Oncogenesis最新文献_第2页

Tumor suppressor BAP1 suppresses disulfidptosis through the regulation of SLC7A11 and NADPH levels 肿瘤抑制因子 BAP1 通过调节 SLC7A11 和 NADPH 水平抑制二硫化硫作用

IF 6.2 2区医学

Oncogenesis Pub Date : 2024-09-12 DOI: 10.1038/s41389-024-00535-0

Jin Wang, Minglin Wang, Shaobo Wu, Yanan Zhu, Kexin Fan, Yuhan Chen, Zhengtao Xiao, Jing Chen, Kangsheng Tu, Dongsheng Huang, Yilei Zhang, Qiuran Xu

{"title":"Tumor suppressor BAP1 suppresses disulfidptosis through the regulation of SLC7A11 and NADPH levels","authors":"Jin Wang, Minglin Wang, Shaobo Wu, Yanan Zhu, Kexin Fan, Yuhan Chen, Zhengtao Xiao, Jing Chen, Kangsheng Tu, Dongsheng Huang, Yilei Zhang, Qiuran Xu","doi":"10.1038/s41389-024-00535-0","DOIUrl":"https://doi.org/10.1038/s41389-024-00535-0","url":null,"abstract":"BAP1, BRCA1-Associated Protein 1, serves as a novel tumor suppressor through the deubiquitination of monoubiquitination of H2A and subsequent gene transcriptional regulation. Regulated cell death like apoptosis or ferroptosis is considered an essential mechanism mediating tumor suppression. Previous reports, including ours, have demonstrated that BAP1 could promote apoptosis and ferroptosis to inhibit tumor development. Whether BAP1 regulated additional types of cell death remains unclear. Disulfidptosis is a recently identified novel cell death mode characterized by aberrant accumulation of intracellular disulfide (e.g., cystine) and depletion of NADPH. In this study, we first demonstrated that BAP1 could significantly protect disulfidptosis induced by glucose starvation, which is validated by various cell death inhibitors and the accumulation of disulfide bonds in the cytoskeleton proteins. BAP1 is known to inhibit SLC7A11 expression. We found that the protective effect of BAP1 against disulfidptosis was counteracted when overexpressing SLC7A11 or adding additional cystine. Conversely, BAP1-mediated suppression of disulfidptosis was largely abrogated when SLC7A11-mediated cystine uptake was inhibited by the knockout of SLC7A11 or erastin treatment. Besides, high BAP1 expression showed lower NADP+/NADPH levels, which might confer resistance to disulfidptosis. Consistent with these observations, the expression level of BAP1 was also positively correlated with NADPH-related genes in KIRC patients, though the underlying mechanism mediating NADPH regulation remains further investigation. In summary, our results revealed the role of BAP1 in the regulation disulfidptosis and provided new insights into the understanding of disulfidptosis in tumor development.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"68 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142189059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Peptidylarginine deiminase 3 modulates response to neratinib in HER2 positive breast cancer. 肽基精氨酸脱氨酶3调节HER2阳性乳腺癌患者对奈瑞替尼的反应

IF 5.9 2区医学

Oncogenesis Pub Date : 2024-08-04 DOI: 10.1038/s41389-024-00531-4

Inés Romero-Pérez, Elena Díaz-Rodríguez, Laura Sánchez-Díaz, Juan Carlos Montero, Atanasio Pandiella

{"title":"Peptidylarginine deiminase 3 modulates response to neratinib in HER2 positive breast cancer.","authors":"Inés Romero-Pérez, Elena Díaz-Rodríguez, Laura Sánchez-Díaz, Juan Carlos Montero, Atanasio Pandiella","doi":"10.1038/s41389-024-00531-4","DOIUrl":"10.1038/s41389-024-00531-4","url":null,"abstract":"Neratinib is a tyrosine kinase inhibitor that is used for the therapy of patients with HER2+ breast tumors. However, despite its clinical benefit, resistance to the drug may arise. Here we have created cellular models of neratinib resistance to investigate the mechanisms underlying such resistance. Chronic neratinib exposure of BT474 human HER2+ breast cancer cells resulted in the selection of several clones resistant to the antiproliferative action of the drug. The clones were characterized biochemically and biologically using a variety of techniques. These clones retained HER2 levels similar to parental cells. Knockdown experiments showed that the neratinib-resistant clones retained oncogenic dependence on HER2. Moreover, the tyrosine phosphorylation status of BT474 and the resistant clones was equally sensitive to neratinib. Transcriptomic and Western analyses showed that peptidylarginine deiminase 3 was overexpressed in the three neratinib-resistant clones studied but was undetectable in BT474 cells. Experiments performed in the neratinib-resistant clones showed that reduction of PADI3 or inhibition of its function restored sensitivity to the antiproliferative action of neratinib. Moreover, overexpression of FLAG-tagged PADI3 in BT474 cells provoked resistance to the antiproliferative action of neratinib. Together, these results uncover a role of PADI3 in the regulation of sensitivity to neratinib in breast cancer cells overexpressing HER2 and open the possibility of using PADI3 inhibitors to fight resistance to neratinib.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"30"},"PeriodicalIF":5.9,"publicationDate":"2024-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Combined Inhibition of PI3K and STAT3 signaling effectively inhibits bladder cancer growth 联合抑制 PI3K 和 STAT3 信号传导可有效抑制膀胱癌生长

IF 6.2 2区医学

Oncogenesis Pub Date : 2024-07-27 DOI: 10.1038/s41389-024-00529-y

Weidong Peng, Haojie Zhang, Mingwei Yin, Dejie Kong, Liping Kang, Xinkun Teng, Jingjing Wang, Zhimin Chu, Yating Sun, Pengpeng Long, Chengying Cui, Bin Lyu, Jinzhi Zhang, Han Xiao, Mingqing Wu, Yongqiang Wang, Yang Li

{"title":"Combined Inhibition of PI3K and STAT3 signaling effectively inhibits bladder cancer growth","authors":"Weidong Peng, Haojie Zhang, Mingwei Yin, Dejie Kong, Liping Kang, Xinkun Teng, Jingjing Wang, Zhimin Chu, Yating Sun, Pengpeng Long, Chengying Cui, Bin Lyu, Jinzhi Zhang, Han Xiao, Mingqing Wu, Yongqiang Wang, Yang Li","doi":"10.1038/s41389-024-00529-y","DOIUrl":"https://doi.org/10.1038/s41389-024-00529-y","url":null,"abstract":"Bladder cancer is characterized by aberrant activation of the phosphatidylinositol-3-OH kinase (PI3K) signaling, underscoring the significance of directing therapeutic efforts toward the PI3K pathway as a promising strategy. In this study, we discovered that PI3K serves as a potent therapeutic target for bladder cancer through a high-throughput screening of inhibitory molecules. The PI3K inhibitor demonstrated a robust anti-tumor efficacy, validated both in vitro and in vivo settings. Nevertheless, the feedback activation of JAK1-STAT3 signaling reinstated cell and organoid survival, leading to resistance against the PI3K inhibitor. Mechanistically, the PI3K inhibitor suppresses PTPN11 expression, a negative regulator of the JAK-STAT pathway, thereby activating STAT3. Conversely, restoration of PTPN11 enhances the sensitivity of cancer cells to the PI3K inhibitor. Simultaneous inhibition of both PI3K and STAT3 with small-molecule inhibitors resulted in sustained tumor regression in patient-derived bladder cancer xenografts. These findings advocate for a combinational therapeutic approach targeting both PI3K and STAT3 pathways to achieve enduring cancer eradication in vitro and in vivo, underscoring their promising therapeutic efficacy for treating bladder cancer.<figure></figure>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"40 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141782188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Cell competition in primary and metastatic colorectal cancer. 原发性和转移性结直肠癌中的细胞竞争。

IF 5.9 2区医学

Oncogenesis Pub Date : 2024-07-26 DOI: 10.1038/s41389-024-00530-5

Merel Elise van Luyk, Ana Krotenberg Garcia, Maria Lamprou, Saskia Jacoba Elisabeth Suijkerbuijk

引用次数: 0

USP32 facilitates non-small cell lung cancer progression via deubiquitinating BAG3 and activating RAF-MEK-ERK signaling pathway. USP32 通过去泛素化 BAG3 和激活 RAF-MEK-ERK 信号通路促进非小细胞肺癌的进展。

IF 5.9 2区医学

Oncogenesis Pub Date : 2024-07-19 DOI: 10.1038/s41389-024-00528-z

Shuang Li, Lina Yang, Xiaoyan Ding, Hongxiao Sun, Xiaolei Dong, Fanghao Yang, Mengjun Wang, Huhu Zhang, Ya Li, Bing Li, Chunyan Liu

{"title":"USP32 facilitates non-small cell lung cancer progression via deubiquitinating BAG3 and activating RAF-MEK-ERK signaling pathway.","authors":"Shuang Li, Lina Yang, Xiaoyan Ding, Hongxiao Sun, Xiaolei Dong, Fanghao Yang, Mengjun Wang, Huhu Zhang, Ya Li, Bing Li, Chunyan Liu","doi":"10.1038/s41389-024-00528-z","DOIUrl":"10.1038/s41389-024-00528-z","url":null,"abstract":"The regulatory significance of ubiquitin-specific peptidase 32 (USP32) in tumor is significant, nevertheless, the biological roles and regulatory mechanisms of USP32 in non-small cell lung cancer (NSCLC) remain unclear. According to our research, USP32 was strongly expressed in NSCLC cell lines and tissues and was linked to a bad prognosis for NSCLC patients. Interference with USP32 resulted in a significant inhibition of NSCLC cell proliferation, migration potential, and EMT development; on the other hand, USP32 overexpression had the opposite effect. To further elucidate the mechanism of action of USP32 in NSCLC, we screened H1299 cells for interacting proteins and found that USP32 interacts with BAG3 (Bcl2-associated athanogene 3) and deubiquitinates and stabilizes BAG3 in a deubiquitinating activity-dependent manner. Functionally, restoration of BAG3 expression abrogated the antitumor effects of USP32 silencing. Furthermore, USP32 increased the phosphorylation level of the RAF/MEK/ERK signaling pathway in NSCLC cells by stabilizing BAG3. In summary, these findings imply that USP32 is critical to the development of NSCLC and could offer a theoretical framework for the clinical diagnosis and management of NSCLC patients in the future.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"27"},"PeriodicalIF":5.9,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11271578/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

YAP/TAZ interacts with RBM39 to confer resistance against indisulam. YAP/TAZ 与 RBM39 相互作用，赋予茚虫威抗性。

IF 5.9 2区医学

Oncogenesis Pub Date : 2024-07-15 DOI: 10.1038/s41389-024-00527-0

Toshinori Ando, Kento Okamoto, Yume Ueda, Nanako Kataoka, Tomoaki Shintani, Souichi Yanamoto, Mutsumi Miyauchi, Mikihito Kajiya

{"title":"YAP/TAZ interacts with RBM39 to confer resistance against indisulam.","authors":"Toshinori Ando, Kento Okamoto, Yume Ueda, Nanako Kataoka, Tomoaki Shintani, Souichi Yanamoto, Mutsumi Miyauchi, Mikihito Kajiya","doi":"10.1038/s41389-024-00527-0","DOIUrl":"10.1038/s41389-024-00527-0","url":null,"abstract":"The Hippo pathway and its downstream effectors, Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ), are essential for cell growth and organ development. Emerging evidence revealed that the Hippo pathway and YAP/TAZ are frequently dysregulated by multiple genetic alterations in solid cancers including head and neck squamous cell carcinoma (HNSCC); however, the YAP/TAZ-nuclear interactome remains unclear. RNA-binding motif protein 39 (RBM39) enhances transcriptional activity of several transcription factors and also regulates mRNA splicing. Indisulam degrading RBM39 induces alternative splicing, leading to cell death. However, clinical trials of indisulam have failed to show effectiveness. Therefore, clarifying the resistance mechanism against splicing inhibitors is urgently required. In this study, we identified RBM39 as a novel YAP/TAZ-interacting molecule by proteome analysis. RBM39 promoted YAP/TAZ transcriptional activity. We further elucidated that indisulam reduces RBM39/YAP/TAZ-mediated integrin or collagen expression, thereby inactivating focal adhesion kinase (FAK) important for cell survival. Moreover, indisulam also induced alternative splicing of cell cycle- or DNA metabolism-related genes. YAP/TAZ hyperactivation delayed indisulam-induced RBM39 degradation, which restored the integrin/collagen expression to activate FAK, and alternative splicing, thereby conferring resistance against indisulam in vitro and in vivo. Our findings may aid to develop a novel cancer therapy focusing on YAP/TAZ/RBM39 interaction.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"25"},"PeriodicalIF":5.9,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11247092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gemcitabine as chemotherapy of head and neck cancer in Fanconi anemia patients. 吉西他滨作为范可尼贫血症患者头颈癌的化疗药物。

IF 5.9 2区医学

Oncogenesis Pub Date : 2024-07-11 DOI: 10.1038/s41389-024-00525-2

Anne M van Harten, Ronak Shah, D Vicky de Boer, Marijke Buijze, Maaike Kreft, Ji-Ying Song, Lisa M Zürcher, Heinz Jacobs, Ruud H Brakenhoff

{"title":"Gemcitabine as chemotherapy of head and neck cancer in Fanconi anemia patients.","authors":"Anne M van Harten, Ronak Shah, D Vicky de Boer, Marijke Buijze, Maaike Kreft, Ji-Ying Song, Lisa M Zürcher, Heinz Jacobs, Ruud H Brakenhoff","doi":"10.1038/s41389-024-00525-2","DOIUrl":"10.1038/s41389-024-00525-2","url":null,"abstract":"Fanconi anemia (FA) is a rare hereditary disease resulting from an inactivating mutation in the FA/BRCA pathway, critical for the effective repair of DNA interstrand crosslinks (ICLs). The disease is characterized by congenital abnormalities, progressing bone marrow failure, and an increased risk of developing malignancies early in life, in particular head and neck squamous cell carcinoma (HNSCC). While ICL-inducing cisplatin combined with radiotherapy is a mainstay of HNSCC treatment, cisplatin is contra-indicated for FA-HNSCC patients. This dilemma necessitates the identification of novel treatment modalities tolerated by FA-HNSCC patients. To identify druggable targets, an siRNA-based genetic screen was previously performed in HNSCC-derived cell lines from FA and non-FA tumor origin. Here, we report that the Ribonucleotide Reductase (RNR) complex, consisting of the RRM1 and RRM2 subunits, was identified as a therapeutic target for both, FA and non-FA HNSCC. While non-FA HNSCC cells responded differentially to RNR depletion, FA-HNSCC cells were consistently found hypersensitive. This insight was confirmed pharmacologically using 2', 2'-difluoro 2'deoxycytidine (dFdC), also known as gemcitabine, a clinically used nucleotide analog that is a potent inhibitor of the RNR complex. Importantly, while cisplatin exposure displayed severe, long-lasting toxicity on the hematopoietic stem and progenitor compartments in Fancg-/- mice, gemcitabine was well tolerated and had only a mild, transient impact. Taken together, our data implicate that gemcitabine-based chemoradiotherapy could serve as an alternative HNSCC treatment in Fanconi patients, and deserves clinical testing.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"26"},"PeriodicalIF":5.9,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11239817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141590964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Involvement of Kindlin-1 in cutaneous squamous cell carcinoma. 皮肤鳞状细胞癌中 Kindlin-1 的参与。

IF 5.9 2区医学

Oncogenesis Pub Date : 2024-07-09 DOI: 10.1038/s41389-024-00526-1

Giovana Carrasco, Ifigeneia Stavrou, Mairi Treanor-Taylor, Henry Beetham, Martin Lee, Roza Masalmeh, Artur Carreras-Soldevila, David Hardman, Miguel O Bernabeu, Alex von Kriegsheim, Gareth J Inman, Adam Byron, Valerie G Brunton

{"title":"Involvement of Kindlin-1 in cutaneous squamous cell carcinoma.","authors":"Giovana Carrasco, Ifigeneia Stavrou, Mairi Treanor-Taylor, Henry Beetham, Martin Lee, Roza Masalmeh, Artur Carreras-Soldevila, David Hardman, Miguel O Bernabeu, Alex von Kriegsheim, Gareth J Inman, Adam Byron, Valerie G Brunton","doi":"10.1038/s41389-024-00526-1","DOIUrl":"10.1038/s41389-024-00526-1","url":null,"abstract":"Kindler syndrome (KS) is a rare genodermatosis resulting from loss-of-function mutations in FERMT1, the gene that encodes Kindlin-1. KS patients have a high propensity to develop aggressive and metastatic cutaneous squamous cell carcinoma (cSCC). Here we show in non-KS-associated patients that elevation of FERMT1 expression is increased in actinic keratoses compared to normal skin, with a further increase in cSCC supporting a pro-tumorigenic role in this population. In contrast, we show that loss of Kindlin-1 leads to increased SCC tumor growth in vivo and in 3D spheroids, which was associated with the development of a hypoxic tumor environment and increased glycolysis. The metalloproteinase Mmp13 was upregulated in Kindlin-1-depleted tumors, and increased expression of MMP13 was responsible for driving increased invasion of the Kindlin-1-depleted SCC cells. These results provide evidence that Kindlin-1 loss in SCC can promote invasion through the upregulation of MMP13, and offer novel insights into how Kindlin-1 loss leads to the development of a hypoxic environment that is permissive for tumor growth.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"24"},"PeriodicalIF":5.9,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11233684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141563991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

USP21-mediated G3BP1 stabilization accelerates proliferation and metastasis of esophageal squamous cell carcinoma via activating Wnt/β-Catenin signaling. USP21 介导的 G3BP1 稳定通过激活 Wnt/β-Catenin 信号加速了食管鳞状细胞癌的增殖和转移。

IF 5.9 2区医学

Oncogenesis Pub Date : 2024-06-21 DOI: 10.1038/s41389-024-00524-3

Jiazhong Guo, Yunpeng Zhao, Huacong Sui, Lei Liu, Fanrong Liu, Lingxiao Yang, Fengyuan Gao, Jinfu Wang, Yilin Zhu, Lingbing Li, Xiangqing Song, Peng Li, Zhongxian Tian, Peichao Li, Xiaogang Zhao

{"title":"USP21-mediated G3BP1 stabilization accelerates proliferation and metastasis of esophageal squamous cell carcinoma via activating Wnt/β-Catenin signaling.","authors":"Jiazhong Guo, Yunpeng Zhao, Huacong Sui, Lei Liu, Fanrong Liu, Lingxiao Yang, Fengyuan Gao, Jinfu Wang, Yilin Zhu, Lingbing Li, Xiangqing Song, Peng Li, Zhongxian Tian, Peichao Li, Xiaogang Zhao","doi":"10.1038/s41389-024-00524-3","DOIUrl":"10.1038/s41389-024-00524-3","url":null,"abstract":"Lacking effective therapeutic targets heavily restricts the improvement of clinical prognosis for patients diagnosed with esophageal squamous cell carcinoma (ESCC). Ubiquitin Specific Peptidase 21 (USP21) is dysregulated in plenty of human cancers, however, its potential function and relevant molecular mechanisms in ESCC malignant progression as well as its value in clinical translation remain largely unknown. Here, in vitro and in vivo experiments revealed that aberrant upregulation of USP21 accelerated the proliferation and metastasis of ESCC in a deubiquitinase-dependent manner. Mechanistically, we found that USP21 binds to, deubiquitinates, and stabilizes the G3BP Stress Granule Assembly Factor 1 (G3BP1) protein, which is required for USP21-mediated ESCC progression. Further molecular studies demonstrated that the USP21/G3BP1 axis played a tumor-promoting role in ESCC progression by activating the Wnt/β-Catenin signaling pathway. Additionally, disulfiram (DSF), an inhibitor against USP21 deubiquitylation activity, markedly abolished the USP21-mediated stability of G3BP1 protein and significantly displayed an anti-tumor effect on USP21-driving ESCC progression. Finally, the regulatory axis of USP21/G3BP1 was demonstrated to be aberrantly activated in ESCC tumor tissues and closely associated with advanced clinical stages and unfavorable prognoses, which provides a promising therapeutic strategy targeting USP21/G3BP1 axis for ESCC patients.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"23"},"PeriodicalIF":5.9,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11192907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141437268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Activated platelet-derived exosomal LRG1 promotes multiple myeloma cell growth. 活化的血小板衍生外泌体 LRG1 可促进多发性骨髓瘤细胞的生长。

IF 6.2 2区医学

Oncogenesis Pub Date : 2024-06-13 DOI: 10.1038/s41389-024-00522-5

Meng Gao, Hang Dong, Siyi Jiang, Fangping Chen, Yunfeng Fu, Yanwei Luo

{"title":"Activated platelet-derived exosomal LRG1 promotes multiple myeloma cell growth.","authors":"Meng Gao, Hang Dong, Siyi Jiang, Fangping Chen, Yunfeng Fu, Yanwei Luo","doi":"10.1038/s41389-024-00522-5","DOIUrl":"10.1038/s41389-024-00522-5","url":null,"abstract":"The hypercoagulable state is a hallmark for patients with multiple myeloma (MM) and is associated with disease progression. Activated platelets secrete exosomes and promote solid tumor growth. However, the role of platelet-derived exosomes in MM is not fully clear. We aim to study the underlying mechanism of how platelet-derived exosomes promote MM cell growth. Flow cytometry, Western blot, proteome analysis, co-immunoprecipitation, immunofluorescence staining, and NOD/SCID mouse subcutaneous transplantation model were performed to investigate the role of exosomal LRG1 on multiple myeloma cell growth. Peripheral blood platelets in MM patients were in a highly activated state, and platelet-rich plasma from MM patients significantly promoted cell proliferation and decreased apoptotic cells in U266 and RPMI8226 cells. Leucine-rich-alpha-2-glycoprotein 1 (LRG1) was significantly enriched in MM platelet-derived exosomes. Blocking LRG1 in recipient cells using LRG1 antibody could significantly eliminate the proliferation-promoting effect of platelet-derived exosomes on MM cells. And high exosomal LRG1 was associated with poor prognosis of patients with MM. Mechanistic studies revealed that LRG1 interacted with Olfactomedin 4 (OLFM4) to accelerate MM progression by activating the epithelial-to-mesenchymal transition (EMT) signaling pathway and promoting angiogenesis. Our results revealed that blocking LRG1 is a promising therapeutic strategy for the treatment of MM.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"21"},"PeriodicalIF":6.2,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11176168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141317934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0