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Retraction Note: IFIT1 modulates the proliferation, migration and invasion of pancreatic cancer cells via Wnt/β-catenin signaling. 退缩注:IFIT1通过Wnt/β-catenin信号调节胰腺癌症细胞的增殖、迁移和侵袭。
IF 6.6 2区 医学 Q2 CELL BIOLOGY Pub Date : 2023-12-01 DOI: 10.1007/s13402-023-00897-4
Tian-Hao Li, Bang-Bo Zhao, Cheng Qin, Yuan-Yang Wang, Ze-Ru Li, Hong-Tao Cao, Xiao-Ying Yang, Xing-Tong Zhou, Wei-Bin Wang
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引用次数: 0
Triggering pyroptosis enhances the antitumor efficacy of PARP inhibitors in prostate cancer. 触发焦亡可增强PARP抑制剂对前列腺癌的抗肿瘤作用。
IF 6.6 2区 医学 Q2 CELL BIOLOGY Pub Date : 2023-12-01 Epub Date: 2023-08-23 DOI: 10.1007/s13402-023-00860-3
Ao Tian, Tingyu Wu, Yanshuang Zhang, Jiachen Chen, Jianjun Sha, Weiliang Xia

Purpose: PARP inhibitors have revolutionized the treatment landscape for advanced prostate cancer (PCa) patients who harboring mutations in homologous recombination repair (HRR) genes. However, the molecular mechanisms underlying PARP inhibitors function beyond DNA damage repair pathways remain elusive, and identifying novel predictive targets that favorably respond to PARP inhibitors in PCa is an active area of research.

Methods: The expression of GSDME in PCa cell lines and human PCa samples was determined by western blotting. Targeted bisulfite sequencing, gene enrichment analysis (GSEA), clone formation, construction of the stably transfected cell lines, lactate dehydrogenase (LDH) assay, western blotting as well as a mouse model of subcutaneous xenografts were used to investigate the role of GSDME in PCa. The combinational therapeutic effect of olaparib and decitabine was determined using both in vitro and in vivo experiments.

Results: We have found low expression of GSDME in PCa. Interestingly, we demonstrated that GSDME activity is robustly induced in olaparib-treated cells undergoing pyroptosis, and that high methylation of the GSDME promoter dampens its activity in PCa cells. Intriguingly, genetically overexpressing GSDME does not inhibit tumor cell proliferation but instead confers sensitivity to olaparib. Furthermore, pharmacological treatment with the combination of olaparib and decitabine synergistically induces GSDME expression and cleavage through caspase-3 activation, thus promoting pyroptosis and enhancing anti-tumor response, ultimately resulting in tumor remission.

Conclusion: Our findings highlight a novel therapeutic strategy for enhancing the long-term response to olaparib beyond HRR-deficient tumors in PCa, underscoring the critical role of GSDME in regulating tumorigenesis.

目的:PARP抑制剂彻底改变了携带同源重组修复(HRR)基因突变的晚期前列腺癌(PCa)患者的治疗前景。然而,PARP抑制剂在DNA损伤修复途径之外的作用的分子机制仍然难以捉摸,在PCa中识别对PARP抑制剂有利的新的预测靶点是一个活跃的研究领域。方法:采用western blotting法检测GSDME在PCa细胞株和人PCa标本中的表达。通过亚硫酸氢盐靶向测序、基因富集分析(GSEA)、克隆形成、稳定转染细胞系构建、乳酸脱氢酶(LDH)检测、western blotting以及小鼠皮下异种移植模型研究GSDME在PCa中的作用。通过体外和体内实验确定奥拉帕尼与地西他滨的联合治疗效果。结果:GSDME在前列腺癌中低表达。有趣的是,我们证明了GSDME活性在奥拉帕尼处理的细胞中被强烈诱导,并且GSDME启动子的高甲基化抑制了其在PCa细胞中的活性。有趣的是,基因过表达GSDME并不会抑制肿瘤细胞的增殖,反而会使其对奥拉帕尼敏感。此外,奥拉帕尼联合地西他滨的药物治疗通过激活caspase-3协同诱导GSDME的表达和裂解,从而促进焦亡,增强抗肿瘤反应,最终达到肿瘤缓解的目的。结论:我们的研究结果强调了一种新的治疗策略,可以增强奥拉帕尼对PCa中hrr缺陷肿瘤的长期反应,强调了GSDME在调节肿瘤发生中的关键作用。
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引用次数: 1
TGF-β-p-STAT1-LAIR2 axis has a "self-rescue" role for exhausted CD8+ T cells in hepatocellular carcinoma. TGF-β-p-STAT1-LAIR2轴对肝癌中耗尽的CD8+ T细胞具有“自救”作用。
IF 6.6 2区 医学 Q2 CELL BIOLOGY Pub Date : 2023-12-01 Epub Date: 2023-05-24 DOI: 10.1007/s13402-023-00830-9
Banglun Pan, Zengbin Wang, Yuxin Yao, Xiaoling Ke, Shuling Shen, Weihong Chen, Xiaoxia Zhang, Jiacheng Qiu, Xiaoxuan Wu, Nanhong Tang

Background: TGF-β is related to the function of T cells in the tumor microenvironment. However, the characteristics of TGF-β affecting the function of CD8+ T cells in hepatocellular carcinoma (HCC) have not been clearly resolved.

Methods: In this study, flow cytometry, mass cytometry, immunohistochemistry, RNA-seq, single-cell RNA-seq, assay for transposase-accessible chromatin with high throughput sequencing, chromatin immunoprecipitation, and dual-luciferase reporter gene assay were used to study the regulatory effect and molecular mechanism of TGF-β on HCC infiltrating CD8+ T cells.

Results: Here, we demonstrated that the overall effect of TGF-β on CD8+ T cells in HCC was to activate p-p38 to induce exhaustion, but it also initiated cell-intrinsic resistance mechanisms: 1) TGF-β upregulated the levels of p-STAT1 (S727) and promoted LAIR2 secretion; 2) the TGF-β-p-STAT1-LAIR2 axis relieved CD8+ T cells from exhaustion, which we called "self-rescue"; 3) this "self-rescue" behavior showed time and dose limitations on TGF-β stimulation, which was easily masked by stronger inhibitory signals; 4) the function of CD8+ T cells was improved by using TAK-981 to amplify "self-rescue" signal.

Conclusion: Our study describes a "self-rescue" mechanism of CD8+ T cells in HCC against exhaustion and the good effects from amplifying this signal.

背景:TGF-β与肿瘤微环境中T细胞的功能有关。然而,TGF-β在肝细胞癌(HCC)中影响CD8+ T细胞功能的特点尚未明确解决。方法:本研究采用流式细胞术、大量细胞术、免疫组织化学、RNA-seq、单细胞RNA-seq、转座酶可及染色质高通量测序、染色质免疫沉淀、双荧光素酶报告基因检测等方法,研究TGF-β对HCC浸润CD8+ T细胞的调控作用及分子机制。结果:本研究表明,TGF-β对HCC中CD8+ T细胞的总体作用是激活p-p38诱导衰竭,但也启动了细胞内在抵抗机制:1)TGF-β上调p-STAT1 (S727)水平,促进LAIR2分泌;2) TGF-β-p-STAT1-LAIR2轴缓解了CD8+ T细胞的衰竭,我们称之为“自救”;3)这种“自救”行为对TGF-β刺激具有时间和剂量限制,容易被较强的抑制信号所掩盖;4) TAK-981可增强CD8+ T细胞的“自救”信号,提高其功能。结论:我们的研究描述了HCC中CD8+ T细胞对抗衰竭的“自我拯救”机制以及放大这一信号的良好效果。
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引用次数: 2
CircGLIS3 inhibits thyroid cancer invasion and metastasis through miR-146b-3p/AIF1L axis. cirglis3通过miR-146b-3p/AIF1L轴抑制甲状腺癌的侵袭转移。
IF 6.6 2区 医学 Q2 CELL BIOLOGY Pub Date : 2023-12-01 Epub Date: 2023-08-23 DOI: 10.1007/s13402-023-00845-2
Siting Cao, Yali Yin, Huijuan Hu, Shubin Hong, Weiman He, Weiming Lv, Rengyun Liu, Yanbing Li, Shuang Yu, Haipeng Xiao

Purpose: Studies have shown that circRNA is involved in the occurrence and development of human cancers. However, it remains unclear that the contribution of circRNA in thyroid carcinoma and its role in the process of tumorigenesis.

Methods: The expression profile of circRNA-miRNA-mRNA in thyroid carcinoma was detected by RNA sequencing and verified by qRT-PCR. The characteristics of circGLIS3 were verified by RNase R and actinomycin assays, subcellular fractionation, and fluorescence in situ hybridization. The functions of circGLIS3 and AIF1L were detected by wound healing, transwell, 3D culture and Western blot. RNA Immunoprecipitation (RIP), RNA pulldown and dual-luciferase reporter assays were used to verify the target genes of circGLIS3 and downstream miRNAs. Functional rescue experiments were performed by transfecting miRNA mimics or siRNA of target genes. Finally, metastatic mouse models were used to investigate circGLIS3 function in vivo.

Results: In this study, we discovered a novel circRNA (has_circ_0007368, named as circGLIS3) by RNA sequencing. CircGLIS3 was down-regulated in thyroid carcinoma tissues and cells line, and was negatively associated with malignant clinical features of thyroid carcinoma. Functional studies found that circGLIS3 could inhibit the migration and invasion of thyroid carcinoma cells, and was related to the EMT process. Mechanistically, circGLIS3 can upregulate the expression of the AIF1L gene by acting as a miR-146b-3p sponge to inhibit the progression of thyroid carcinoma.

Conclusion: Our study identified circGLIS3 as a novel tumor suppressor in thyroid cancer, indicating the potential of circGLIS3 as a promising diagnostic and prognostic marker for thyroid cancer.

目的:研究表明,circRNA参与了人类癌症的发生发展。然而,circRNA在甲状腺癌中的作用及其在肿瘤发生过程中的作用尚不清楚。方法:采用RNA测序法检测circRNA-miRNA-mRNA在甲状腺癌组织中的表达谱,并采用qRT-PCR方法进行验证。通过RNase R和放线菌素检测、亚细胞分离和荧光原位杂交验证了cirglis3的特性。采用创面愈合、transwell、3D培养和Western blot检测cirglis3和AIF1L的功能。采用RNA免疫沉淀(RIP)、RNA拉下和双荧光素酶报告基因法验证cirglis3和下游mirna的靶基因。通过转染靶基因的miRNA模拟物或siRNA进行功能挽救实验。最后,使用转移小鼠模型来研究circGLIS3在体内的功能。结果:本研究通过RNA测序发现了一种新的circRNA (has_circ_0007368,命名为circGLIS3)。CircGLIS3在甲状腺癌组织细胞系中表达下调,与甲状腺癌的恶性临床特征呈负相关。功能研究发现,cirglis3能够抑制甲状腺癌细胞的迁移和侵袭,并与EMT过程有关。机制上,cirglis3可以作为miR-146b-3p海绵,上调AIF1L基因的表达,抑制甲状腺癌的进展。结论:我们的研究确定了circGLIS3在甲状腺癌中是一种新的肿瘤抑制因子,表明circGLIS3有潜力作为甲状腺癌的诊断和预后标志物。
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引用次数: 0
Therapeutic effects against high-grade glioblastoma mediated by engineered induced neural stem cells combined with GD2-specific CAR-NK. 工程诱导神经干细胞联合gd2特异性CAR-NK治疗高级别胶质母细胞瘤的疗效
IF 6.6 2区 医学 Q2 CELL BIOLOGY Pub Date : 2023-12-01 Epub Date: 2023-07-07 DOI: 10.1007/s13402-023-00842-5
Weihua Liu, Yu Zhao, Zhongfeng Liu, Guangji Zhang, Huantong Wu, Xin Zheng, Xihe Tang, Zhiguo Chen

Purpose: High-grade glioblastoma is extremely challenging to treat because of its aggressiveness and resistance to conventional chemo- and radio-therapies. On the contrary, genetic and cellular immunotherapeutic strategies based on the stem and immune cells are emerging as promising treatments against glioblastoma (GBM). We aimed to developed a novel combined immunotherapeutic strategy to improve the treatment efficacy using genetically engineered PBMC-derived induced neural stem cells (iNSCs) expressing HSV-TK and second-generation CAR-NK cells against GBM.

Methods: iNSCs cells expressing HSV-TK (iNSCsTK) and GD2-specific CAR-NK92 (GD2NK92) were generated from PBMC-derived iNSCs and NK92 cell lines, respectively. The anti-tumor effect of iNSCsTK and the combinational therapeutics of iNSCsTK and GD2NK92 were evaluated by GBM cell line using in vitro and in vivo experiments.

Results: PBMC-derived iNSCsTK possessed tumor-tropism migration ability in vitro and in vivo, which exhibited considerable anti-tumor activity via bystander effect in the presence of ganciclovir (GCV). iNSCsTK/GCV could slow GBM progression and prolong median survival in tumor-bearing mice. However, the anti-tumor effect was limited to single therapy. Therefore, the combinational therapeutic effect of iNSCsTK/GCV and GD2NK92 against GBM was investigated. This approach displayed a more significant anti-tumor effect in vitro and in xenograft tumor mice.

Conclusions: PBMC-derived iNSCsTK showed a significant tumor-tropic migration and an effective anti-tumor activity with GCV in vitro and in vivo. In addition, combined with GD2NK92, iNSCsTK therapeutic efficacy improved dramatically to prolong the tumor-bearing animal model's median survival.

目的:高级别胶质母细胞瘤由于其侵袭性和对常规化疗和放疗的耐药性,治疗极具挑战性。相反,基于干细胞和免疫细胞的遗传和细胞免疫治疗策略正在成为治疗胶质母细胞瘤(GBM)的有希望的治疗方法。我们的目标是开发一种新的联合免疫治疗策略,以提高表达HSV-TK和第二代CAR-NK细胞的基因工程pbmc衍生的诱导神经干细胞(iNSCs)治疗GBM的疗效。方法:用pbmc来源的iNSCs和NK92细胞系分别生成表达HSV-TK (inskstk)和gd2特异性CAR-NK92 (GD2NK92)的iNSCs细胞。通过体外和体内实验,评价了iNSCsTK的抗肿瘤作用以及iNSCsTK与GD2NK92联合治疗GBM细胞的效果。结果:pbmc衍生的iNSCsTK在体外和体内均具有向肿瘤迁移的能力,在更昔洛韦(GCV)存在下通过旁观者效应表现出相当的抗肿瘤活性。iNSCsTK/GCV可减缓荷瘤小鼠GBM的进展并延长中位生存期。然而,抗肿瘤效果仅限于单一治疗。因此,我们研究了inskstk /GCV和GD2NK92联合治疗GBM的疗效。该方法在体外和异种移植瘤小鼠中显示出更显著的抗肿瘤作用。结论:pbmc衍生的iNSCsTK在体外和体内均表现出明显的致瘤性迁移和抗GCV的有效活性。此外,与GD2NK92联合使用,显著提高了iNSCsTK的治疗效果,延长了荷瘤动物模型的中位生存期。
{"title":"Therapeutic effects against high-grade glioblastoma mediated by engineered induced neural stem cells combined with GD2-specific CAR-NK.","authors":"Weihua Liu, Yu Zhao, Zhongfeng Liu, Guangji Zhang, Huantong Wu, Xin Zheng, Xihe Tang, Zhiguo Chen","doi":"10.1007/s13402-023-00842-5","DOIUrl":"10.1007/s13402-023-00842-5","url":null,"abstract":"<p><strong>Purpose: </strong>High-grade glioblastoma is extremely challenging to treat because of its aggressiveness and resistance to conventional chemo- and radio-therapies. On the contrary, genetic and cellular immunotherapeutic strategies based on the stem and immune cells are emerging as promising treatments against glioblastoma (GBM). We aimed to developed a novel combined immunotherapeutic strategy to improve the treatment efficacy using genetically engineered PBMC-derived induced neural stem cells (iNSCs) expressing HSV-TK and second-generation CAR-NK cells against GBM.</p><p><strong>Methods: </strong>iNSCs cells expressing HSV-TK (iNSCs<sup>TK</sup>) and GD2-specific CAR-NK92 (GD2NK92) were generated from PBMC-derived iNSCs and NK92 cell lines, respectively. The anti-tumor effect of iNSCs<sup>TK</sup> and the combinational therapeutics of iNSCs<sup>TK</sup> and GD2NK92 were evaluated by GBM cell line using in vitro and in vivo experiments.</p><p><strong>Results: </strong>PBMC-derived iNSCs<sup>TK</sup> possessed tumor-tropism migration ability in vitro and in vivo, which exhibited considerable anti-tumor activity via bystander effect in the presence of ganciclovir (GCV). iNSCs<sup>TK</sup>/GCV could slow GBM progression and prolong median survival in tumor-bearing mice. However, the anti-tumor effect was limited to single therapy. Therefore, the combinational therapeutic effect of iNSCs<sup>TK</sup>/GCV and GD2NK92 against GBM was investigated. This approach displayed a more significant anti-tumor effect in vitro and in xenograft tumor mice.</p><p><strong>Conclusions: </strong>PBMC-derived iNSCs<sup>TK</sup> showed a significant tumor-tropic migration and an effective anti-tumor activity with GCV in vitro and in vivo. In addition, combined with GD2NK92, iNSCs<sup>TK</sup> therapeutic efficacy improved dramatically to prolong the tumor-bearing animal model's median survival.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1747-1762"},"PeriodicalIF":6.6,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9761816","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
Correction: Targeting ARHGEF12 promotes neuroblastoma differentiation, MYCN degradation, and reduces tumorigenicity. 更正:靶向ARHGEF12可促进神经母细胞瘤分化、MYCN降解并降低致瘤性。
IF 6.6 2区 医学 Q2 CELL BIOLOGY Pub Date : 2023-12-01 DOI: 10.1007/s13402-023-00890-x
Yi Yang, Siqi Wang, Jiaoyang Cai, Jianwei Liang, Yingwen Zhang, Yangyang Xie, Fei Luo, Jingyan Tang, Yijin Gao, Shuhong Shen, Haizhong Feng, Yanxin Li
{"title":"Correction: Targeting ARHGEF12 promotes neuroblastoma differentiation, MYCN degradation, and reduces tumorigenicity.","authors":"Yi Yang, Siqi Wang, Jiaoyang Cai, Jianwei Liang, Yingwen Zhang, Yangyang Xie, Fei Luo, Jingyan Tang, Yijin Gao, Shuhong Shen, Haizhong Feng, Yanxin Li","doi":"10.1007/s13402-023-00890-x","DOIUrl":"10.1007/s13402-023-00890-x","url":null,"abstract":"","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1871-1872"},"PeriodicalIF":6.6,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41240236","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
Targeting nucleolin improves sensitivity to chemotherapy in acute lymphoblastic leukemia. 靶向核蛋白提高急性淋巴细胞白血病化疗敏感性。
IF 6.6 2区 医学 Q2 CELL BIOLOGY Pub Date : 2023-12-01 Epub Date: 2023-07-24 DOI: 10.1007/s13402-023-00837-2
Yanxin Chen, Zhengjun Wu, Lingyan Wang, Minhui Lin, Peifang Jiang, Jingjing Wen, Jiazheng Li, Yunda Hong, Xiaoyun Zheng, Xiaozhu Yang, Jing Zheng, Robert Peter Gale, Ting Yang, Jianda Hu

Purpose: Most patients with acute lymphoblastic leukemia (ALL) are treated with chemotherapy as primary care. Although the treatment response is usually positive, resistance and relapse often occur via unknown mechanisms. The purpose of this study was to identify factors associated with chemotherapy resistance in ALL. Here, we present clinical and experimental evidence that overexpression of nucleolin (NCL), a multifunctional nucleolar protein, is linked to drug resistance in ALL.

Methods: NCL mRNA and protein levels were compared between cell lines and patient samples using qRT-PCR and immunoblotting. NCL mRNA levels were compared between patients of different disease stages from our clinic patients' specimens and publicly available ALL patient datasets. Cells and patient-derived xenograft mouse experiments were performed to assess the effect of NCL inhibition on ALL chemotherapy effectiveness.

Results: Analysis of patient specimens, and publicly available RNA-sequencing datasets revealed a strong correlation between the abundance of NCL and disease relapse or poor survival in B-ALL. Altering NCL expression results in changes in drug sensitivity in ALL cell lines. High levels of NCL upregulated components of the ATP-binding cassette transporters via activation of the ERK pathway, resulting in a decrease in drug accumulation inside the cells. Targeting NCL with AS1411, an NCL-binding oligonucleotide aptamer, significantly increased the sensitivity of ALL cell lines and cells/patient-derived ALL xenograft mice to chemotherapeutic drugs and prolonged mouse survival.

Conclusion: Our results highlight NCL as a prognostic marker in B-ALL and a potential therapeutic target to combat chemotherapy resistance in ALL.

目的:大多数急性淋巴细胞白血病(ALL)患者以化疗作为主要治疗手段。虽然治疗反应通常是积极的,但耐药性和复发往往是通过未知的机制发生的。本研究的目的是确定与ALL化疗耐药相关的因素。在这里,我们提出了临床和实验证据,证明核仁蛋白(NCL),一种多功能核仁蛋白,过表达与ALL的耐药性有关。方法:采用qRT-PCR和免疫印迹法比较不同细胞系和患者标本NCL mRNA和蛋白水平。我们比较了来自临床患者标本和公开可获得的ALL患者数据集的不同疾病分期患者的NCL mRNA水平。通过细胞和患者来源的异种移植小鼠实验来评估NCL抑制对ALL化疗效果的影响。结果:对患者标本和公开可获得的rna测序数据集的分析显示,NCL的丰度与B-ALL的疾病复发或生存率差之间存在很强的相关性。NCL表达的改变导致ALL细胞系药物敏感性的改变。高水平的NCL通过激活ERK途径上调atp结合盒转运体的成分,导致细胞内药物积累减少。用NCL结合寡核苷酸适配体AS1411靶向NCL,可显著提高ALL细胞系和细胞/患者来源的ALL异种移植小鼠对化疗药物的敏感性,延长小鼠生存期。结论:我们的研究结果强调NCL是B-ALL的预后标志物,也是对抗ALL化疗耐药的潜在治疗靶点。
{"title":"Targeting nucleolin improves sensitivity to chemotherapy in acute lymphoblastic leukemia.","authors":"Yanxin Chen, Zhengjun Wu, Lingyan Wang, Minhui Lin, Peifang Jiang, Jingjing Wen, Jiazheng Li, Yunda Hong, Xiaoyun Zheng, Xiaozhu Yang, Jing Zheng, Robert Peter Gale, Ting Yang, Jianda Hu","doi":"10.1007/s13402-023-00837-2","DOIUrl":"10.1007/s13402-023-00837-2","url":null,"abstract":"<p><strong>Purpose: </strong>Most patients with acute lymphoblastic leukemia (ALL) are treated with chemotherapy as primary care. Although the treatment response is usually positive, resistance and relapse often occur via unknown mechanisms. The purpose of this study was to identify factors associated with chemotherapy resistance in ALL. Here, we present clinical and experimental evidence that overexpression of nucleolin (NCL), a multifunctional nucleolar protein, is linked to drug resistance in ALL.</p><p><strong>Methods: </strong>NCL mRNA and protein levels were compared between cell lines and patient samples using qRT-PCR and immunoblotting. NCL mRNA levels were compared between patients of different disease stages from our clinic patients' specimens and publicly available ALL patient datasets. Cells and patient-derived xenograft mouse experiments were performed to assess the effect of NCL inhibition on ALL chemotherapy effectiveness.</p><p><strong>Results: </strong>Analysis of patient specimens, and publicly available RNA-sequencing datasets revealed a strong correlation between the abundance of NCL and disease relapse or poor survival in B-ALL. Altering NCL expression results in changes in drug sensitivity in ALL cell lines. High levels of NCL upregulated components of the ATP-binding cassette transporters via activation of the ERK pathway, resulting in a decrease in drug accumulation inside the cells. Targeting NCL with AS1411, an NCL-binding oligonucleotide aptamer, significantly increased the sensitivity of ALL cell lines and cells/patient-derived ALL xenograft mice to chemotherapeutic drugs and prolonged mouse survival.</p><p><strong>Conclusion: </strong>Our results highlight NCL as a prognostic marker in B-ALL and a potential therapeutic target to combat chemotherapy resistance in ALL.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1709-1724"},"PeriodicalIF":6.6,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10216801","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
Effect of infiltrating immune cells in tumor microenvironment on metastasis of hepatocellular carcinoma. 肿瘤微环境中浸润性免疫细胞对肝癌转移的影响。
IF 6.6 2区 医学 Q2 CELL BIOLOGY Pub Date : 2023-12-01 Epub Date: 2023-07-06 DOI: 10.1007/s13402-023-00841-6
Yiwen Chen, Yuhang Zhou, Ziyang Yan, Peilin Tong, Qiang Xia, Kang He

Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent human malignancies, leading to poor prognosis due to its high recurrence and metastasis rates. In recent years it has become increasingly evident that the tumor microenvironment (TME) plays an important role in tumor progression and metastasis. Tumor microenvironment (TME) refers to the complex tissue environment of tumor occurrence and development. Here, we summarize the development of HCC and the role of cellular and non-cellular components of the TME in the metastasis HCC, with particular reference to tumor-infiltrating immune cells. We also discuss some of the possible therapeutic targets for the TME and the future prospectives of this evolving field. SIGNIFICANCE: This review provides a comprehensive analysis of the role of the infiltrating immune cells in TME in the metastasis of HCC and highlights the future outlook for targeted therapy of the TME in the context of recent experiments revealing a number of therapeutic targets targeting the TME.

肝细胞癌(HCC)是最致命和最常见的人类恶性肿瘤之一,由于其高复发和转移率,导致预后不良。近年来,肿瘤微环境(tumor microenvironment, TME)在肿瘤进展和转移过程中起着重要作用的研究越来越明显。肿瘤微环境(Tumor microenvironment, TME)是指肿瘤发生发展的复杂组织环境。在这里,我们总结了HCC的发展以及TME的细胞和非细胞成分在HCC转移中的作用,特别是肿瘤浸润性免疫细胞。我们还讨论了TME的一些可能的治疗靶点以及这一不断发展的领域的未来前景。意义:本综述全面分析了TME浸润性免疫细胞在HCC转移中的作用,并在最近的实验中揭示了一些针对TME的治疗靶点,强调了TME靶向治疗的未来前景。
{"title":"Effect of infiltrating immune cells in tumor microenvironment on metastasis of hepatocellular carcinoma.","authors":"Yiwen Chen, Yuhang Zhou, Ziyang Yan, Peilin Tong, Qiang Xia, Kang He","doi":"10.1007/s13402-023-00841-6","DOIUrl":"10.1007/s13402-023-00841-6","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent human malignancies, leading to poor prognosis due to its high recurrence and metastasis rates. In recent years it has become increasingly evident that the tumor microenvironment (TME) plays an important role in tumor progression and metastasis. Tumor microenvironment (TME) refers to the complex tissue environment of tumor occurrence and development. Here, we summarize the development of HCC and the role of cellular and non-cellular components of the TME in the metastasis HCC, with particular reference to tumor-infiltrating immune cells. We also discuss some of the possible therapeutic targets for the TME and the future prospectives of this evolving field. SIGNIFICANCE: This review provides a comprehensive analysis of the role of the infiltrating immune cells in TME in the metastasis of HCC and highlights the future outlook for targeted therapy of the TME in the context of recent experiments revealing a number of therapeutic targets targeting the TME.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1595-1604"},"PeriodicalIF":6.6,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9758694","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: 1
Targeting TRIM24 promotes neuroblastoma differentiation and decreases tumorigenicity via LSD1/CoREST complex. 靶向TRIM24可通过LSD1/CoREST复合物促进神经母细胞瘤分化并降低致瘤性。
IF 6.6 2区 医学 Q2 CELL BIOLOGY Pub Date : 2023-12-01 Epub Date: 2023-07-19 DOI: 10.1007/s13402-023-00843-4
Qiqi Shi, Bo Yu, Yingwen Zhang, Yi Yang, Chenxin Xu, Mingda Zhang, Guoyu Chen, Fei Luo, Bowen Sun, Ru Yang, Yanxin Li, Haizhong Feng

Purpose: High-risk neuroblastoma (NB) still has an unfavorable prognosis and inducing NB differentiation is a potential strategy in clinical treatment, yet underlying mechanisms are still elusive. Here we identify TRIM24 as an important regulator of NB differentiation.

Methods: Multiple datasets and clinical specimens were analyzed to define the role of TRIM24 in NB. The effects of TRIM24 on differentiation and growth of NB were determined by cell morphology, spheres formation, soft agar assay, and subcutaneous xenograft in nude mice. RNA-Seq and qRT-PCR were used to identify genes and pathways involved. Mass spectrometry and co-immunoprecipitation were used to explore the interaction of proteins.

Results: Trim24 is highly expressed in spontaneous NB in TH-MYCN transgenic mice and clinical NB specimens. It is associated with poor NB differentiation and unfavorable prognostic. Knockout of TRIM24 in neuroblastoma cells promotes cell differentiation, reduces cell stemness, and inhibits colony formation in soft agar and subcutaneous xenograft tumor growth in nude mice. Mechanistically, TRIM24 knockout alters genes and pathways related to neural differentiation and development by suppressing LSD1/CoREST complex formation. Besides, TRIM24 knockout activates the retinoic acid pathway. Targeting TRIM24 in combination with retinoic acid (RA) synergistically promotes NB cell differentiation and inhibits cell viability.

Conclusion: Our findings demonstrate that TRIM24 is critical for NB differentiation and suggest that TRIM24 is a promising therapeutic target in combination with RA in NB differentiation therapy.

目的:高危神经母细胞瘤(NB)预后不良,诱导NB分化是临床治疗的一种潜在策略,但其机制尚不明确。在这里,我们发现TRIM24是NB分化的重要调节因子。方法:分析多个数据集和临床标本,确定TRIM24在NB中的作用。通过裸鼠细胞形态、球形成、软琼脂实验和皮下移植观察TRIM24对NB分化和生长的影响。采用RNA-Seq和qRT-PCR鉴定相关基因和通路。采用质谱法和免疫共沉淀法研究蛋白间的相互作用。结果:在TH-MYCN转基因小鼠和临床NB标本中,Trim24在自发性NB中高表达。它与NB分化差和预后不良有关。敲除神经母细胞瘤细胞中的TRIM24可促进细胞分化,降低细胞干性,抑制裸小鼠软琼脂和皮下异种移植物肿瘤生长中的集落形成。从机制上讲,敲除TRIM24通过抑制LSD1/CoREST复合体的形成来改变与神经分化和发育相关的基因和途径。此外,TRIM24敲除激活维甲酸途径。靶向TRIM24与维甲酸(RA)联合可协同促进NB细胞分化并抑制细胞活力。结论:我们的研究结果表明TRIM24对NB分化至关重要,提示TRIM24联合RA在NB分化治疗中是一个有希望的治疗靶点。
{"title":"Targeting TRIM24 promotes neuroblastoma differentiation and decreases tumorigenicity via LSD1/CoREST complex.","authors":"Qiqi Shi, Bo Yu, Yingwen Zhang, Yi Yang, Chenxin Xu, Mingda Zhang, Guoyu Chen, Fei Luo, Bowen Sun, Ru Yang, Yanxin Li, Haizhong Feng","doi":"10.1007/s13402-023-00843-4","DOIUrl":"10.1007/s13402-023-00843-4","url":null,"abstract":"<p><strong>Purpose: </strong>High-risk neuroblastoma (NB) still has an unfavorable prognosis and inducing NB differentiation is a potential strategy in clinical treatment, yet underlying mechanisms are still elusive. Here we identify TRIM24 as an important regulator of NB differentiation.</p><p><strong>Methods: </strong>Multiple datasets and clinical specimens were analyzed to define the role of TRIM24 in NB. The effects of TRIM24 on differentiation and growth of NB were determined by cell morphology, spheres formation, soft agar assay, and subcutaneous xenograft in nude mice. RNA-Seq and qRT-PCR were used to identify genes and pathways involved. Mass spectrometry and co-immunoprecipitation were used to explore the interaction of proteins.</p><p><strong>Results: </strong>Trim24 is highly expressed in spontaneous NB in TH-MYCN transgenic mice and clinical NB specimens. It is associated with poor NB differentiation and unfavorable prognostic. Knockout of TRIM24 in neuroblastoma cells promotes cell differentiation, reduces cell stemness, and inhibits colony formation in soft agar and subcutaneous xenograft tumor growth in nude mice. Mechanistically, TRIM24 knockout alters genes and pathways related to neural differentiation and development by suppressing LSD1/CoREST complex formation. Besides, TRIM24 knockout activates the retinoic acid pathway. Targeting TRIM24 in combination with retinoic acid (RA) synergistically promotes NB cell differentiation and inhibits cell viability.</p><p><strong>Conclusion: </strong>Our findings demonstrate that TRIM24 is critical for NB differentiation and suggest that TRIM24 is a promising therapeutic target in combination with RA in NB differentiation therapy.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1763-1775"},"PeriodicalIF":6.6,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9834776","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
Survivin degradation by bergenin overcomes pemetrexed resistance. 卑尔根素降解生存素克服培美曲塞耐药性。
IF 6.6 2区 医学 Q2 CELL BIOLOGY Pub Date : 2023-12-01 Epub Date: 2023-08-05 DOI: 10.1007/s13402-023-00850-5
Xiaoying Li, Qi Liang, Li Zhou, Gaoyan Deng, Yeqing Xiao, Yu Gan, Shuangze Han, Jinzhuang Liao, Ruirui Wang, Xiang Qing, Wei Li

Purpose: Chemoresistance is a primary factor for treatment failure and tumor recurrence in non-small cell lung cancer (NSCLC) patients. The oncoprotein survivin is commonly upregulated in human malignancies and is associated with poor prognosis, but its effect on carcinogenesis and chemoresistance in NSCLC is not yet evident, and to explore an effective inhibitor targeting survivin expression is urgently needed.

Methods: The protumor characteristics of survivin and antitumor activities of bergenin in NSCLC cells were examined by MTS, colony formation assays, immunoblot, immunohistochemistry, and in vivo xenograft development.

Results: Survivin was upregulated in non-small cell lung cancer (NSCLC) tissues, while its depletion inhibited NSCLC tumorigenesis. The current study focused on bergenin, identifying its effective antitumor effect on NSCLC cells both in vivo and in vitro. The results showed that bergenin could inhibit cell proliferation and induce the intrinsic pathway of apoptosis via downregulating survivin. Mechanistically, bergenin reduced the phosphorylation of survivin via inhibiting the Akt/Wee1/CDK1 signaling pathway, thus resulting in enhanced interaction between survivin and E3 ligase Fbxl7 to promote survivin ubiquitination and degradation. Furthermore, bergenin promoted chemoresistance in NSCLC cells re-sensitized to pemetrexed treatment.

Conclusions: Survivin overexpression is required for maintaining multiple malignant phenotypes of NSCLC cells. Bergenin exerts a potent antitumor effect on NSCLC via targeting survivin, rendering it a promising agent for the treatment of NSCLC.

目的:化疗耐药是导致非小细胞肺癌(NSCLC)患者治疗失败和肿瘤复发的主要因素。肿瘤蛋白survivin在人类恶性肿瘤中普遍上调,且与预后不良相关,但其在NSCLC的癌变和化疗耐药中的作用尚不明显,迫切需要探索一种针对survivin表达的有效抑制剂。方法:采用MTS法、集落形成法、免疫印迹法、免疫组化法和体内异种移植物发育法检测NSCLC细胞中survivin的肿瘤特征和卑尔根素的抗肿瘤活性。结果:Survivin在非小细胞肺癌(NSCLC)组织中表达上调,而其缺失抑制NSCLC的肿瘤发生。目前的研究主要集中在卑尔根素上,在体内和体外验证其对NSCLC细胞的有效抗肿瘤作用。结果表明,肉芽甘蓝素可通过下调survivin抑制细胞增殖,诱导细胞凋亡的内在途径。在机制上,卑尔根素通过抑制Akt/Wee1/CDK1信号通路降低survivin的磷酸化,从而增强survivin与E3连接酶fbx17的相互作用,促进survivin泛素化和降解。此外,卑尔根素促进了培美曲塞治疗再敏感的NSCLC细胞的化疗耐药。结论:Survivin过表达是维持NSCLC细胞多种恶性表型所必需的。甜菜根素通过靶向survivin对非小细胞肺癌具有较强的抗肿瘤作用,是治疗非小细胞肺癌的一种有前景的药物。
{"title":"Survivin degradation by bergenin overcomes pemetrexed resistance.","authors":"Xiaoying Li, Qi Liang, Li Zhou, Gaoyan Deng, Yeqing Xiao, Yu Gan, Shuangze Han, Jinzhuang Liao, Ruirui Wang, Xiang Qing, Wei Li","doi":"10.1007/s13402-023-00850-5","DOIUrl":"10.1007/s13402-023-00850-5","url":null,"abstract":"<p><strong>Purpose: </strong>Chemoresistance is a primary factor for treatment failure and tumor recurrence in non-small cell lung cancer (NSCLC) patients. The oncoprotein survivin is commonly upregulated in human malignancies and is associated with poor prognosis, but its effect on carcinogenesis and chemoresistance in NSCLC is not yet evident, and to explore an effective inhibitor targeting survivin expression is urgently needed.</p><p><strong>Methods: </strong>The protumor characteristics of survivin and antitumor activities of bergenin in NSCLC cells were examined by MTS, colony formation assays, immunoblot, immunohistochemistry, and in vivo xenograft development.</p><p><strong>Results: </strong>Survivin was upregulated in non-small cell lung cancer (NSCLC) tissues, while its depletion inhibited NSCLC tumorigenesis. The current study focused on bergenin, identifying its effective antitumor effect on NSCLC cells both in vivo and in vitro. The results showed that bergenin could inhibit cell proliferation and induce the intrinsic pathway of apoptosis via downregulating survivin. Mechanistically, bergenin reduced the phosphorylation of survivin via inhibiting the Akt/Wee1/CDK1 signaling pathway, thus resulting in enhanced interaction between survivin and E3 ligase Fbxl7 to promote survivin ubiquitination and degradation. Furthermore, bergenin promoted chemoresistance in NSCLC cells re-sensitized to pemetrexed treatment.</p><p><strong>Conclusions: </strong>Survivin overexpression is required for maintaining multiple malignant phenotypes of NSCLC cells. Bergenin exerts a potent antitumor effect on NSCLC via targeting survivin, rendering it a promising agent for the treatment of NSCLC.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1837-1853"},"PeriodicalIF":6.6,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9936909","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
期刊
Cellular Oncology
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