首页 > 最新文献

Oncogene最新文献

英文 中文
Delactylase effects of SIRT1 on a positive feedback loop involving the H19-glycolysis-histone lactylation in gastric cancer SIRT1在胃癌h19糖酵解-组蛋白乳酸化正反馈回路中的脱乙酰酶作用。
IF 6.9 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-11 DOI: 10.1038/s41388-024-03243-6
Shu Tsukihara, Yoshimitsu Akiyama, Shu Shimada, Megumi Hatano, Yosuke Igarashi, Tomohiko Taniai, Yoshiaki Tanji, Keita Kodera, Koya Yasukawa, Kentaro Umeura, Atsushi Kamachi, Atsushi Nara, Keisuke Okuno, Masanori Tokunaga, Hiroto Katoh, Shumpei Ishikawa, Toru Ikegami, Yusuke Kinugasa, Ken Eto, Shinji Tanaka
Histone lactylation, a novel epigenetic modification, is regulated by the lactate produced by glycolysis. Glycolysis is activated in various cancers, including gastric cancer (GC). However, the molecular mechanism and clinical impact of histone lactylation in GC remain poorly understood. Here, we demonstrate that histone H3K18 lactylation (H3K18la) is elevated in GC, correlating with a worse prognosis. SIRT1 overexpression decreases H3K18la levels, whereas SIRT1 knockdown increases H3K18la levels in GC cells. RNA-seq analysis demonstrates that lncRNA H19 is markedly downregulated in GC cells with SIRT1 overexpression and those grown under glucose free condition, which confirmed decreased H3K18la levels at its promoter region. H19 knockdown decreased the expression levels of LDHA and H3K18la, and LDHA knockdown impaired H19 and H3K18la expression, suggesting an H19/glycolysis/H3K18la-positive feedback loop. Combined treatment with low doses of the SIRT1-specific activator SRT2104 and the LDHA inhibitor oxamate exerted significant antitumor effects on GC cells, with limited adverse effects on normal gastric cells. The SIRT1-weak/H3K18la-strong signature was found to be an independent prognostic factor in patients with GC. Therefore, SIRT1 acts as a histone delactylase for H3K18, and loss of SIRT1 triggers a positive feedback loop involving H19/glycolysis/H3K18la. Targeting this pathway serves as a novel therapeutic strategy for GC treatment.
组蛋白乳酸化是一种新的表观遗传修饰,由糖酵解产生的乳酸调节。糖酵解在多种癌症中被激活,包括胃癌(GC)。然而,GC中组蛋白乳酸化的分子机制和临床影响尚不清楚。在这里,我们证明组蛋白H3K18乳酸化(H3K18la)在胃癌中升高,与较差的预后相关。在GC细胞中,SIRT1过表达会降低H3K18la水平,而SIRT1敲低会增加H3K18la水平。RNA-seq分析显示,lncRNA H19在SIRT1过表达的GC细胞和无糖条件下生长的GC细胞中明显下调,这证实了其启动子区域的H3K18la水平降低。H19敲低降低了LDHA和H3K18la的表达水平,LDHA敲低降低了H19和H3K18la的表达,提示H19/糖酵解/H3K18la正反馈回路。低剂量sirt1特异性激活剂SRT2104和LDHA抑制剂草酸酯联合治疗对胃癌细胞有显著的抗肿瘤作用,对正常胃细胞的不良反应有限。sirt1弱/ h3k18la强信号被发现是胃癌患者的独立预后因素。因此,SIRT1作为H3K18的组蛋白去乙酰化酶,SIRT1的缺失触发了一个涉及H19/糖酵解/H3K18la的正反馈循环。靶向这一途径是胃癌治疗的一种新的治疗策略。
{"title":"Delactylase effects of SIRT1 on a positive feedback loop involving the H19-glycolysis-histone lactylation in gastric cancer","authors":"Shu Tsukihara, Yoshimitsu Akiyama, Shu Shimada, Megumi Hatano, Yosuke Igarashi, Tomohiko Taniai, Yoshiaki Tanji, Keita Kodera, Koya Yasukawa, Kentaro Umeura, Atsushi Kamachi, Atsushi Nara, Keisuke Okuno, Masanori Tokunaga, Hiroto Katoh, Shumpei Ishikawa, Toru Ikegami, Yusuke Kinugasa, Ken Eto, Shinji Tanaka","doi":"10.1038/s41388-024-03243-6","DOIUrl":"10.1038/s41388-024-03243-6","url":null,"abstract":"Histone lactylation, a novel epigenetic modification, is regulated by the lactate produced by glycolysis. Glycolysis is activated in various cancers, including gastric cancer (GC). However, the molecular mechanism and clinical impact of histone lactylation in GC remain poorly understood. Here, we demonstrate that histone H3K18 lactylation (H3K18la) is elevated in GC, correlating with a worse prognosis. SIRT1 overexpression decreases H3K18la levels, whereas SIRT1 knockdown increases H3K18la levels in GC cells. RNA-seq analysis demonstrates that lncRNA H19 is markedly downregulated in GC cells with SIRT1 overexpression and those grown under glucose free condition, which confirmed decreased H3K18la levels at its promoter region. H19 knockdown decreased the expression levels of LDHA and H3K18la, and LDHA knockdown impaired H19 and H3K18la expression, suggesting an H19/glycolysis/H3K18la-positive feedback loop. Combined treatment with low doses of the SIRT1-specific activator SRT2104 and the LDHA inhibitor oxamate exerted significant antitumor effects on GC cells, with limited adverse effects on normal gastric cells. The SIRT1-weak/H3K18la-strong signature was found to be an independent prognostic factor in patients with GC. Therefore, SIRT1 acts as a histone delactylase for H3K18, and loss of SIRT1 triggers a positive feedback loop involving H19/glycolysis/H3K18la. Targeting this pathway serves as a novel therapeutic strategy for GC treatment.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 11","pages":"724-738"},"PeriodicalIF":6.9,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Senescent lung fibroblasts in idiopathic pulmonary fibrosis facilitate non-small cell lung cancer progression by secreting exosomal MMP1 特发性肺纤维化中衰老的肺成纤维细胞通过分泌外泌体MMP1促进非小细胞肺癌的进展。
IF 6.9 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-11 DOI: 10.1038/s41388-024-03236-5
Yuqiong Lei, Cheng Zhong, Jingyuan Zhang, Qi Zheng, Yongle Xu, Zhoubin Li, Chenwen Huang, Tao Ren
Lung cancer is a fatal complication of idiopathic pulmonary fibrosis (IPF) with a poor prognosis. Current treatments are insufficient in improving the prognosis of lung cancer patients with comorbid idiopathic pulmonary fibrosis (IPF-LC). Senescent fibroblasts, as stromal cells in the tumor microenvironment, influence tumor progression via exosomes. With evidence that fibroblast senescence is an important mechanism of IPF, we investigated the impact of senescent IPF lung fibroblast (diseased human lung fibroblasts, DHLF)-derived exosomes on non-small cell lung cancer (NSCLC). We found DHLF expressed significant senescence markers, and promoted NSCLC proliferation, invasion, and epithelial-mesenchymal transition. Specifically, senescent DHLF showed strong secretion of exosomes, and these exosomes enhanced the proliferation and colony-forming ability of cancer cells. Proteomic analysis showed DHLF-derived exosomes exhibited upregulated senescence-associated secretory phenotype (SASP) factors, notably MMP1, which activates the surface receptor PAR1. Knocking down MMP1 or using PAR1 inhibitors reduced the tumor-promoting effects of DHLF-derived exosomes in vivo and in vitro. Mechanistically, MMP1 acted by activating the PI3K-AKT-mTOR pathway. In conclusion, our results suggest that exosomal MMP1 derived from senescent IPF fibroblasts promotes NSCLC proliferation and colony formation by targeting PAR1 and activating the PI3K-AKT-mTOR pathway. These findings provide a novel therapeutic approach for patients with IPF-LC.
肺癌是特发性肺纤维化(IPF)的致命并发症,预后较差。目前的治疗方法不足以改善肺癌合并特发性肺纤维化(IPF-LC)患者的预后。衰老成纤维细胞作为肿瘤微环境中的基质细胞,通过外泌体影响肿瘤的进展。有证据表明成纤维细胞衰老是IPF的一个重要机制,我们研究了衰老的IPF肺成纤维细胞(患病人肺成纤维细胞,DHLF)衍生的外泌体对非小细胞肺癌(NSCLC)的影响。我们发现DHLF表达显著的衰老标志物,促进非小细胞肺癌的增殖、侵袭和上皮-间质转化。具体而言,衰老的DHLF表现出强烈的外泌体分泌,这些外泌体增强了癌细胞的增殖和集落形成能力。蛋白质组学分析显示,dhlf衍生的外泌体表现出衰老相关分泌表型(SASP)因子上调,特别是激活表面受体PAR1的MMP1。在体内和体外,敲除MMP1或使用PAR1抑制剂可降低dhlf衍生外泌体的促肿瘤作用。在机制上,MMP1通过激活PI3K-AKT-mTOR通路起作用。总之,我们的研究结果表明,来自衰老IPF成纤维细胞的外泌体MMP1通过靶向PAR1和激活PI3K-AKT-mTOR途径促进NSCLC的增殖和集落形成。这些发现为IPF-LC患者提供了一种新的治疗方法。
{"title":"Senescent lung fibroblasts in idiopathic pulmonary fibrosis facilitate non-small cell lung cancer progression by secreting exosomal MMP1","authors":"Yuqiong Lei, Cheng Zhong, Jingyuan Zhang, Qi Zheng, Yongle Xu, Zhoubin Li, Chenwen Huang, Tao Ren","doi":"10.1038/s41388-024-03236-5","DOIUrl":"10.1038/s41388-024-03236-5","url":null,"abstract":"Lung cancer is a fatal complication of idiopathic pulmonary fibrosis (IPF) with a poor prognosis. Current treatments are insufficient in improving the prognosis of lung cancer patients with comorbid idiopathic pulmonary fibrosis (IPF-LC). Senescent fibroblasts, as stromal cells in the tumor microenvironment, influence tumor progression via exosomes. With evidence that fibroblast senescence is an important mechanism of IPF, we investigated the impact of senescent IPF lung fibroblast (diseased human lung fibroblasts, DHLF)-derived exosomes on non-small cell lung cancer (NSCLC). We found DHLF expressed significant senescence markers, and promoted NSCLC proliferation, invasion, and epithelial-mesenchymal transition. Specifically, senescent DHLF showed strong secretion of exosomes, and these exosomes enhanced the proliferation and colony-forming ability of cancer cells. Proteomic analysis showed DHLF-derived exosomes exhibited upregulated senescence-associated secretory phenotype (SASP) factors, notably MMP1, which activates the surface receptor PAR1. Knocking down MMP1 or using PAR1 inhibitors reduced the tumor-promoting effects of DHLF-derived exosomes in vivo and in vitro. Mechanistically, MMP1 acted by activating the PI3K-AKT-mTOR pathway. In conclusion, our results suggest that exosomal MMP1 derived from senescent IPF fibroblasts promotes NSCLC proliferation and colony formation by targeting PAR1 and activating the PI3K-AKT-mTOR pathway. These findings provide a novel therapeutic approach for patients with IPF-LC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 11","pages":"769-781"},"PeriodicalIF":6.9,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03236-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Frequent copy number gain of MCL1 is a therapeutic target for osteosarcoma 频繁的MCL1拷贝数增加是骨肉瘤的治疗靶点。
IF 6.9 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-11 DOI: 10.1038/s41388-024-03251-6
Satoshi Takagi, Mikako Nakajima, Sumie Koike, Miho Takami, Yoshiya Sugiura, Seiji Sakata, Satoko Baba, Ai Takemoto, Tianyi Huang, Yosuke Seto, Masanori Saito, Yuki Funauchi, Keisuke Ae, Kengo Takeuchi, Naoya Fujita, Ryohei Katayama
Osteosarcoma (OS) is a primary malignant bone tumor primarily affecting children and adolescents. The lack of progress in drug development for OS is partly due to unidentified actionable oncogenic drivers common to OS. In this study, we demonstrate that copy number gains of MCL1 frequently occur in OS, leading to vulnerability to therapies based on Mcl-1 inhibitors. Fluorescence in situ hybridization analysis of 41 specimens revealed MCL1 amplification in 46.3% of patients with OS. Genetic inhibition of MCL1 induced significant apoptosis in MCL1-amplified OS cells, and the pharmacological efficacy of Mcl-1 inhibitors was correlated with MCL1 copy numbers. Chromosome 1q21.2-3 region, where MCL1 is located, contains multiple genes related to the IGF-1R/PI3K pathway, including PIP5K1A, TARS2, OUTD7B, and ENSA, which also showed increased copy numbers in MCL1-amplified OS cells. Furthermore, combining Mcl-1 inhibitors with IGF-1R inhibitors resulted in synergistic cell death by overcoming drug tolerance conferred by the activation of IGF signaling and suppressed tumor growth in MCL1-amplified OS xenograft models. These results suggest that genomic amplification of MCL1 in the 1q21.2-3 region, which occurred in approximately half of OS patients, may serve as a predictive biomarker for the combination therapy with an Mcl-1 inhibitor and an IGF1R inhibitor.
骨肉瘤(OS)是一种主要影响儿童和青少年的原发性恶性骨肿瘤。OS药物开发缺乏进展的部分原因是OS常见的未确定的可操作的致癌驱动因素。在这项研究中,我们证明了Mcl-1拷贝数的增加经常发生在OS中,导致基于Mcl-1抑制剂的治疗的脆弱性。41例OS患者的荧光原位杂交分析显示,46.3%的OS患者有MCL1扩增。MCL1基因抑制可诱导MCL1扩增的OS细胞显著凋亡,MCL1抑制剂的药理作用与MCL1拷贝数相关。MCL1所在的染色体1q22.1 -3区域包含多个与IGF-1R/PI3K通路相关的基因,包括PIP5K1A、TARS2、OUTD7B和ENSA,这些基因在MCL1扩增的OS细胞中拷贝数也有所增加。此外,在Mcl-1扩增的OS异种移植模型中,Mcl-1抑制剂与IGF- 1r抑制剂联合使用可克服IGF信号激活所带来的药物耐受性,从而导致协同细胞死亡,并抑制肿瘤生长。这些结果表明,在大约一半的OS患者中发生的MCL1在1q22.1 -3区域的基因组扩增,可能作为Mcl-1抑制剂和IGF1R抑制剂联合治疗的预测性生物标志物。
{"title":"Frequent copy number gain of MCL1 is a therapeutic target for osteosarcoma","authors":"Satoshi Takagi, Mikako Nakajima, Sumie Koike, Miho Takami, Yoshiya Sugiura, Seiji Sakata, Satoko Baba, Ai Takemoto, Tianyi Huang, Yosuke Seto, Masanori Saito, Yuki Funauchi, Keisuke Ae, Kengo Takeuchi, Naoya Fujita, Ryohei Katayama","doi":"10.1038/s41388-024-03251-6","DOIUrl":"10.1038/s41388-024-03251-6","url":null,"abstract":"Osteosarcoma (OS) is a primary malignant bone tumor primarily affecting children and adolescents. The lack of progress in drug development for OS is partly due to unidentified actionable oncogenic drivers common to OS. In this study, we demonstrate that copy number gains of MCL1 frequently occur in OS, leading to vulnerability to therapies based on Mcl-1 inhibitors. Fluorescence in situ hybridization analysis of 41 specimens revealed MCL1 amplification in 46.3% of patients with OS. Genetic inhibition of MCL1 induced significant apoptosis in MCL1-amplified OS cells, and the pharmacological efficacy of Mcl-1 inhibitors was correlated with MCL1 copy numbers. Chromosome 1q21.2-3 region, where MCL1 is located, contains multiple genes related to the IGF-1R/PI3K pathway, including PIP5K1A, TARS2, OUTD7B, and ENSA, which also showed increased copy numbers in MCL1-amplified OS cells. Furthermore, combining Mcl-1 inhibitors with IGF-1R inhibitors resulted in synergistic cell death by overcoming drug tolerance conferred by the activation of IGF signaling and suppressed tumor growth in MCL1-amplified OS xenograft models. These results suggest that genomic amplification of MCL1 in the 1q21.2-3 region, which occurred in approximately half of OS patients, may serve as a predictive biomarker for the combination therapy with an Mcl-1 inhibitor and an IGF1R inhibitor.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 12","pages":"794-804"},"PeriodicalIF":6.9,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03251-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
TFF3 drives Hippo dependent EGFR-TKI resistance in lung adenocarcinoma TFF3驱动肺腺癌中Hippo依赖性EGFR-TKI耐药。
IF 6.9 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-10 DOI: 10.1038/s41388-024-03244-5
Shuwei Zhang, Yan Qin Tan, Xi Zhang, Basappa Basappa, Tao Zhu, Vijay Pandey, Peter E. Lobie
Intrinsic and acquired resistance represent major obstacles to optimize outcomes in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeted therapy in lung adenocarcinoma (LUAD). Hence, a deeper understanding of EGFR-TKI resistance mechanisms in LUAD will potentially assist in formulating strategies to delay or overcome such resistance. Herein, it was observed that trefoil factor 3 (TFF3) is a crucial mediator of the LUAD EGFR-TKI response. TFF3 conferred intrinsic resistance to EGFR inhibition in LUAD by promotion of EGFR activation. TFF3 expression was also increased in acquired EGFR-TKI resistant LUAD, accompanied by reduced EGFR activation. YAP, a key mediator of the Hippo signaling, was positively regulated by TFF3 by post-transcriptional mechanisms and was responsible for acquired EGFR-TKI resistance mediated by TFF3. Inhibition of TFF3 by a small molecule inhibitor not only enhanced EGFR-TKI sensitivity in LUAD cells but also restored the sensitivity of acquired EGFR-TKI resistant LUAD cells to EGFR-TKIs in vitro and in vivo. These findings demonstrate a pivotal function of TFF3 in mediating both intrinsic and acquired EGFR-TKI resistance in LUAD and may offer a potential therapeutic mechanism for delaying or overcoming resistance to EGFR-TKIs.
内在和获得性耐药是优化表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKI)靶向治疗肺腺癌(LUAD)疗效的主要障碍。因此,对LUAD中EGFR-TKI耐药机制的深入了解将有助于制定延迟或克服这种耐药的策略。本文观察到三叶因子3 (TFF3)是LUAD EGFR-TKI反应的重要介质。TFF3通过促进EGFR激活,赋予LUAD对EGFR抑制的内在抗性。在获得性EGFR- tki抗性LUAD中,TFF3表达也增加,并伴有EGFR激活降低。YAP是Hippo信号通路的关键介质,通过转录后机制受到TFF3的正调控,并参与了TFF3介导的获得性EGFR-TKI耐药。小分子抑制剂抑制TFF3不仅增强了LUAD细胞对EGFR-TKI的敏感性,而且在体外和体内恢复了获得性EGFR-TKI抗性LUAD细胞对EGFR-TKI的敏感性。这些发现证明了TFF3在LUAD中介导内源性和获得性EGFR-TKI抗性的关键功能,并可能提供延缓或克服对EGFR-TKI抗性的潜在治疗机制。
{"title":"TFF3 drives Hippo dependent EGFR-TKI resistance in lung adenocarcinoma","authors":"Shuwei Zhang, Yan Qin Tan, Xi Zhang, Basappa Basappa, Tao Zhu, Vijay Pandey, Peter E. Lobie","doi":"10.1038/s41388-024-03244-5","DOIUrl":"10.1038/s41388-024-03244-5","url":null,"abstract":"Intrinsic and acquired resistance represent major obstacles to optimize outcomes in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeted therapy in lung adenocarcinoma (LUAD). Hence, a deeper understanding of EGFR-TKI resistance mechanisms in LUAD will potentially assist in formulating strategies to delay or overcome such resistance. Herein, it was observed that trefoil factor 3 (TFF3) is a crucial mediator of the LUAD EGFR-TKI response. TFF3 conferred intrinsic resistance to EGFR inhibition in LUAD by promotion of EGFR activation. TFF3 expression was also increased in acquired EGFR-TKI resistant LUAD, accompanied by reduced EGFR activation. YAP, a key mediator of the Hippo signaling, was positively regulated by TFF3 by post-transcriptional mechanisms and was responsible for acquired EGFR-TKI resistance mediated by TFF3. Inhibition of TFF3 by a small molecule inhibitor not only enhanced EGFR-TKI sensitivity in LUAD cells but also restored the sensitivity of acquired EGFR-TKI resistant LUAD cells to EGFR-TKIs in vitro and in vivo. These findings demonstrate a pivotal function of TFF3 in mediating both intrinsic and acquired EGFR-TKI resistance in LUAD and may offer a potential therapeutic mechanism for delaying or overcoming resistance to EGFR-TKIs.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 11","pages":"753-768"},"PeriodicalIF":6.9,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03244-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Tissue factor promotes TREX1 protein stability to evade cGAS-STING innate immune response in pancreatic ductal adenocarcinoma 组织因子促进TREX1蛋白稳定性以逃避胰腺导管腺癌的cGAS-STING先天免疫反应。
IF 6.9 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-10 DOI: 10.1038/s41388-024-03248-1
Yinyin Xue, Yue Wang, Zhiqiang Ren, Ker Yu
Pancreatic ductal adenocarcinoma (PDAC) remains the most challenging human malignancy that urgently needs effective therapy. Tissue factor (TF) is expressed in ~80% of PDAC and represents a potential therapeutic target. While a novel TF-ADC (MRG004A) demonstrated efficacy for PDAC and TNBC in a Phase I/II trial [Ref. 18], the functional role of TF in PDAC remains incompletely understood. We investigated the relationship between TF and the innate STING pathway. We found that patients with TF-overexpression had poor survival, very low levels of P-STING/P-TBK1, reduced amounts of ISGs and chemokines as well as low numbers of cytotoxic immunocytes in their tumor. In experimental models of mouse and human PDAC, tumor cell-intrinsic TF expression played a major role in silencing the cytosolic micronuclei sensing and cGAS-STING activation. This process involved a TREX1 exonuclease-dependent clearance of micronucleus-DNA accumulated in tumor cells. Treatment of tumors with TF-KO/shRNA or anti-TF antibody HuSC1-39 (parent antibody of MRG004A) triggered a rapid and proteasome-dependent degradation of TREX1 thereby restoring the STING/TBK1 cascade phosphorylation. TF-inhibition therapy promoted a robust STING/IRF3-dependent IFN/CCL5/CXCL9-11 production, immune effector cell infiltration and antitumor efficacy. Moreover, in the PBMC and cancer cell co-culture, TF-inhibition synergized with a STING agonist compound. A covalently conjugated TF antibody-STING agonist ADC strongly increased the efficacy of tumor-targeted STING agonism on chemokine secretion and tumor inhibition in vitro and in vivo. Thus, TF-inhibition reshapes an “immune hot” tumor environment. TF-targeted therapy warrants clinical investigation as a single agent or in combination with immunotherapy for treating TF-positive PDAC and TNBC.
胰腺导管腺癌(PDAC)仍然是最具挑战性的人类恶性肿瘤,迫切需要有效的治疗。组织因子(TF)在约80%的PDAC中表达,是潜在的治疗靶点。虽然一种新型TF- adc (MRG004A)在I/II期试验中显示出对PDAC和TNBC的疗效[文献18],但TF在PDAC中的功能作用仍不完全清楚。我们研究了TF与先天STING通路之间的关系。我们发现,tnf过表达的患者生存率较低,P-STING/P-TBK1水平非常低,肿瘤中isg和趋化因子数量减少,细胞毒性免疫细胞数量减少。在小鼠和人PDAC的实验模型中,肿瘤细胞内固有的TF表达在沉默细胞质微核传感和cGAS-STING激活中起主要作用。这一过程涉及TREX1外切酶依赖性清除肿瘤细胞中积累的微核dna。用TF-KO/shRNA或抗tf抗体HuSC1-39 (MRG004A的亲本抗体)治疗肿瘤可触发TREX1的快速和蛋白酶体依赖性降解,从而恢复STING/TBK1级联磷酸化。tnf抑制治疗促进了STING/ irf3依赖性IFN/CCL5/CXCL9-11的产生、免疫效应细胞浸润和抗肿瘤疗效。此外,在PBMC和癌细胞共培养中,tf抑制与STING激动剂化合物协同作用。一种共价偶联的TF抗体-STING激动剂ADC在体外和体内均能显著提高肿瘤靶向STING激动剂对趋化因子分泌和肿瘤抑制的作用。因此,tf抑制重塑了“免疫热”肿瘤环境。tnf靶向治疗作为单一药物或与免疫疗法联合治疗tnf阳性PDAC和TNBC值得临床研究。
{"title":"Tissue factor promotes TREX1 protein stability to evade cGAS-STING innate immune response in pancreatic ductal adenocarcinoma","authors":"Yinyin Xue, Yue Wang, Zhiqiang Ren, Ker Yu","doi":"10.1038/s41388-024-03248-1","DOIUrl":"10.1038/s41388-024-03248-1","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) remains the most challenging human malignancy that urgently needs effective therapy. Tissue factor (TF) is expressed in ~80% of PDAC and represents a potential therapeutic target. While a novel TF-ADC (MRG004A) demonstrated efficacy for PDAC and TNBC in a Phase I/II trial [Ref. 18], the functional role of TF in PDAC remains incompletely understood. We investigated the relationship between TF and the innate STING pathway. We found that patients with TF-overexpression had poor survival, very low levels of P-STING/P-TBK1, reduced amounts of ISGs and chemokines as well as low numbers of cytotoxic immunocytes in their tumor. In experimental models of mouse and human PDAC, tumor cell-intrinsic TF expression played a major role in silencing the cytosolic micronuclei sensing and cGAS-STING activation. This process involved a TREX1 exonuclease-dependent clearance of micronucleus-DNA accumulated in tumor cells. Treatment of tumors with TF-KO/shRNA or anti-TF antibody HuSC1-39 (parent antibody of MRG004A) triggered a rapid and proteasome-dependent degradation of TREX1 thereby restoring the STING/TBK1 cascade phosphorylation. TF-inhibition therapy promoted a robust STING/IRF3-dependent IFN/CCL5/CXCL9-11 production, immune effector cell infiltration and antitumor efficacy. Moreover, in the PBMC and cancer cell co-culture, TF-inhibition synergized with a STING agonist compound. A covalently conjugated TF antibody-STING agonist ADC strongly increased the efficacy of tumor-targeted STING agonism on chemokine secretion and tumor inhibition in vitro and in vivo. Thus, TF-inhibition reshapes an “immune hot” tumor environment. TF-targeted therapy warrants clinical investigation as a single agent or in combination with immunotherapy for treating TF-positive PDAC and TNBC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 11","pages":"739-752"},"PeriodicalIF":6.9,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03248-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Pseudokinase TRIB3 stabilizes SSRP1 via USP10-mediated deubiquitination to promote multiple myeloma progression 假激酶TRIB3通过usp10介导的去泛素化来稳定SSRP1,促进多发性骨髓瘤的进展。
IF 6.9 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-09 DOI: 10.1038/s41388-024-03245-4
Haiqin Wang, Long Liang, Yifang Xie, Han Gong, Feifan Fan, Chengcai Wen, Yu Jiang, Shiying Lei, Xili Qiu, Hongling Peng, Mao Ye, Xiaojuan Xiao, Jing Liu
Multiple myeloma (MM), the world’s second most common hematologic malignancy, poses considerable clinical challenges due to its aggressive progression and resistance to therapy. Addressing these challenges requires a detailed understanding of the mechanisms driving MM initiation, progression, and therapeutic resistance. This study identifies the pseudokinase tribble homolog 3 (TRIB3) as a high-risk factor that promotes MM malignancy in vitro and in vivo. Mechanistically, TRIB3 directly interacts with structure-specific recognition protein 1 (SSRP1) and ubiquitin-specific peptidase 10 (USP10), facilitating the formation of a TRIB3/USP10/SSRP1 ternary complex. This complex stabilizes SSRP1 via USP10-mediated deubiquitination, thereby driving MM cell proliferation. Furthermore, a stapled peptide, SP-A, was developed, which effectively disrupts the TRIB3/USP10/SSRP1 complex, leading to a decrease in SSRP1 levels by inhibiting its stabilization through USP10. Notably, SP-A exhibits strong synergistic effects when combined with the proteasome inhibitor bortezomib. Given the critical role of the TRIB3/USP10/SSRP1 complex in MM pathophysiology, it represents a promising therapeutic target for MM treatment.
多发性骨髓瘤(MM)是世界上第二大最常见的血液系统恶性肿瘤,由于其侵袭性进展和耐药性,给临床治疗带来了相当大的挑战。要应对这些挑战,就必须详细了解驱动多发性骨髓瘤发病、进展和耐药的机制。本研究发现,伪激酶tribble同源物3(TRIB3)是体外和体内促进MM恶性发展的高危因素。从机理上讲,TRIB3直接与结构特异性识别蛋白1(SSRP1)和泛素特异性肽酶10(USP10)相互作用,促进TRIB3/USP10/SSRP1三元复合物的形成。该复合物通过 USP10 介导的去泛素化作用稳定 SSRP1,从而推动 MM 细胞增殖。此外,还开发了一种钉肽 SP-A,它能有效破坏 TRIB3/USP10/SSRP1 复合物,通过抑制 USP10 稳定 SSRP1,从而降低 SSRP1 的水平。值得注意的是,SP-A与蛋白酶体抑制剂硼替佐米(bortezomib)联用时会产生很强的协同效应。鉴于TRIB3/USP10/SSRP1复合物在MM病理生理学中的关键作用,它是治疗MM的一个很有希望的治疗靶点。在 MM 细胞中,TRIB3、USP10 和 SSRP1 形成三元复合物,TRIB3 可增强 USP10 对 SSRP1 的去泛素化作用,从而导致 MM 恶性进展。在药物干预的情况下,SP-A通过抑制TRIB3和SSRP1之间的蛋白相互作用,减弱SSRP1和USP10的结合,促进SSRP1蛋白降解,从而显著抑制MM的发展。使用 Biorender 创建的可视化摘要。
{"title":"Pseudokinase TRIB3 stabilizes SSRP1 via USP10-mediated deubiquitination to promote multiple myeloma progression","authors":"Haiqin Wang, Long Liang, Yifang Xie, Han Gong, Feifan Fan, Chengcai Wen, Yu Jiang, Shiying Lei, Xili Qiu, Hongling Peng, Mao Ye, Xiaojuan Xiao, Jing Liu","doi":"10.1038/s41388-024-03245-4","DOIUrl":"10.1038/s41388-024-03245-4","url":null,"abstract":"Multiple myeloma (MM), the world’s second most common hematologic malignancy, poses considerable clinical challenges due to its aggressive progression and resistance to therapy. Addressing these challenges requires a detailed understanding of the mechanisms driving MM initiation, progression, and therapeutic resistance. This study identifies the pseudokinase tribble homolog 3 (TRIB3) as a high-risk factor that promotes MM malignancy in vitro and in vivo. Mechanistically, TRIB3 directly interacts with structure-specific recognition protein 1 (SSRP1) and ubiquitin-specific peptidase 10 (USP10), facilitating the formation of a TRIB3/USP10/SSRP1 ternary complex. This complex stabilizes SSRP1 via USP10-mediated deubiquitination, thereby driving MM cell proliferation. Furthermore, a stapled peptide, SP-A, was developed, which effectively disrupts the TRIB3/USP10/SSRP1 complex, leading to a decrease in SSRP1 levels by inhibiting its stabilization through USP10. Notably, SP-A exhibits strong synergistic effects when combined with the proteasome inhibitor bortezomib. Given the critical role of the TRIB3/USP10/SSRP1 complex in MM pathophysiology, it represents a promising therapeutic target for MM treatment.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 10","pages":"694-708"},"PeriodicalIF":6.9,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
SPTLC2 drives an EGFR-FAK-HBEGF signaling axis to promote ovarian cancer progression SPTLC2驱动EGFR-FAK-HBEGF信号轴促进卵巢癌进展。
IF 6.9 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-07 DOI: 10.1038/s41388-024-03249-0
Xingyue Zhai, Ning Shen, Tao Guo, Jianxin Wang, Chunrui Xie, Yukai Cao, Ling Liu, Yumei Yan, Songshu Meng, Sha Du
The epidermal growth factor receptor (EGFR) signaling pathway is frequently associated with ovarian cancer (OC) progression. However, inhibition of EGFR signaling in OC patients achieved limited therapeutic effects, highlighting the need to define the mechanism of EGFR deregulation in OC development. Herein we showed that serine palmitoyltransferase long chain base subunit 2 (SPTLC2) acts as a positive regulator in the EGFR signaling pathway in OC. Phenotypically, depletion of SPTLC2 suppressed clonogenic growth and migration of OC cells in vitro and in ovo, as well as metastasis in OC xenograft models, whereas overexpression of SPTLC2 yielded opposite effects. Mechanistically, SPTLC2 drives an EGFR-FAK-HBEGF signaling axis via binding with EGFR. Notably, the serine palmitoyltransferase activity of SPTLC2 is critical for regulation of the EGFR-FAK-HBEGF signaling axis and activity in OC progression. Clinically, high SPTLC2 expression is associated with high-grade serous ovarian cancer and metastasis. Collectively, our findings establish an oncogenic role of SPTLC2 in OC growth and progression though upregulation of EGFR signaling and suggest that SPTLC2 represents a potential therapeutic target in EGFR-driven ovarian cancer patients.
表皮生长因子受体(EGFR)信号通路通常与卵巢癌(OC)的进展有关。然而,在OC患者中,抑制EGFR信号通路的治疗效果有限,因此需要明确EGFR调控在OC发展中的机制。本研究表明,丝氨酸棕榈酰转移酶长链碱基亚基2 (SPTLC2)在OC的EGFR信号通路中起积极调节作用。从表型上看,SPTLC2的缺失抑制了体外和卵内OC细胞的克隆生长和迁移,以及OC异种移植模型的转移,而SPTLC2的过表达则产生相反的效果。从机制上讲,SPTLC2通过与EGFR结合驱动EGFR- fb - hbegf信号轴。值得注意的是,SPTLC2的丝氨酸棕榈酰转移酶活性对于调节EGFR-FAK-HBEGF信号轴和OC进展中的活性至关重要。临床上,SPTLC2高表达与高级别浆液性卵巢癌及转移有关。总的来说,我们的研究结果通过上调EGFR信号,确立了SPTLC2在卵巢癌生长和进展中的致癌作用,并表明SPTLC2代表了EGFR驱动的卵巢癌患者的潜在治疗靶点。
{"title":"SPTLC2 drives an EGFR-FAK-HBEGF signaling axis to promote ovarian cancer progression","authors":"Xingyue Zhai, Ning Shen, Tao Guo, Jianxin Wang, Chunrui Xie, Yukai Cao, Ling Liu, Yumei Yan, Songshu Meng, Sha Du","doi":"10.1038/s41388-024-03249-0","DOIUrl":"10.1038/s41388-024-03249-0","url":null,"abstract":"The epidermal growth factor receptor (EGFR) signaling pathway is frequently associated with ovarian cancer (OC) progression. However, inhibition of EGFR signaling in OC patients achieved limited therapeutic effects, highlighting the need to define the mechanism of EGFR deregulation in OC development. Herein we showed that serine palmitoyltransferase long chain base subunit 2 (SPTLC2) acts as a positive regulator in the EGFR signaling pathway in OC. Phenotypically, depletion of SPTLC2 suppressed clonogenic growth and migration of OC cells in vitro and in ovo, as well as metastasis in OC xenograft models, whereas overexpression of SPTLC2 yielded opposite effects. Mechanistically, SPTLC2 drives an EGFR-FAK-HBEGF signaling axis via binding with EGFR. Notably, the serine palmitoyltransferase activity of SPTLC2 is critical for regulation of the EGFR-FAK-HBEGF signaling axis and activity in OC progression. Clinically, high SPTLC2 expression is associated with high-grade serous ovarian cancer and metastasis. Collectively, our findings establish an oncogenic role of SPTLC2 in OC growth and progression though upregulation of EGFR signaling and suggest that SPTLC2 represents a potential therapeutic target in EGFR-driven ovarian cancer patients.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 10","pages":"679-693"},"PeriodicalIF":6.9,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03249-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Metabolic imaging distinguishes ovarian cancer subtypes and detects their early and variable responses to treatment 代谢成像区分卵巢癌亚型,并检测其早期和可变的治疗反应。
IF 6.9 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-06 DOI: 10.1038/s41388-024-03231-w
Ming Li Chia, Flaviu Bulat, Adam Gaunt, Susana Ros, Alan J. Wright, Ashley Sawle, Luca Porcu, Maria Vias, James D. Brenton, Kevin M. Brindle
High grade serous ovarian cancer displays two metabolic subtypes; a high OXPHOS subtype that shows increased expression of genes encoding electron transport chain components, increased oxygen consumption, and increased chemosensitivity, and a low OXPHOS subtype that exhibits glycolytic metabolism and is more drug resistant. We show here in patient-derived organoids and in the xenografts obtained by their subcutaneous implantation that the low OXPHOS subtype shows higher lactate dehydrogenase activity and monocarboxylate transporter 4 expression than the high OXPHOS subtype and increased lactate labeling in 13C magnetic resonance spectroscopy (MRS) measurements of hyperpolarized [1-13C]pyruvate metabolism. There was no difference between the subtypes in PET measurements of 2-deoxy-2-[fluorine-18]fluoro-D-glucose ([18F]FDG) uptake. Both metabolic imaging techniques could detect the early response to Carboplatin treatment in drug-sensitive high OXPHOS xenografts and no response in drug-resistant in low OXPHOS xenografts. 13C magnetic resonance spectroscopic imaging of hyperpolarized [1-13C]pyruvate metabolism has the potential to be used clinically to distinguish low OXPHOS and high OXPHOS tumor deposits in HGSOC patients and to detect their differential responses to treatment.
高级别浆液性卵巢癌表现为两种代谢亚型;高OXPHOS亚型表现为编码电子传递链组分的基因表达增加,耗氧量增加,化学敏感性增加;低OXPHOS亚型表现为糖酵解代谢,更耐药。我们在患者来源的类器官和通过皮下植入获得的异种移植物中发现,在超极化[1-13C]丙酮酸代谢的13C磁共振波谱(MRS)测量中,低OXPHOS亚型比高OXPHOS亚型表现出更高的乳酸脱氢酶活性和单羧酸转运蛋白4表达,并且乳酸标记增加。PET测量2-脱氧-2-[氟-18]氟-d -葡萄糖([18F]FDG)摄取的亚型之间没有差异。两种代谢成像技术均能检测出对药物敏感的高氧phos异种移植物对卡铂治疗的早期反应,而对低氧phos的耐药异种移植物无反应。超极化[1-13C]丙酮酸代谢的13C磁共振波谱成像有可能在临床上用于区分HGSOC患者低OXPHOS和高OXPHOS肿瘤沉积,并检测其对治疗的差异反应。
{"title":"Metabolic imaging distinguishes ovarian cancer subtypes and detects their early and variable responses to treatment","authors":"Ming Li Chia, Flaviu Bulat, Adam Gaunt, Susana Ros, Alan J. Wright, Ashley Sawle, Luca Porcu, Maria Vias, James D. Brenton, Kevin M. Brindle","doi":"10.1038/s41388-024-03231-w","DOIUrl":"10.1038/s41388-024-03231-w","url":null,"abstract":"High grade serous ovarian cancer displays two metabolic subtypes; a high OXPHOS subtype that shows increased expression of genes encoding electron transport chain components, increased oxygen consumption, and increased chemosensitivity, and a low OXPHOS subtype that exhibits glycolytic metabolism and is more drug resistant. We show here in patient-derived organoids and in the xenografts obtained by their subcutaneous implantation that the low OXPHOS subtype shows higher lactate dehydrogenase activity and monocarboxylate transporter 4 expression than the high OXPHOS subtype and increased lactate labeling in 13C magnetic resonance spectroscopy (MRS) measurements of hyperpolarized [1-13C]pyruvate metabolism. There was no difference between the subtypes in PET measurements of 2-deoxy-2-[fluorine-18]fluoro-D-glucose ([18F]FDG) uptake. Both metabolic imaging techniques could detect the early response to Carboplatin treatment in drug-sensitive high OXPHOS xenografts and no response in drug-resistant in low OXPHOS xenografts. 13C magnetic resonance spectroscopic imaging of hyperpolarized [1-13C]pyruvate metabolism has the potential to be used clinically to distinguish low OXPHOS and high OXPHOS tumor deposits in HGSOC patients and to detect their differential responses to treatment.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 9","pages":"563-574"},"PeriodicalIF":6.9,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03231-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142786152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
LGALS9B stabilizes EEF1D protein and activates the PI3K/AKT signaling pathway to promote gastric cancer occurrence and metastasis LGALS9B稳定EEF1D蛋白,激活PI3K/AKT信号通路,促进胃癌发生转移。
IF 6.9 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-05 DOI: 10.1038/s41388-024-03247-2
Huolun Feng, Wei Yao, Yucheng Zhang, Yongfeng Liu, Bin Liu, Ji Zhou, Jiehui Li, Zhuosheng Jiang, Fa Ling, Jianlong Zhou, Deqing Wu, Yong Li, Juan Yang, Jiabin Zheng
Gastric cancer ranks among the most prevalent malignancies globally, characterized by limited treatment efficacy and high recurrence rates. Effective management of this disease requires a comprehensive understanding of its underlying pathogenic mechanisms. Galectins have emerged as promising targets in gastric cancer therapy, with Galectin-9 (LGALS9) receiving considerable attention in recent years. However, Galectin-9B (LGALS9B) remains relatively under-explored in gastric cancer research. Our study investigates the role of LGALS9B in gastric cancer progression, demonstrating that its over-expression enhances cellular proliferation, migration, and invasion, while its knockdown inhibits these processes both in vitro and in vivo. We further elucidate that LGALS9B competes with the E3 ligase HERC5 for binding to eukaryotic translation elongation factor 1 delta (EEF1D), thereby preventing its protein degradation. This interaction results in the enrichment of EEF1D, which activates the PI3K/AKT signaling pathway and ultimately promotes gastric cancer progression. These findings highlight the regulatory role of LGALS9B in the pathogenesis of gastric cancer, offering valuable insights into potential novel therapeutic strategies for managing this challenging disease.
胃癌是全球最常见的恶性肿瘤之一,其特点是治疗效果有限,复发率高。对这种疾病的有效管理需要对其潜在的致病机制有全面的了解。近年来,半乳糖凝集素(Galectin-9, LGALS9)已成为胃癌治疗中很有前景的靶点。然而,半乳糖凝集素- 9b (LGALS9B)在胃癌研究中的探索相对较少。我们的研究探讨了LGALS9B在胃癌进展中的作用,表明其过表达增强细胞增殖、迁移和侵袭,而其敲低在体外和体内均抑制这些过程。我们进一步阐明,LGALS9B与E3连接酶HERC5竞争,以结合真核翻译延伸因子1 δ (EEF1D),从而阻止其蛋白质降解。这种相互作用导致EEF1D富集,激活PI3K/AKT信号通路,最终促进胃癌进展。这些发现强调了LGALS9B在胃癌发病机制中的调节作用,为管理这种具有挑战性的疾病的潜在新治疗策略提供了有价值的见解。
{"title":"LGALS9B stabilizes EEF1D protein and activates the PI3K/AKT signaling pathway to promote gastric cancer occurrence and metastasis","authors":"Huolun Feng, Wei Yao, Yucheng Zhang, Yongfeng Liu, Bin Liu, Ji Zhou, Jiehui Li, Zhuosheng Jiang, Fa Ling, Jianlong Zhou, Deqing Wu, Yong Li, Juan Yang, Jiabin Zheng","doi":"10.1038/s41388-024-03247-2","DOIUrl":"10.1038/s41388-024-03247-2","url":null,"abstract":"Gastric cancer ranks among the most prevalent malignancies globally, characterized by limited treatment efficacy and high recurrence rates. Effective management of this disease requires a comprehensive understanding of its underlying pathogenic mechanisms. Galectins have emerged as promising targets in gastric cancer therapy, with Galectin-9 (LGALS9) receiving considerable attention in recent years. However, Galectin-9B (LGALS9B) remains relatively under-explored in gastric cancer research. Our study investigates the role of LGALS9B in gastric cancer progression, demonstrating that its over-expression enhances cellular proliferation, migration, and invasion, while its knockdown inhibits these processes both in vitro and in vivo. We further elucidate that LGALS9B competes with the E3 ligase HERC5 for binding to eukaryotic translation elongation factor 1 delta (EEF1D), thereby preventing its protein degradation. This interaction results in the enrichment of EEF1D, which activates the PI3K/AKT signaling pathway and ultimately promotes gastric cancer progression. These findings highlight the regulatory role of LGALS9B in the pathogenesis of gastric cancer, offering valuable insights into potential novel therapeutic strategies for managing this challenging disease.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 10","pages":"652-664"},"PeriodicalIF":6.9,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142786098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
BEX4 inhibits the progression of clear cell renal cell carcinoma by stabilizing SH2D4A, which is achieved by blocking SIRT2 activity BEX4通过稳定SH2D4A抑制透明细胞肾细胞癌的进展,这是通过阻断SIRT2活性实现的。
IF 6.9 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-05 DOI: 10.1038/s41388-024-03235-6
Ziyao Li, Shiyong Xin, Liqun Huang, Ye Tian, Weihua Chen, Xiang Liu, Bowen Ye, Rong Bai, Guosheng Yang, Wenwen Wang, Lin Ye
Clear cell renal cell carcinoma (ccRCC) is one of the most common malignancies. Recently, the role of brain-expressed X-linked 4 (BEX4) in cancer progression has received increasing attention. This study aimed to investigate the function of BEX4 in ccRCC and to reveal the underlying mechanisms. We first confirmed that BEX4 was significantly downregulated in ccRCC by bioinformatics analysis and that patients with low BEX4 expression tended to have prolonged overall survival time. Subsequently, we confirmed that BEX4 inhibited ccRCC cell proliferation in vitro and tumorigenesis in vivo through a series of cell function assays and the establishment of a nude mouse xenograft model, respectively. Mechanistically, we found that BEX4 positively regulates the expression of Src homology 2 domain-containing 4A (SH2D4A), an inhibitor of the NOTCH pathway, which further promoted the tumor-suppressive effects of BEX4. In addition, our study confirmed that the promoting effect of BEX4 on SH2D4A was achieved by inhibiting the deacetylase sirtuin 2 (SIRT2) activity. On this basis, we found that there was a competition between acetylation and ubiquitination modifications at the K69 site of SH2DA4 and that BEX4-induced upregulation of acetylation at the k69 site stabilizes SH2D4A protein expression by inhibiting ubiquitination at the same site. In addition, dual-luciferase assays showed that the transcriptional activity of BEX4 was positively regulated by activation transcription factor 3 (ATF3). Our study suggests that BEX4 plays a role in inhibiting tumor progression in ccRCC and maybe a new diagnostic and therapeutic target for ccRCC patients.
透明细胞肾细胞癌(ccRCC)是最常见的恶性肿瘤之一。最近,脑表达的X-linked 4 (BEX4)在癌症进展中的作用受到越来越多的关注。本研究旨在探讨BEX4在ccRCC中的功能并揭示其潜在机制。我们首先通过生物信息学分析证实BEX4在ccRCC中显著下调,BEX4低表达的患者总生存时间往往延长。随后,我们分别通过一系列细胞功能测定和建立裸鼠异种移植模型,证实了BEX4在体外抑制ccRCC细胞增殖和体内抑制肿瘤发生。在机制上,我们发现BEX4正调控NOTCH通路抑制剂Src homology 2 domain containing 4A (SH2D4A)的表达,进一步促进BEX4的肿瘤抑制作用。此外,我们的研究证实了BEX4对SH2D4A的促进作用是通过抑制去乙酰化酶sirtuin 2 (SIRT2)活性来实现的。在此基础上,我们发现SH2DA4的K69位点乙酰化修饰和泛素化修饰之间存在竞争,bex4诱导的K69位点乙酰化修饰上调通过抑制同一位点的泛素化修饰来稳定SH2D4A蛋白的表达。此外,双荧光素酶实验显示BEX4的转录活性受到激活转录因子3 (ATF3)的正调控。本研究提示BEX4在ccRCC中具有抑制肿瘤进展的作用,可能成为ccRCC患者新的诊断和治疗靶点。
{"title":"BEX4 inhibits the progression of clear cell renal cell carcinoma by stabilizing SH2D4A, which is achieved by blocking SIRT2 activity","authors":"Ziyao Li, Shiyong Xin, Liqun Huang, Ye Tian, Weihua Chen, Xiang Liu, Bowen Ye, Rong Bai, Guosheng Yang, Wenwen Wang, Lin Ye","doi":"10.1038/s41388-024-03235-6","DOIUrl":"10.1038/s41388-024-03235-6","url":null,"abstract":"Clear cell renal cell carcinoma (ccRCC) is one of the most common malignancies. Recently, the role of brain-expressed X-linked 4 (BEX4) in cancer progression has received increasing attention. This study aimed to investigate the function of BEX4 in ccRCC and to reveal the underlying mechanisms. We first confirmed that BEX4 was significantly downregulated in ccRCC by bioinformatics analysis and that patients with low BEX4 expression tended to have prolonged overall survival time. Subsequently, we confirmed that BEX4 inhibited ccRCC cell proliferation in vitro and tumorigenesis in vivo through a series of cell function assays and the establishment of a nude mouse xenograft model, respectively. Mechanistically, we found that BEX4 positively regulates the expression of Src homology 2 domain-containing 4A (SH2D4A), an inhibitor of the NOTCH pathway, which further promoted the tumor-suppressive effects of BEX4. In addition, our study confirmed that the promoting effect of BEX4 on SH2D4A was achieved by inhibiting the deacetylase sirtuin 2 (SIRT2) activity. On this basis, we found that there was a competition between acetylation and ubiquitination modifications at the K69 site of SH2DA4 and that BEX4-induced upregulation of acetylation at the k69 site stabilizes SH2D4A protein expression by inhibiting ubiquitination at the same site. In addition, dual-luciferase assays showed that the transcriptional activity of BEX4 was positively regulated by activation transcription factor 3 (ATF3). Our study suggests that BEX4 plays a role in inhibiting tumor progression in ccRCC and maybe a new diagnostic and therapeutic target for ccRCC patients.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 10","pages":"665-678"},"PeriodicalIF":6.9,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03235-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
期刊
Oncogene
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1