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TOP2A modulates signaling via the AKT/mTOR pathway to promote ovarian cancer cell proliferation. TOP2A 通过 AKT/mTOR 通路调节信号,促进卵巢癌细胞增殖。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-03-06 DOI: 10.1080/15384047.2024.2325126
Kaiwen Zhang, Xingyu Zheng, Yiqing Sun, Xinyu Feng, Xirong Wu, Wenlu Liu, Chao Gao, Ye Yan, Wenyan Tian, Yingmei Wang

Ovarian cancer (OC) is a form of gynecological malignancy that is associated with worse patient outcomes than any other cancer of the female reproductive tract. Topoisomerase II α (TOP2A) is commonly regarded as an oncogene that is associated with malignant disease progression in a variety of cancers, its mechanistic functions in OC have yet to be firmly established. We explored the role of TOP2A in OC through online databases, clinical samples, in vitro and in vivo experiments. And initial analyses of public databases revealed high OC-related TOP2A expression in patient samples that was related to poorer prognosis. This was confirmed by clinical samples in which TOP2A expression was elevated in OC relative to healthy tissue. Kaplan-Meier analyses further suggested that higher TOP2A expression levels were correlated with worse prognosis in OC patients. In vitro, TOP2A knockdown resulted in the inhibition of OC cell proliferation, with cells entering G1 phase arrest and undergoing consequent apoptotic death. In rescue assays, TOP2A was confirmed to regulate cell proliferation and cell cycle through AKT/mTOR pathway activity. Mouse model experiments further affirmed the key role that TOP2A plays as a driver of OC cell proliferation. These data provide strong evidence supporting TOP2A as an oncogenic mediator and prognostic biomarker related to OC progression and poor outcomes. At the mechanistic level, TOP2A can control tumor cell growth via AKT/mTOR pathway modulation. These preliminary results provide a foundation for future research seeking to explore the utility of TOP2A inhibitor-based combination treatment regimens in platinum-resistant recurrent OC patients.

卵巢癌(OC)是一种妇科恶性肿瘤,与女性生殖道的其他癌症相比,卵巢癌患者的预后更差。拓扑异构酶 II α(TOP2A)通常被认为是一种与多种癌症的恶性疾病进展相关的致癌基因,但它在卵巢癌中的机理功能尚未得到确定。我们通过在线数据库、临床样本、体外和体内实验探索了TOP2A在OC中的作用。对公共数据库的初步分析显示,患者样本中与 OC 相关的 TOP2A 高表达与较差的预后有关。这一点在临床样本中得到了证实,与健康组织相比,OC 中的 TOP2A 表达更高。Kaplan-Meier分析进一步表明,TOP2A表达水平越高,OC患者的预后越差。在体外,TOP2A 基因敲除可抑制 OC 细胞的增殖,使细胞进入 G1 期停滞并随之凋亡。在挽救实验中,TOP2A被证实通过AKT/mTOR通路的活性调节细胞增殖和细胞周期。小鼠模型实验进一步证实了 TOP2A 在 OC 细胞增殖中的关键驱动作用。这些数据提供了强有力的证据,支持 TOP2A 成为与 OC 进展和不良预后相关的致癌介质和预后生物标志物。在机理层面,TOP2A 可通过 AKT/mTOR 通路调节控制肿瘤细胞的生长。这些初步结果为今后的研究奠定了基础,有助于探索基于TOP2A抑制剂的联合治疗方案在铂耐药复发性OC患者中的应用。
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引用次数: 0
Efficacy and pharmacodynamic effect of anti-CD73 and anti-PD-L1 monoclonal antibodies in combination with cytotoxic therapy: observations from mouse tumor models. 抗CD73和抗PD-L1单克隆抗体联合细胞毒疗法的疗效和药效学效应:小鼠肿瘤模型观察。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-01-11 DOI: 10.1080/15384047.2023.2296048
Brajesh P Kaistha, Gozde Kar, Andreas Dannhorn, Amanda Watkins, Grace Opoku-Ansah, Kristina Ilieva, Stefanie Mullins, Judith Anderton, Elena Galvani, Fabien Garcon, Jean-Martin Lapointe, Lee Brown, James Hair, Tim Slidel, Nadia Luheshi, Kelli Ryan, Elizabeth Hardaker, Simon Dovedi, Rakesh Kumar, Robert W Wilkinson, Scott A Hammond, Jim Eyles

CD73 is a cell surface 5'nucleotidase (NT5E) and key node in the catabolic process generating immunosuppressive adenosine in cancer. Using a murine monoclonal antibody surrogate of Oleclumab, we investigated the effect of CD73 inhibition in concert with cytotoxic therapies (chemotherapies as well as fractionated radiotherapy) and PD-L1 blockade. Our results highlight improved survival in syngeneic tumor models of colorectal cancer (CT26 and MC38) and sarcoma (MCA205). This therapeutic outcome was in part driven by cytotoxic CD8 T-cells, as evidenced by the detrimental effect of CD8 depleting antibody treatment of MCA205 tumor bearing mice treated with anti-CD73, anti-PD-L1 and 5-Fluorouracil+Oxaliplatin (5FU+OHP). We hypothesize that the improved responses are tumor microenvironment (TME)-driven, as suggested by the lack of anti-CD73 enhanced cytopathic effects mediated by 5FU+OHP on cell lines in vitro. Pharmacodynamic analysis, using imaging mass cytometry and RNA-sequencing, revealed noteworthy changes in specific cell populations like cytotoxic T cells, B cells and NK cells in the CT26 TME. Transcriptomic analysis highlighted treatment-related modulation of gene profiles associated with an immune response, NK and T-cell activation, T cell receptor signaling and interferon (types 1 & 2) pathways. Inclusion of comparator groups representing the various components of the combination allowed deconvolution of contribution of the individual therapeutic elements; highlighting specific effects mediated by the anti-CD73 antibody with respect to immune-cell representation, chemotaxis and myeloid biology. These pre-clinical data reflect complementarity of adenosine blockade with cytotoxic therapy, and T-cell checkpoint inhibition, and provides new mechanistic insights in support of combination therapy.

CD73 是一种细胞表面 5'nucleotidase (NT5E),是癌症中产生免疫抑制腺苷的分解过程中的关键节点。我们使用小鼠单克隆抗体奥利珠单抗(Oleclumab)替代物,研究了CD73抑制与细胞毒疗法(化疗和分次放疗)和PD-L1阻断的协同作用。我们的研究结果表明,结直肠癌(CT26 和 MC38)和肉瘤(MCA205)共生肿瘤模型的生存率得到了改善。这种治疗结果部分是由细胞毒性 CD8 T 细胞驱动的,这一点可以从 CD8 清除抗体对接受抗 CD73、抗 PD-L1 和 5-氟尿嘧啶+奥沙利铂(5FU+OHP)治疗的 MCA205 肿瘤小鼠的不利影响得到证明。我们推测,抗 CD73 对体外细胞系的细胞病理效应没有增强,这说明反应的改善是由肿瘤微环境(TME)驱动的。利用成像质谱和 RNA 序列进行的药效学分析显示,CT26 TME 中的特定细胞群(如细胞毒性 T 细胞、B 细胞和 NK 细胞)发生了显著变化。转录组分析强调了与免疫反应、NK 和 T 细胞活化、T 细胞受体信号转导和干扰素(1 型和 2 型)通路相关的基因谱的治疗相关调控。纳入代表联合疗法各种成分的比较组后,可以对单个治疗要素的贡献进行解构;突出了抗 CD73 抗体在免疫细胞代表性、趋化性和骨髓生物学方面介导的特定效应。这些临床前数据反映了腺苷阻断与细胞毒疗法和 T 细胞检查点抑制的互补性,并为支持联合疗法提供了新的机理见解。
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引用次数: 0
Correction. 更正。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-05-15 DOI: 10.1080/15384047.2024.2352926
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引用次数: 0
Correction. 更正。
IF 4.4 4区 医学 Q2 ONCOLOGY Pub Date : 2024-12-31 Epub Date: 2024-07-01 DOI: 10.1080/15384047.2024.2375109
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引用次数: 0
miR-10b-5p promotes tumor growth by regulating cell metabolism in liver cancer via targeting SLC38A2. miR-10b-5p 通过靶向 SLC38A2 调节肝癌细胞代谢促进肿瘤生长
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-02-23 DOI: 10.1080/15384047.2024.2315651
Mingzhi Xia, Jie Chen, Yingyun Hu, Bin Qu, Qianqian Bu, Haoming Shen

Metabolic reprogramming plays a critical role in hepatocarcinogenesis. However, the mechanisms regulating metabolic reprogramming in primary liver cancer (PLC) are unknown. Differentially expressed miRNAs between PLC and normal tissues were identified using bioinformatic analysis. RT-qPCR was used to determine miR-10b-5p and SCL38A2 expression levels. IHC, WB, and TUNEL assays were used to assess the proliferation and apoptosis of the tissues. The proliferation, migration, invasion, and apoptosis of PLC cells were determined using the CCK-8 assay, Transwell assay, and flow cytometry. The interaction between miR-10b-5p and SLC38A2 was determined using dual-luciferase reporter assay. A PLC xenograft model in BALB/c nude mice was established, and tumorigenicity and SLC38A2 expression were estimated. Finally, liquid chromatography - mass spectrometry (LC-MS) untargeted metabolomics was used to analyze the metabolic profiles of xenograft PLC tissues in nude mice. miR-10b-5p was a key molecule in the regulation of PLC. Compared with para-carcinoma tissues, miR-10b-5p expression was increased in tumor tissues. miR-10b-5p facilitated proliferation, migration, and invasion of PLC cells. Mechanistically, miR-10b-5p targeted SLC38A2 to promote PLC tumor growth. Additionally, miR-10b-5p altered the metabolic features of PLC in vivo. Overexpression of miR-10b-5p resulted in remarkably higher amounts of lumichrome, folic acid, octanoylcarnitine, and Beta-Nicotinamide adenine dinucleotide, but lower levels of 2-methylpropanal, glycyl-leucine, and 2-hydroxycaproic acid. miR-10b-5p facilitates the metabolic reprogramming of PLC by targeting SLC38A2, which ultimately boosts the proliferation, migration, and invasion of PLC cells. Therefore, miR-10b-5p and SLC38A2 are potential targets for PLC diagnosis and treatment.

代谢重编程在肝癌发生过程中起着至关重要的作用。然而,原发性肝癌(PLC)代谢重编程的调控机制尚不清楚。通过生物信息学分析确定了原发性肝癌和正常组织中表达不同的 miRNA。采用 RT-qPCR 确定 miR-10b-5p 和 SCL38A2 的表达水平。采用 IHC、WB 和 TUNEL 检测法评估组织的增殖和凋亡。利用 CCK-8 试验、Transwell 试验和流式细胞术测定了 PLC 细胞的增殖、迁移、侵袭和凋亡。使用双荧光素酶报告实验测定了 miR-10b-5p 与 SLC38A2 之间的相互作用。在 BALB/c 裸鼠中建立了 PLC 异种移植模型,并对其致瘤性和 SLC38A2 表达进行了评估。最后,利用液相色谱-质谱(LC-MS)非靶向代谢组学分析了裸鼠异种移植 PLC 组织的代谢谱。与癌旁组织相比,miR-10b-5p在肿瘤组织中的表达增加。从机制上看,miR-10b-5p靶向SLC38A2,促进了PLC肿瘤的生长。此外,miR-10b-5p 还改变了 PLC 在体内的代谢特征。通过靶向 SLC38A2,miR-10b-5p 促进了 PLC 的代谢重编程,最终促进了 PLC 细胞的增殖、迁移和侵袭。因此,miR-10b-5p 和 SLC38A2 是诊断和治疗 PLC 的潜在靶点。
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引用次数: 0
MiR-378a-5p exerts a radiosensitizing effect on CRC through LRP8/β-catenin axis. MiR-378a-5p通过LRP8/β-catenin轴对CRC产生放射增敏作用。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-02-22 DOI: 10.1080/15384047.2024.2308165
Guolin Hu, Pengbiao Che, Ling Deng, Lei Liu, Jia Liao, Qi Liu

Background: MiRNAs are closely related to tumor radiosensitivity. MiR-378a-5p level is down-regulated in colorectal cancer (CRC). Therefore, this study intends to explore the role of miR-378a-5p in CRC, especially radiosensitivity.

Methods: The expression of miR-378a-5p was analyzed in CRC samples. CRC cell lines were treated with different doses of X-rays. Bioinformatics analysis, dual-luciferase reporter assay and RT-qPCR were used to detect the expressions and binding relationship of miR-378a-5p and low-density lipoprotein receptor-related protein 8 (LRP8). MiR-378a-5p inhibitor or/and siLRP8 were transfected into CRC cells with or without irradiation. Subsequently, clonogenic assay, flow cytometry and in vivo experiments including tumorigenesis assay, immunohistochemistry, RT-qPCR and Western blot were performed to clarify the role of miR-378a-5p/LRP8 axis in the radiosensitivity of CRC.

Results: The down-regulated expression of miR-378a-5p in CRC is related to histological differentiation and tumor-node-metastasis (TNM) stage. After irradiation, the survival fraction of CRC cells was decreased, while the apoptotic rate and the level of miR-378a-5p were increased. Restrained miR-378a-5p repressed apoptosis and apoptosis-related protein expressions, yet promoted the proliferation and the radioresistance of cells by regulating β-catenin in CRC cells. LRP8 was highly expressed in CRC, and targeted by miR-378a-5p. SiLRP8 improved radiosensitivity and reversed the effect of miR-378a-5p down-regulation on CRC cells. Overexpressed miR-378a-5p and irradiation enhanced the level of miR-378a-5p, yet suppressed the expressions of Ki67 and LRP8 as well as tumorigenesis.

Conclusion: MiR-378a-5p may exert a radiosensitizing effect on CRC through the LRP8/β-catenin axis, which may be a new therapeutic target for CRC radioresistance.

背景MiRNA与肿瘤放射敏感性密切相关。MiR-378a-5p水平在结直肠癌(CRC)中下调。因此,本研究旨在探讨 miR-378a-5p 在 CRC 中的作用,尤其是放射敏感性:方法:分析 CRC 样本中 miR-378a-5p 的表达。方法:分析 miR-378a-5p 在 CRC 样本中的表达。生物信息学分析、双荧光素酶报告分析和 RT-qPCR 检测了 miR-378a-5p 和低密度脂蛋白受体相关蛋白 8(LRP8)的表达及结合关系。将 MiR-378a-5p 抑制剂或/和 siLRP8 转染至接受或不接受辐照的 CRC 细胞。随后,进行了克隆生成试验、流式细胞术和体内实验,包括肿瘤发生试验、免疫组化、RT-qPCR和Western印迹,以明确miR-378a-5p/LRP8轴在CRC放射敏感性中的作用:结果:miR-378a-5p在CRC中的下调表达与组织学分化和肿瘤-结节-转移(TNM)分期有关。辐照后,CRC 细胞的存活率下降,而凋亡率和 miR-378a-5p 水平上升。受抑制的miR-378a-5p抑制了CRC细胞的凋亡和凋亡相关蛋白的表达,但通过调节β-catenin促进了细胞的增殖和放射抗性。LRP8在CRC中高表达,并被miR-378a-5p靶向。SiLRP8能改善CRC细胞的放射敏感性,并逆转miR-378a-5p下调对CRC细胞的影响。过表达的miR-378a-5p和辐照提高了miR-378a-5p的水平,但却抑制了Ki67和LRP8的表达以及肿瘤的发生:MiR-378a-5p可能通过LRP8/β-catenin轴对CRC产生放射增敏作用,这可能是治疗CRC放射耐药的新靶点。
{"title":"MiR-378a-5p exerts a radiosensitizing effect on CRC through LRP8/β-catenin axis.","authors":"Guolin Hu, Pengbiao Che, Ling Deng, Lei Liu, Jia Liao, Qi Liu","doi":"10.1080/15384047.2024.2308165","DOIUrl":"10.1080/15384047.2024.2308165","url":null,"abstract":"<p><strong>Background: </strong>MiRNAs are closely related to tumor radiosensitivity. MiR-378a-5p level is down-regulated in colorectal cancer (CRC). Therefore, this study intends to explore the role of miR-378a-5p in CRC, especially radiosensitivity.</p><p><strong>Methods: </strong>The expression of miR-378a-5p was analyzed in CRC samples. CRC cell lines were treated with different doses of X-rays. Bioinformatics analysis, dual-luciferase reporter assay and RT-qPCR were used to detect the expressions and binding relationship of miR-378a-5p and low-density lipoprotein receptor-related protein 8 (LRP8). MiR-378a-5p inhibitor or/and siLRP8 were transfected into CRC cells with or without irradiation. Subsequently, clonogenic assay, flow cytometry and <i>in vivo</i> experiments including tumorigenesis assay, immunohistochemistry, RT-qPCR and Western blot were performed to clarify the role of miR-378a-5p/LRP8 axis in the radiosensitivity of CRC.</p><p><strong>Results: </strong>The down-regulated expression of miR-378a-5p in CRC is related to histological differentiation and tumor-node-metastasis (TNM) stage. After irradiation, the survival fraction of CRC cells was decreased, while the apoptotic rate and the level of miR-378a-5p were increased. Restrained miR-378a-5p repressed apoptosis and apoptosis-related protein expressions, yet promoted the proliferation and the radioresistance of cells by regulating β-catenin in CRC cells. LRP8 was highly expressed in CRC, and targeted by miR-378a-5p. SiLRP8 improved radiosensitivity and reversed the effect of miR-378a-5p down-regulation on CRC cells. Overexpressed miR-378a-5p and irradiation enhanced the level of miR-378a-5p, yet suppressed the expressions of Ki67 and LRP8 as well as tumorigenesis.</p><p><strong>Conclusion: </strong>MiR-378a-5p may exert a radiosensitizing effect on CRC through the LRP8/β-catenin axis, which may be a new therapeutic target for CRC radioresistance.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10896128/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139930203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
CD46 and CD59 inhibitors enhance complement-dependent cytotoxicity of anti-CD38 monoclonal antibodies daratumumab and isatuximab in multiple myeloma and other B-cell malignancy cells. CD46和CD59抑制剂能增强抗CD38单克隆抗体daratumumab和isatuximab对多发性骨髓瘤和其他B细胞恶性肿瘤细胞的补体依赖性细胞毒性。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-02-15 DOI: 10.1080/15384047.2024.2314322
Hongjie Wang, Theo Koob, Jonathan R Fromm, Ajay Gopal, Darrick Carter, André Lieber

Multiple myeloma (MM) is an incurable malignancy of the B-cell lineage. Remarkable progress has been made in the treatment of MM with anti-CD38 monoclonal antibodies such as daratumumab and isatuximab, which can kill MM cells by inducing complement-dependent cytotoxicity (CDC). We showed that the CDC efficacy of daratumumab and isatuximab is limited by membrane complement inhibitors, including CD46 and CD59, which are upregulated in MM cells. We recently developed a small recombinant protein, Ad35K++, which is capable of transiently removing CD46 from the cell surface. We also produced a peptide inhibitor of CD59 (rILYd4). In this study, we tested Ad35K++ and rILYd4 in combination with daratumumab and isatuximab in MM cells as well as in cells from two other B-cell malignancies. We showed that Ad35K++ and rILYd4 increased CDC triggered by daratumumab and isatuximab. The combination of both inhibitors had an additive effect in vitro in primary MM cells as well as in vivo in a mouse xenograft model of MM. Daratumumab and isatuximab treatment of MM lines (without Ad35K++ or rILYd4) resulted in the upregulation of CD46/CD59 and/or survival of CD46high/CD59high MM cells that escaped the second round of daratumumab and isatuximab treatment. The escape in the second treatment cycle was prevented by the pretreatment of cells with Ad35K++. Overall, our data demonstrate that Ad35K++ and rILYd4 are efficient co-therapeutics of daratumumab and isatuximab, specifically in multi-cycle treatment regimens, and could be used to improve treatment of multiple myeloma.

多发性骨髓瘤(MM)是一种无法治愈的B细胞系恶性肿瘤。达拉土单抗和伊沙妥昔单抗等抗CD38单克隆抗体可通过诱导补体依赖性细胞毒性(CDC)杀死骨髓瘤细胞,在治疗骨髓瘤方面取得了显著进展。我们的研究表明,达拉土单抗和伊沙妥昔单抗的补体依赖性细胞毒性(CDC)疗效受到膜补体抑制剂的限制,包括在 MM 细胞中上调的 CD46 和 CD59。我们最近开发了一种小型重组蛋白 Ad35K++,它能够瞬时清除细胞表面的 CD46。我们还生产了一种 CD59 多肽抑制剂(rILYd4)。在这项研究中,我们测试了 Ad35K++ 和 rILYd4 与达拉单抗和伊沙妥昔单抗在 MM 细胞以及其他两种 B 细胞恶性肿瘤细胞中的联合应用。我们发现,Ad35K++ 和 rILYd4 增加了达拉土单抗和伊沙妥昔单抗引发的 CDC。在体外原发性 MM 细胞以及体内小鼠异种移植 MM 模型中,这两种抑制剂的组合具有叠加效应。达拉土单抗和伊沙妥昔单抗治疗 MM 株系(不含 Ad35K++ 或 rILYd4)会导致 CD46/CD59 上调和/或 CD46 高/CD59 高的 MM 细胞存活,这些细胞逃脱了第二轮达拉土单抗和伊沙妥昔单抗的治疗。用 Ad35K++ 对细胞进行预处理可防止细胞在第二轮治疗中逃逸。总之,我们的数据表明,Ad35K++和rILYd4是达拉单抗和伊沙妥昔单抗的高效协同治疗药物,特别是在多周期治疗方案中,可用于改善多发性骨髓瘤的治疗。
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引用次数: 0
Dynamic evolution of bone marrow adipocyte in B cell acute lymphoblastic leukemia: insights from diagnosis to post-chemotherapy. 骨髓脂肪细胞在 B 细胞急性淋巴细胞白血病中的动态演变:从诊断到化疗后的启示。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-03-11 DOI: 10.1080/15384047.2024.2323765
Xi Jia, Naying Liao, Yunqian Yao, Xutao Guo, Kai Chen, Pengcheng Shi

Adipocyte is a unique and versatile component of bone marrow microenvironment (BMM). However, the dynamic evolution of Bone Marrow (BM) adipocytes from the diagnosis of B cell Acute Lymphoblastic Leukemia (B-ALL) to the post-treatment state, and how they affect the progression of leukemia, remains inadequately explicated. Primary patient-derived xenograft models (PDXs) and stromal cell co-culture system are employed in this study. We show that the dynamic evolution of BM adipocytes from initial diagnosis of B-ALL to the post-chemotherapy phase, transitioning from cellular depletion in the initial leukemia niche to a fully restored state upon remission. Increased BM adipocytes retards engraftment of B-ALL cells in PDX models and inhibits cells growth of B-ALL in vitro. Mechanistically, the proliferation arrest of B-ALL cells in the context of adipocytes-enrichment niche, might attribute to the presence of adiponectin secreted by adipocytes themselves and the absence of cytokines secreted by mesenchymal stem cell (MSCs). In summary, our findings offer a novel perspective for further in-depth understanding of the dynamic balance between BMM and B-ALL.

脂肪细胞是骨髓微环境(BMM)中独特而多变的组成部分。然而,骨髓(BM)脂肪细胞从诊断为 B 细胞急性淋巴细胞白血病(B-ALL)到治疗后状态的动态演变,以及它们如何影响白血病的进展,仍未得到充分阐述。本研究采用了原代患者异种移植模型(PDX)和基质细胞共培养系统。我们发现,从 B-ALL 最初诊断到化疗后阶段,BM 脂肪细胞发生了动态演变,从最初白血病龛中的细胞耗竭过渡到缓解后的完全恢复状态。BM 脂肪细胞的增加会延缓 B-ALL 细胞在 PDX 模型中的移植,并抑制 B-ALL 细胞在体外的生长。从机理上讲,B-ALL 细胞在脂肪细胞富集的龛位中增殖受阻,可能是由于脂肪细胞本身分泌脂肪连素,而间充质干细胞(MSCs)不分泌细胞因子。总之,我们的发现为进一步深入了解BMM与B-ALL之间的动态平衡提供了一个新的视角。
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引用次数: 0
eIf3a mediates malignant biological behaviors in colorectal cancer through the PI3K/AKT signaling pathway. eIf3a 通过 PI3K/AKT 信号通路介导结直肠癌的恶性生物学行为。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-05-23 DOI: 10.1080/15384047.2024.2355703
Chao Huo, Disheng Wu, Xiaodan Li, Yan Zhang, Baoguang Hu, Taoming Zhang, Jianwei Ren, Tianbao Wang, Yi Liu

Colorectal cancer (CRC) is among the most common gastrointestinal malignancies worldwide. eIF3a is highly expressed in a variety of cancer types, yet its role in CRC remains unclear. We introduced ectopic eIF3a expression in CRC cells to investigate its relevance to various malignant behaviors. Further, we silenced eIF3a to explore its effect on tumor growth in a nude mouse tumor xenograft model. Finally, the molecular mechanisms through which eIF3a regulates malignancy in CRC cells were explored through bioinformatics analysis combined with the use of a specific PI3K inhibitor (LY294002). eIF3a was highly expressed in the peripheral blood and cancer tissue of CRC patients. Malignancy and tumor growth were significantly inhibited by silencing eIF3a, while overexpression promoted malignant behaviors, with a positive correlation between PI3K/AKT activation and eIF3a expression. Taken together, eIF3a plays an oncogenic role in CRC by regulating PI3K/AKT signaling and is a potential biomarker for CRC diagnosis and prognostic monitoring.

大肠癌(CRC)是全球最常见的胃肠道恶性肿瘤之一。eIF3a在多种癌症类型中高度表达,但它在CRC中的作用仍不清楚。我们在 CRC 细胞中引入了 eIF3a 的异位表达,以研究它与各种恶性行为的相关性。此外,我们还在裸鼠肿瘤异种移植模型中沉默了 eIF3a,以探讨其对肿瘤生长的影响。最后,我们通过生物信息学分析,结合使用特异性 PI3K 抑制剂(LY294002),探讨了 eIF3a 调节 CRC 细胞恶性程度的分子机制。沉默eIF3a能显著抑制恶性肿瘤的发生和生长,而过表达则会促进恶性行为,PI3K/AKT的激活与eIF3a的表达呈正相关。综上所述,eIF3a通过调控PI3K/AKT信号在CRC中发挥致癌作用,是CRC诊断和预后监测的潜在生物标志物。
{"title":"eIf3a mediates malignant biological behaviors in colorectal cancer through the PI3K/AKT signaling pathway.","authors":"Chao Huo, Disheng Wu, Xiaodan Li, Yan Zhang, Baoguang Hu, Taoming Zhang, Jianwei Ren, Tianbao Wang, Yi Liu","doi":"10.1080/15384047.2024.2355703","DOIUrl":"10.1080/15384047.2024.2355703","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is among the most common gastrointestinal malignancies worldwide. eIF3a is highly expressed in a variety of cancer types, yet its role in CRC remains unclear. We introduced ectopic eIF3a expression in CRC cells to investigate its relevance to various malignant behaviors. Further, we silenced eIF3a to explore its effect on tumor growth in a nude mouse tumor xenograft model. Finally, the molecular mechanisms through which eIF3a regulates malignancy in CRC cells were explored through bioinformatics analysis combined with the use of a specific PI3K inhibitor (LY294002). eIF3a was highly expressed in the peripheral blood and cancer tissue of CRC patients. Malignancy and tumor growth were significantly inhibited by silencing eIF3a, while overexpression promoted malignant behaviors, with a positive correlation between PI3K/AKT activation and eIF3a expression. Taken together, eIF3a plays an oncogenic role in CRC by regulating PI3K/AKT signaling and is a potential biomarker for CRC diagnosis and prognostic monitoring.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11123456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Circ_RPPH1 facilitates progression of breast cancer via miR-1296-5p/TRIM14 axis. Circ_RPPH1 通过 miR-1296-5p/TRIM14 轴促进乳腺癌的进展。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-05-30 DOI: 10.1080/15384047.2024.2360768
Jing Jiang, Shenghong Shi, Wei Zhang, Chao Li, Long Sun, Qidong Ge, Xujun Li

Circular RNA Ribonuclease P RNA Component H1 (circ_RPPH1) and microRNA (miRNA) miR-1296-5p play a crucial role in breast cancer (BC), but the molecular mechanism is vague. Evidence showed that miR-1296-5p can activate tripartite motif-containing 14 (TRIM14). Clinical indications of eighty BC patients were collected and the circ_RPPH1 expression was detected using real-time quantitative PCR. MCF-7 and MDA-MB-231 cells were transfected with overexpression or knockdown of circ_RPPH1, miR-1296-5p, or TRIM14. Cell counting kit-8, cell cloning formation, wound healing, Transwell, and flow cytometry assays were performed to investigate the malignant phenotype of BC. The dual-luciferase reporter gene analyses were applied to reveal the interaction between these target genes. Subcutaneous tumorigenic model mice were established with circ_RPPH1 overexpression MDA-MB-231 cells in vivo; the tumor weight and volume, levels of miR-1296-5 and TRIM14 mRNA were measured. Western blot and immunohistochemistry were used to detect TRIM14 in cells and mice. Circ_RPPH1 levels were notably higher in BC patients and have been found to promote cell proliferation, invasion, and migration of BC cells. Circ_RPPH1 altered cell cycle and hindered apoptosis. Circ_RPPH1 knockdown or miR-1296-5p overexpression inhibited the malignant phenotype of BC. Furthermore, miR-1296-5p knockdown reversed circ_RPPH1's promotion effects on BC. Interestingly, TRIM14 overexpression counteracts the inhibitory effects of miR-1296-5p overexpression and circ_RPPH1 silencing on BC. Moreover, in BC tumor-bearing mice, circ_RPPH1 overexpression led to increased TRIM14 expression and facilitated tumor growth. Circ_RPPH1 enhanced BC progression through miR-1296-5p/TRIM14 axis, indicating its potential as a biomarker and therapeutic target in BC.

环状 RNA 核糖核酸酶 P RNA 成分 H1(circ_RPPH1)和 microRNA(miRNA)miR-1296-5p 在乳腺癌(BC)中起着至关重要的作用,但其分子机制尚不清楚。有证据表明,miR-1296-5p 能激活含三方基序 14(TRIM14)。研究人员收集了 80 例 BC 患者的临床指征,并使用实时定量 PCR 检测了 circ_RPPH1 的表达。用过表达或敲除 circ_RPPH1、miR-1296-5p 或 TRIM14 的方法转染 MCF-7 和 MDA-MB-231 细胞。进行了细胞计数试剂盒-8、细胞克隆形成、伤口愈合、Transwell 和流式细胞术检测,以研究 BC 的恶性表型。应用双荧光素酶报告基因分析揭示了这些靶基因之间的相互作用。用circ_RPPH1过表达的MDA-MB-231细胞建立皮下肿瘤模型小鼠,测量肿瘤的重量和体积、miR-1296-5和TRIM14 mRNA的水平。采用 Western 印迹和免疫组织化学方法检测细胞和小鼠中的 TRIM14。BC患者的Circ_RPPH1水平明显较高,研究发现它能促进BC细胞的增殖、侵袭和迁移。Circ_RPPH1会改变细胞周期并阻碍细胞凋亡。Circ_RPPH1敲除或miR-1296-5p过表达可抑制BC的恶性表型。此外,miR-1296-5p 的敲除逆转了 circ_RPPH1 对 BC 的促进作用。有趣的是,TRIM14 的过表达抵消了 miR-1296-5p 过表达和 circ_RPPH1 沉默对 BC 的抑制作用。此外,在BC肿瘤小鼠中,circ_RPPH1过表达会导致TRIM14表达增加,并促进肿瘤生长。circ_RPPH1通过miR-1296-5p/TRIM14轴促进了BC的进展,表明它有可能成为BC的生物标记物和治疗靶点。
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Cancer Biology & Therapy
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