated by intracellular constitutive active TrkB (NTRK2) kinase domains and a solely intracellular NTRK2-fusion oncogene","authors":"Rohini Gupta, Melanie Dittmeier, Gisela Wohlleben, Vera Nickl, Thorsten Bischler, Vanessa Luzak, Vanessa Wegat, Dennis Doll, Annemarie Sodmann, Elena Bady, Georg Langlhofer, Britta Wachter, Steven Havlicek, Jahnve Gupta, Evi Horn, Patrick Lüningschrör, Carmen Villmann, Bülent Polat, Jörg Wischhusen, Camelia M. Monoranu, Jochen Kuper, Robert Blum","doi":"10.1038/s41417-024-00809-0","DOIUrl":"10.1038/s41417-024-00809-0","url":null,"abstract":"Trk (NTRK) receptor and NTRK gene fusions are oncogenic drivers of a wide variety of tumors. Although Trk receptors are typically activated at the cell surface, signaling of constitutive active Trk and diverse intracellular NTRK fusion oncogenes is barely investigated. Here, we show that a high intracellular abundance is sufficient for neurotrophin-independent, constitutive activation of TrkB kinase domains. In HEK293 cells, constitutive active TrkB kinase and an intracellular NTRK2-fusion oncogene (SQSTM1-NTRK2) reduced actin filopodia dynamics, phosphorylated FAK, and altered the cell morphology. Atypical cellular responses could be mimicked with the intracellular kinase domain, which did not activate the Trk-associated MAPK/ERK pathway. In glioblastoma-like U87MG cells, expression of TrkB or SQSTM1-NTRK2 reduced cell motility and caused drastic changes in the transcriptome. Clinically approved Trk inhibitors or mutating Y705 in the kinase domain, blocked the cellular effects and transcriptome changes. Atypical signaling was also seen for TrkA and TrkC. Moreover, hallmarks of atypical pTrk kinase were found in biopsies of Nestin-positive glioblastoma. Therefore, we suggest Western blot-like immunoassay screening of NTRK-related (brain) tumor biopsies to identify patients with atypical panTrk or phosphoTrk signals. Such patients could be candidates for treatment with NTRK inhibitors such as Larotrectinhib or Entrectinhib.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"31 9","pages":"1357-1379"},"PeriodicalIF":4.8,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-024-00809-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141744511","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

HADHA promotes glioma progression by accelerating MDM2-mediated p53 ubiquitination HADHA 通过加速 MDM2- 介导的 p53 泛素化促进胶质瘤进展

IF 4.8 3区医学

Cancer gene therapy Pub Date : 2024-07-22 DOI: 10.1038/s41417-024-00801-8

Rudong Chen, Hao Chen, Changchen Hu

{"title":"HADHA promotes glioma progression by accelerating MDM2-mediated p53 ubiquitination","authors":"Rudong Chen, Hao Chen, Changchen Hu","doi":"10.1038/s41417-024-00801-8","DOIUrl":"10.1038/s41417-024-00801-8","url":null,"abstract":"Glioma represents a notoriously aggressive and malignant tumor that targets the central nervous system, with a poor prognosis for patients. In this research, we set out to examine the role of hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA) in glioma, its clinical significance, as well as its potential biological mechanisms. In this study, we used immunohistochemistry staining to assess the expression level of HADHA in glioma tissues. We also evaluated the correlation between HADHA expression and patient survival using the Kaplan–Meier method. To determine the role of HADHA in glioma cells, we conducted loss-of-function assays in vitro and in vivo. Additionally, we utilized co-immunoprecipitation and protein stability assays to investigate the potential mechanisms involving HADHA, MDM2, and p53 in glioma. Our research findings indicate that gliomas exhibit high levels of HADHA. Clinically, high expression of HADHA suggests an increased risk of malignant tumors, recurrence, and reduced survival rates. Functionally, knocking down HADHA can lead to decreased proliferation, enhanced apoptosis, and inhibited migration of glioma cells. Mechanistically, HADHA accelerates MDM2-mediated p53 ubiquitination through interaction with MDM2. Consistently, MDM2 knockdown or overexpression of p53 can attenuate the promoting effect of HADHA overexpression on the malignant progression of glioma. We have discovered a novel role of HADHA in promoting MDM2-mediated p53 ubiquitination, which contributes to the progression of glioma. This finding provides a new perspective to understand the pathogenesis of glioma and offers a potential target for developing innovative therapeutic strategies.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"31 9","pages":"1380-1389"},"PeriodicalIF":4.8,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141744509","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

NF-κB role on tumor proliferation, migration, invasion and immune escape NF-κB 在肿瘤增殖、迁移、侵袭和免疫逃逸中的作用。

IF 4.8 3区医学

Cancer gene therapy Pub Date : 2024-07-20 DOI: 10.1038/s41417-024-00811-6

Afrasyab Khan, Yao Zhang, Ningna Ma, Juanjuan Shi, Yongzhong Hou

引用次数: 0