更新于：2024-05-01

Yb-1

Y-box binding protein 1

更新于：2024-05-01

基本信息

别名

BP-8、CBF-A、CCAAT-binding transcription factor I subunit A

+ [16]

简介

DNA- and RNA-binding protein involved in various processes, such as translational repression, RNA stabilization, mRNA splicing, DNA repair and transcription regulation (PubMed:8188694, PubMed:10817758, PubMed:11698476, PubMed:14718551, PubMed:18809583, PubMed:31358969). Predominantly acts as a RNA-binding protein: binds preferentially to the 5'-[CU]CUGCG-3' RNA motif and specifically recognizes mRNA transcripts modified by C5-methylcytosine (m5C) (PubMed:19561594, PubMed:31358969). Promotes mRNA stabilization: acts by binding to m5C-containing mRNAs and recruiting the mRNA stability maintainer ELAVL1, thereby preventing mRNA decay (PubMed:10817758, PubMed:11698476, PubMed:31358969). Component of the CRD-mediated complex that promotes MYC mRNA stability (PubMed:19029303). Contributes to the regulation of translation by modulating the interaction between the mRNA and eukaryotic initiation factors (By similarity). Plays a key role in RNA composition of extracellular exosomes by defining the sorting of small non-coding RNAs, such as tRNAs, Y RNAs, Vault RNAs and miRNAs (PubMed:27559612, PubMed:29073095). Probably sorts RNAs in exosomes by recognizing and binding C5-methylcytosine (m5C)-containing RNAs (PubMed:28341602, PubMed:29073095). Acts as a key effector of epidermal progenitors by preventing epidermal progenitor senescence: acts by regulating the translation of a senescence-associated subset of cytokine mRNAs, possibly by binding to m5C-containing mRNAs (PubMed:29712925). Also involved in pre-mRNA alternative splicing regulation: binds to splice sites in pre-mRNA and regulates splice site selection (PubMed:12604611). Also able to bind DNA: regulates transcription of the multidrug resistance gene MDR1 is enhanced in presence of the APEX1 acetylated form at 'Lys-6' and 'Lys-7' (PubMed:18809583). Binds to promoters that contain a Y-box (5'-CTGATTGGCCAA-3'), such as MDR1 and HLA class II genes (PubMed:8188694, PubMed:18809583). Promotes separation of DNA strands that contain mismatches or are modified by cisplatin (PubMed:14718551). Has endonucleolytic activity and can introduce nicks or breaks into double-stranded DNA, suggesting a role in DNA repair (PubMed:14718551). The secreted form acts as an extracellular mitogen and stimulates cell migration and proliferation (PubMed:19483673).

关联

项与 Yb-1 相关的药物

STEMVAC

靶点

CDH3 x ENG x MDM2 x SOX2 x Yb-1

作用机制

CDH3抑制剂 [+4]

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

SU056

靶点

Yb-1

作用机制

Yb-1抑制剂

在研机构

Oregon Health & Science University

原研机构

Oregon Health & Science University

在研适应症

肺癌

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

CET-056

靶点-

作用机制

Yb-1抑制剂

在研机构

Oregon Health & Science University

原研机构

Oregon Health & Science University

在研适应症

骨肉瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 Yb-1 相关的临床试验

NCT05242965 / Recruiting临床2期IIT

A Phase II Randomized Study of Safety and Efficacy of a Multiple Antigen Vaccine (STEMVAC) in Non-Small-Cell Lung Cancer Patients

This phase II trial tests whether CD105/Yb-1/SOX2/CDH3/MDM2-polyepitope plasmid DNA vaccine (STEMVAC) works to shrink tumors in patients with stage IV non-small cell lung cancer. STEMVAC targets specific immunogenic proteins that help lung cancer cells to grow. STEMVAC is made up of deoxyribonucleic acid (DNA), which is a natural substance in every living organism. DNA acts like a blueprint that tells all the cells in your body how to function. The DNA used in this study contains instructions for your body to produce parts of the 5 proteins the investigators identified (CDH3, CD105, YB-1, MDM2 and SOX2). STEMVAC is given with granulocyte-macrophage colony stimulating factor (GM-CSF) which is being used as an adjuvant to help create a stronger immune response. Giving STEMVAC with GM-CSF to patients while on maintenance therapy for non-small cell lung cancer (NSCLC) may help activate certain immune cells to recognize and kill lung cancer cells.

开始日期2023-03-24

申办/合作机构

University of Washington

[+1]

NCT05455658 / Recruiting临床2期IIT

A Phase II Trial of The Immunogenicity of a DNA Plasmid Based Vaccine (STEMVAC) Encoding Th1 Selective Epitopes From Five Antigens Associated With Breast Cancer Stem Cells (MDM2, YB1, SOX2, CDC25B, CD105) in Participants With Early Stage Triple Negative Breast Cancer

This phase II trial studies the effect of DNA plasmid based vaccine (STEMVAC) in treating patients with patients with stage IB-III triple negative breast cancer. STEMVAC may wake up the immune system in patients who have had a diagnosis of triple negative breast cancer and have been treated. STEMVAC targets proteins that are expressed on breast cancer cells and works by boosting the immune system to recognize and destroy the invader cancer cell proteins that are causing the disease. The purpose of this trial is to test the immune system's response to STEMVAC.

开始日期2022-11-17

申办/合作机构

University of Washington

[+2]

NCT02157051 / Active, not recruiting临床1期IIT

A Phase I Trial of the Safety and Immunogenicity of a Multiple Antigen Vaccine (STEMVAC) in HER2 Negative Advanced Stage Breast Cancer Patients

This phase I trial studies the side effects and best dose of multiantigen deoxyribonucleic acid (DNA) plasmid-based vaccine in treating patients with human epidermal growth factor receptor 2 (HER2)-negative stage III-IV breast cancer. Multiantigen DNA plasmid-based vaccine may target immunogenic proteins expressed in breast cancer stem cells which are the component of breast cancer that is resistant to chemotherapy and has the ability to spread. Vaccines made from DNA may help the body build an effective immune response to kill tumor cells.

开始日期2015-06-01

申办/合作机构

University of Washington

[+2]

100 项与 Yb-1 相关的临床结果

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100 项与 Yb-1 相关的转化医学

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0 项与 Yb-1 相关的专利（医药）

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1,689

项与 Yb-1 相关的文献（医药）

2024-02-20·Cell death & disease

Hsa_circ_0007990 promotes breast cancer growth via inhibiting YBX1 protein degradation to activate E2F1 transcription.

Article

作者: Tao Xu ; Mengqiu Xiong ; Qiwei Hong ; Bei Pan ; Mu Xu ; Ying Wang ; Yalan Sun ; Huiling Sun ; Yuqin Pan ; Shukui Wang ; Bangshun He

Breast cancer (BC) is the most commonly diagnosed malignant tumour in females worldwide. Although remarkable advances in early detection and treatment strategies have led to decreased mortality, recurrence and metastasis remain the major causes of cancer death in BC patients. Increasing evidence has demonstrated that circular RNAs (circRNAs) play critical roles in cancer progression. However, the detailed biological functions and molecular mechanisms of circRNAs in BC are unclear. The aim of this study was to investigate the possible role of circRNAs in the progression of BC. Differentially expressed circRNAs in BC were identified by integrating breast tumour-associated somatic CNV data and circRNA high-throughput sequencing. Aberrant hsa_circ_0007990 expression and host gene copy number were detected in BC cell lines via quantitative polymerase chain reaction (qPCR). The expression level of hsa_circ_0007990 in BC tissues was validated by in situ hybridization (ISH). Loss- and gain-of-function experiments were performed in vitro and in vivo, respectively, to explore the potential biological function of hsa_circ_0007990 in BC. The underlying mechanisms of hsa_circ_0007990 were investigated through MS2 RNA pull-down, RNA immunoprecipitation, RNA fluorescence in situ hybridization, immunofluorescence, chromatin immunoprecipitation and luciferase reporter assays. The levels of hsa_circ_0007990 were elevated in BC tissues and cell lines, an effect that was partly due to host gene copy number gains. Functional assays showed that hsa_circ_0007990 promoted BC cell growth. Mechanistically, hsa_circ_0007990 could bind to YBX1 and inhibit its degradation by preventing ubiquitin/proteasome-dependent degradation, thus enhancing the expression of the cell cycle-associated gene E2F1. Rescue experiments suggested that hsa_circ_0007990 promoted BC progression through YBX1. In general, our study demonstrated that hsa_circ_0007990 modulates the ubiquitination and degradation of YBX1 protein and further regulates E2F1 expression to promote BC progression. We explored the possible function and molecular mechanism of hsa_circ_0007990 in BC and identified a novel candidate target for the treatment of BC.

2024-02-15·Environmental toxicology

Yifei Sanjie formula alleviates lung cancer progression via regulating PRMT6-YBX1-CDC25A axis.

Article

作者: Jie Tang ; Chenyan Yin ; Meiyun Chen ; Mengjia Dong ; Youqi Xu

Lung cancer (LC) is the most prevalent cancer type, with a high mortality rate worldwide. The current treatment options for LC have not been particularly successful in improving patient outcomes. Yifei Sanjie (YFSJ), a well-applicated traditional Chinese medicine formula, is widely used to treat pulmonary diseases, especially LC, yet little is known about its molecular mechanisms. This study was conducted to explore the molecular mechanism by which YFSJ ameliorated LC progression. The A549, NCI-H1975, and Calu-3 cells were treated with the YFSJ formula and observed for colony number, apoptosis, migration, and invasion properties recorded via corresponding assays. The PRMT6-YBX1-CDC25A axis was tested and verified through luciferase reporter, RNA immunoprecipitation, and chromatin immunoprecipitation assays and rescue experiments. Our results demonstrated that YFSJ ameliorated LC cell malignant behaviors by increasing apoptosis and suppressing proliferation, migration, and invasion processes. We also noticed that the xenograft mouse model treated with YFSJ significantly reduced tumor growth compared with the control untreated group in vivo. Mechanistically, it was found that YFSJ suppressed the expression of PRMT6, YBX1, and CDC25A, while the knockdown of these proteins significantly inhibited colony growth, migration, and invasion, and boosted apoptosis in LC cells. In summary, our results suggest that YFSJ alleviates LC progression via the PRMT6-YBX1-CDC25A axis, confirming its efficacy in clinical use. The findings of our study provide a new regulatory network for LC growth and metastasis, which could shed new insights into pulmonary medical research.

2024-02-14·Cancer letters

Modulation of YBX1-mediated PANoptosis inhibition by PPM1B and USP10 confers chemoresistance to oxaliplatin in gastric cancer.

Article

作者: Chunlin Lin ; Penghang Lin ; Hengxin Yao ; Songyi Liu ; Xiang Lin ; Ruofan He ; Zuhong Teng ; Xinyi Zuo ; Yuxuan Li ; Jianxin Ye ; Guangwei Zhu

Gastric cancer (GC) is a common malignant tumor of the digestive tract, and chemoresistance significantly impacts GC patients' prognosis. PANoptosis has been associated with oxaliplatin-induced cell death. However, the direct regulatory role of YBX1 in cellular chemoresistance through PANoptosis remains unclear. In this study, we investigated the impact of YBX1 on regulating PANoptosis and its influence on the resistance of gastric cancer cells to oxaliplatin. Through overexpression and silencing experiments, we assessed YBX1's effect on proliferation and PANoptosis regulation in gastric cancer cells. Additionally, we identified PPM1B and USP10 as interacting proteins with YBX1 and confirmed their influence on YBX1 molecular function and protein expression levels. Our results demonstrate that YBX1 suppresses PANoptosis, leading to enhanced resistance of gastric cancer cells to oxaliplatin. Furthermore, we found that PPM1B and USP10 play critical roles in regulating YBX1-mediated PANoptosis inhibition. PPM1B directly interacts with YBX1, causing dephosphorylation of YBX1 at serine 314 residue. This dephosphorylation process affects the deubiquitination of YBX1 mediated by USP10, resulting in decreased YBX1 protein expression levels and impacting PANoptosis and oxaliplatin resistance in gastric cancer cells. Additionally, we discovered that the 314th amino acid of YBX1 has a profound impact on its own protein expression abundance, thereby affecting the functionality of YBX1. In conclusion, our study reveals the significance of PPM1B-mediated dephosphorylation of YBX1 and USP10-mediated deubiquitination in regulating PANoptosis and sensitivity to oxaliplatin in gastric cancer cells. These findings offer a potential therapeutic strategy for patients with oxaliplatin-resistant gastric cancer.

项与 Yb-1 相关的新闻（医药）

2024-03-25

·今日头条

“三联疗法”抗肿瘤效果最强！华中科技大学同济医学院附属协和医院徐双兵、陈静发布肺癌治疗新策略

本文为转化医学网原创，转载请注明出处作者：Sophia 导读：肿瘤细胞通过程序性死亡配体 1 （PD-L1）逃避免疫反应已被确定为导致肺癌患者对放射免疫治疗产生耐药性的一个因素。然而，PD-L1调控的确切分子机制仍不完全清楚。 2024年3月22日，华中科技大学同济医学院附属协和医院徐双兵教授和陈静教授共同通讯在《Journal of Experimental & Clinical Cancer Research》上发表题为“CDKL1 potentiates the antitumor efficacy of radioimmunotherapy by binding to transcription factor YBX1 and blocking PD-L1 expression in lung cancer”的研究论文，研究发现，CDKL1下调并抑制肺癌细胞的生长和增殖，并增加体外和体内的放射敏感性。从机制上讲，CDKL1 与转录因子 YBX1 相互作用，降低 YBX1 对 PD-L1 基因启动子的结合亲和力，从而抑制 PD-L1 的表达，最终导致 CD8 T 细胞的活化和肺癌免疫逃逸的抑制。此外，CDKL1 过表达、放疗和抗 PD-L1 抗体疗法的组合对肺癌表现出最有效的抗肿瘤功效。总之，本研究结果表明，CDKL1在调节PD-L1表达中起着至关重要的作用，从而增强了放射免疫疗法的抗肿瘤作用。这些结果表明，CDKL1可能是治疗肺癌的一个有前途的治疗靶点。 https://jeccr-biomedcentral-com.libproxy1.nus.edu.sg/articles/10.1186/s13046-024-03007-w 研究背景 01 肺癌是全球公认的癌症相关死亡的主要原因，也是癌症中死亡率最高的癌症。肺癌的主要治疗选择包括手术干预、放疗（RT）、化疗、靶向治疗和免疫治疗。在这些方式中，检查点阻断免疫疗法，特别是针对程序性细胞死亡蛋白 1 （PD-1）和程序性细胞死亡蛋白 1 配体 1 （PD-L1）的疗法，已被证明可为非小细胞肺癌（NSCLC）患者提供长期临床益处。此外，局部放疗有可能诱导从免疫冷肿瘤表型转变为热肿瘤表型，从而增加免疫治疗的影响。然而，免疫治疗与放疗联合的临床结果仍然不尽如人意。帕博利珠单抗联合放疗治疗的转移性非小细胞肺癌患者的远隔缓解率为 41.7%。大量证据表明，肿瘤PD-L1的表达水平是评估肺癌患者对抗PD-1/PD-L1治疗临床反应的关键生物标志物。因此，探索PD-L1调控机制对于改善肺癌免疫治疗的反应非常重要。研究进展 02 肿瘤细胞上高水平的 PD-L1 的存在阻碍了 CD8 T 细胞的活化，从而促进了肿瘤细胞的免疫逃避。因此，我们认为 CDKL1 介导的 PD-L1 调节可能会影响 CD8 T 细胞的活化。为了验证这一假设，我们培养了具有CDKL1过表达的Lewis细胞和从小鼠脾脏中提取的CD8 T细胞。流式细胞术清楚地表明，当CD8 T细胞与过表达CDKL1的细胞一起培养时，细胞毒性标志物IFN-γ和GZMB的表达显著增加（图6A）。随后，我们将过表达CDKL1的稳定Lewis细胞系接种到C57BL / 6J小鼠中，以建立皮下肿瘤模型。结果显示，在CDKL1过表达后，移植肿瘤的生长速度显著减慢，同时肿瘤的湿重降低（图6B，C）。为了阐明 CDKL1 在免疫逃逸中的作用，我们将肿瘤移植到单细胞悬浮液中，随后进行流式细胞术染色以评估 CD8 T 细胞的比例及其在肿瘤内分泌因子的水平。如图6D所示，在CDKL1过表达的肿瘤中，CD45+细胞中CD8 T细胞的比例增加，伴有IFN-γ和GZMB分泌的增加。这一发现表明，CDKL1具有刺激CD8 T细胞活化的潜力。总之，我们的研究结果表明， CDKL1诱导CD8 T细胞的活化，从而增强抗肿瘤免疫反应。 CDKL1 过表达在体内和体外抑制免疫逃避，三联疗法在肺癌中产生最有效的抗肿瘤结果。鉴于裸鼠中CDKL1过表达与放疗的联合治疗效果增加，CDKL1过表达抑制PD-L1表达同时刺激CD8 T细胞活化，我们假设CDKL1过表达、放疗和免疫疗法（抗PD-L1抗体）的组合可能协同增强抗肿瘤反应。我们进行了一项研究，其中我们实施了单药治疗、双药治疗和三药治疗，涉及 CDKL1、RT 和抗 PD-L1 免疫疗法的过表达（图 6E）。为了评估这些治疗的疗效，我们建立了9组皮下移植肿瘤的C57BL / 6J小鼠，并评估了这些组的抗肿瘤作用。我们的研究结果表明，单独使用任何一种疗法治疗都能有效抑制肿瘤生长（图6F）。与对照组相比，其中两种疗法的组合具有更强的阻挠肿瘤生长的能力，而三联疗法对肿瘤生长的影响最大（图6F）。此外，单药组和双药组CD8 T细胞比例和细胞毒性IFN-γ CD8 T细胞比例均有所增加，三联疗法组的效果最为明显（图6G，H）。值得注意的是，当CD8 T细胞耗尽时，三联疗法的有效性显著降低（图6F-H），这表明CD8 T细胞在针对肿瘤的免疫反应中不可或缺。总的来说，这些发现表明， CDKL1过表达、放疗和抗PD-L1抗体治疗的联合给药对肺癌的抗肿瘤作用最强。研究结论 03 综上所述，我们的研究全面了解了CDKL1在增强肺癌细胞的放射敏感性和抑制免疫逃逸方面的作用。此外，我们证明了 CDKL1 与 YBX1 相互作用，通过减少 YBX1 与 PD-L1 启动子的结合导致抑制 PD-L1 表达，从而激活 CD8 T 细胞反应并最终导致放射免疫治疗致敏（图 7）。这些发现为开发治疗肺癌的放射免疫增敏策略提供了新的分子靶点和临床前证据。 CDKL1 参与肺癌免疫逃逸的机制模型。（A） CDKL1 的缺失促进 YBX1 与 PD-L1 启动子的结合，从而上调 PD-L1 的表达。这反过来又导致CD8 T细胞失活和随后的免疫逃逸，最终赋予对放射免疫治疗的耐药性。（B） CDKL1 与 YBX1 结合并抑制 YBX1 在 PD-L1 启动子上的积累，从而下调 PD-L1 的表达。PD-L1 表达的降低促进了 CD8 T 细胞的活化，最终使肺癌对放射免疫治疗敏感。参考资料： https://jeccr-biomedcentral-com.libproxy1.nus.edu.sg/articles/10.1186/s13046-024-03007-w 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 上海｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！点击对应文字查看详情

免疫疗法放射疗法

2024-03-13

·今日头条

促进肿瘤发生和进展！中山大学发文：揭示癌症治疗新靶点

本文为转化医学网原创，转载请注明出处作者：Jerry 导读： NSUN2是m5C形成的重要的RNA甲基转移酶之一，参与许多重要的生物过程。然而，NSUN2介导的m5C修饰在结直肠癌(CRC)中的作用和潜在的分子机制尚不清楚。 3月11日，中山大学方乐堃研究团队在期刊《Clinical And Translational Medicine》上发表了研究论文，题为“NSUN2 promotes colorectal cancer progression by enhancing SKIL mRNA stabilization”。本研究强调了NSUN2通过m5c - ybx1依赖的SKIL转录稳定在CRC的初始和进展中的重要性，为CRC提供了一个有前景的靶向治疗策略。 https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/full/10.1002/ctm2.1621 研究背景 01 结直肠癌(CRC)是全球第三大常见癌症。手术是根治性治疗的重头戏。然而，大多数CRC患者因诊断晚和治疗方式无效而死亡。因此，迫切需要针对CRC的新型治疗靶点。 SKIL,也称为SnoN，是转化生长因子-β(TGF-β)信号传导的负向控制器。在哺乳动物中，SnoN在胚胎和成人组织中广泛表达。SKIL在许多癌细胞和组织中表达水平升高，包括来自非小细胞肺癌(NSCLC)和乳腺癌的细胞。有证据表明，SKIL与Hippo通路的多个组分相互作用，抑制大肿瘤抑制因子激酶2(Lats2)与TAZ的结合，致使TAZ稳定。此外，SKIL通过上调TAZ/自噬轴和抑制STING通路促进NSCLC细胞的肿瘤发生和免疫逃逸。相反，一些研究表明SKIL发挥肿瘤抑制作用。比如，沉默SKIL增加了食管鳞癌细胞系的增殖，表明了SKIL在肿瘤发生中的复杂作用。研究进展 02 为了研究NSUN2对CRC细胞行为的影响，研究人员使用shRNAs敲低NSUN2，并通过蛋白印迹法确定其效率。利用诱导细胞和克隆形成实验来探索NSUN2对CRC细胞增殖的调节作用。此外，重新引入NSUN2挽救了CRC细胞的生长。同样，克隆形成实验表明，NSUN2促进了克隆形成能力。研究人员还发现，在NSUN2被敲低后，迁移细胞的数量显著减少。相比之下，上调NSUN2增加了细胞的迁移能力。挽救实验表明，NSUN2参与了促进CRC细胞迁移的进程，这进一步证实了NSUN2的致癌作用。另外，研究人员将稳定感染的DLD1细胞接种到裸鼠的腹侧，观察NSUN2对异种移植瘤生长的影响。与对照组相比，NSUN2敲低组的肿瘤大小和重量明显降低，而重新引入NSUN2后可以挽救。总的来说，这些结果表明，NSUN2在体内外均促进CRC生长。研究人员还设计了挽救性功能实验，实验表明，SKIL过表达恢复了NSUN2敲低对CRC细胞增殖、克隆形成和迁移的抑制作用，相反，SKIL敲低消除了NSUN2促进CRC细胞克隆形成、细胞增殖和迁移的作用。研究人员将shNSUN2和PLVX-SKIL处理过或未处理的DLD1细胞接种到裸鼠的侧腹部。结果显示，NSUN2敲低抑制了肿瘤生长，降低了肿瘤重量和Ki67表达水平，而SKIL过表达则挽救了这些效果。总之，SKIL是促进CRC恶性肿瘤的关键靶点。 NSUN2 - SKIL轴在体内和体外都能促进结直肠癌的进展研究结论 03 总之，本研究结果证明了SKIL在CRC中的致癌作用，并将其作为CRC患者预后指标的潜力。本研究结果揭示了通过m5C修饰调节SKIL表达的新机制，这表明SKIL表达的调节机制是表观遗传学介导的，并且抑制SKIL中的m5C修饰可能对CRC患者有治疗作用。体外和体内实验证明NSUN2通过SKIL促进了CRC的发展。在CRC肿瘤组织中，NSUN2和SKIL的蛋白表达水平呈显著正相关。因此，进一步研究SKIL和NSUN2介导的m5C修饰在CRC中的协同抗癌作用是有意义的。参考资料： https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/full/10.1002/ctm2.1621 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 上海｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！点击对应文字查看详情

信使RNA

2024-02-22

·今日头条

再取进展！南京医科大学何帮顺/王书奎团队揭示乳腺癌进展新机制及治疗新靶点

本文为转化医学网原创，转载请注明出处作者：Jerry 导读：乳腺癌(BC)是世界范围内女性最常见的恶性肿瘤。尽管早期发现和治疗策略的显著进步导致死亡率下降，但复发和转移仍然是BC患者癌症死亡的主要原因。 2月20日，南京医科大学何帮顺/王书奎研究团队在期刊《Cell Death&Disease》上发表了题为“Hsa_circ_0007990 promotes breast cancer growth via inhibiting YBX1 protein degradation to activate E2F1 transcription”的研究论文，本研究中，研究表明hsa_circ_0007990调节YBX1蛋白的泛素化和降解，并进一步调节E2F1的表达，促进BC的进展。研究人员探索了hsa_circ_0007990在BC中的可能功能和分子机制，并确定了一种新的治疗BC的候选靶点。 https://www-nature-com.libproxy1.nus.edu.sg/articles/s41419-024-06527-7#Sec2 研究背景 01 乳腺癌(BC)已成为世界上最常见的癌症。近年来，由于早期发现和治疗的改善，BC的死亡率显著下降。然而，复发和转移仍然频繁发生，并继续威胁生存。由于对BC发展的分子机制知之甚少，需要进一步的研究来发现新的致病因素和治疗靶点。环状RNA (circRNAs)是一类特殊的RNA，具有共价封闭的单链环状结构。大量研究表明，环状RNA是高度保守、稳定和丰富的，并表现出疾病和组织特异性表达模式，这使它们能够在包括癌症在内的多种疾病中发挥重要的生物学功能。越来越多的证据表明，失调的环状RNA，如胃癌抑制因子circMTHFD2L，结直肠癌进展促进因子circINSIG1和BC过表达的circPVT1，可以作为致癌和肿瘤抑制因子。此外，据报道，circRNAs通过各种调节机制参与癌症的发病机制。尽管circRNAs的研究已经取得了一些进展，但circRNAs在BC肿瘤发生中的作用以及所涉及的详细分子机制还有待进一步阐明。研究进展 02 为探索hsa_circ_0007990在BC中的潜在生物学功能，研究人员设计了针对hsa_circ_0007990后接连接位点的两个敲低序列，并通过慢病毒转导到MCF-7细胞中。通过慢病毒介导的转导，在MDA-MB-231细胞中构建hsa_circ_0007990过表达载体，验证了hsa_circ_0007990的过表达效率。然后进行功能实验观察BC细胞的生物学行为。CCK8实验显示，敲低hsa_circ_0007990显著抑制MCF-7细胞的增殖，而过表达hsa_circ_0007990显著增加MDA-MB-231细胞的增殖。集落形成实验进一步支持了这些结果。此外，EdU实验表明，在MCF-7细胞中，沉默hsa_circ_0007990可抑制DNA合成，而在MDA-MB-231细胞中，上调hsa_circ_0007990则产生相反的效果。综上所述，这些体外实验表明hsa_circ_0007990可以促进BC细胞的生长。为了进一步研究hsa_circ_0007990在体内对BC细胞生长的影响，研究人员进行了裸鼠移植瘤实验。如图1A-C所示，与对照组相比，hsa_circ_0007990敲低组的异种移植瘤表现出较慢的生长速度和较低的肿瘤重量。不出所料，hsa_circ_0007990过表达组的肿瘤表现出相反的效果。免疫组织化学染色结果显示，hsa_circ_0007990敲低组细胞增殖标志物Ki67表达降低。因此，这些结果表明，hsa_circ_0007990可以促进BC细胞在体内的生长。图1：Hsa_circ_0007990可促进BC在体内的生长研究结论 03 综上所述，本研究鉴定并表征了一个新的circRNA hsa_circ_0007990，它在BC细胞中部分由于宿主基因PGAP3的扩增而上调。结果还显示，hsa_circ_0007990在BC组织中过表达，并与BC患者的恶性进展相关，但由于样本量较小，差异不显著。功能上，hsa_circ_0007990在体外和体内均促进BC的增殖和成瘤。机制上，hsa_circ_0007990与YBX1相互作用，抑制其泛素化和降解，进而促进E2F1转录。本研究阐明了hsa_circ_0007990在乳腺癌中的可能作用，为乳腺癌的治疗提供了一个有前景的治疗靶点。参考资料： https://www-nature-com.libproxy1.nus.edu.sg/articles/s41419-024-06527-7#Sec2 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 上海｜3月01日-02日 ▶第三届长三角单细胞组学技术应用论坛暨空间组学前沿论坛将在上海召开，诚邀您的参与！点击对应文字查看详情

临床研究临床结果