更新于：2024-11-01

HOXB8

更新于：2024-11-01

基本信息

别名

homeobox B8、Homeobox protein Hox-2.4、Homeobox protein Hox-2D

+ [4]

简介

Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis.

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100 项与 HOXB8 相关的临床结果

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100 项与 HOXB8 相关的转化医学

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0 项与 HOXB8 相关的专利（医药）

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478

项与 HOXB8 相关的文献（医药）

2024-08-01·Pancreatology

The tumor immune microenvironment in resected treatment-naive pancreatic cancer patients with long-term survival

Article

作者: Doukas, Michael ; van Eijck, Casper W F ; Heij, Lara R ; Vietsch, Eveline E ; Alonso, Lola ; Groot Koerkamp, Bas ; Wiltberger, Georg ; Verheij, Maaike ; van ’t Land, Freek R. ; Malats, Núria ; Stubbs, Andrew ; van 't Land, Freek R ; Ju, Jie ; Heij, Lara R. ; van Eijck, Casper H J ; van Eijck, Casper H.J. ; Vietsch, Eveline E. ; Li, Yunlei ; van Eijck, Casper W.F. ; Lila, Karishma

BACKGROUNDPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Presently, only a fraction of patients undergo successful surgical resection, the most effective treatment. Enhancing treatment strategies necessitates a deep comprehension of the factors underlying extended survival after surgical resection in patients.METHODSThis study aims to identify the important factors of PDAC patients' long-term survival with metatranscriptomics and multiplex immunofluorescence (IF) staining analyses. Specifically, differences in tumor immune microenvironment (TIME) were investigated between treatment-naïve PDAC short-term survivors (STS, overall survival <6 months) and long-term survivors (LTS, overall survival >5 years).RESULTSAs a result, we detected 589 over-expressed genes, including HOXB9, CDA, and HOXB8, and 507 under-expressed genes, including AMY2B, SCARA5, and SLC2A2 in LTS. Most of the Reactome overbiological pathways enriched in our data were over-expressed in LTS, such as RHO GTPase Effectors and Cell Cycle Checkpoints. Eleven microbiomes significantly differed between LTS and STS, including Sphingopyxis and Capnocytophaga. Importantly, we demonstrate that the TIME profile with an increased abundance of memory B cells and the reduction of M0 and pro-tumoral M2 macrophages are associated with a good prognosis in PDAC.CONCLUSIONSIn this study, we delved into the TIME with metatranscriptomics and IF staining analyses to understand the prerequisite of prolonged survival in PDAC patients. In LTS, several biological pathways were overexpressed, and specific microbiomes were identified. Furthermore, apparent differences in driven immune factors were found that provide valuable insights into developing new treatment strategies.

2024-06-01·Molecular Psychiatry

Optogenetic stimulation of mouse Hoxb8 microglia in specific regions of the brain induces anxiety, grooming, or both

Article

作者: Nagarajan, Naveen ; Capecchi, Mario R

AbstractPreviously, we have shown that either disruption of the Hoxb8 gene or ablation of a microglial subpopulation, Hoxb8 microglia, results in mice exhibiting both chronic anxiety and OCSD-like behavior, compulsive pathological hair pulling (trichotillomania), to the point of showing lesions at the sites of overgrooming. Herein we show, that optogenetic stimulation of Hoxb8 microglia in specific regions of the brain induces elevated anxiety, grooming or both. Optogenetic stimulation of Hoxb8 microglia within the dorsomedial striatum (DMS) or the medial prefrontal cortex (mPFC) induces grooming, whereas stimulation of Hoxb8 microglia in the basolateral amygdala (BLA) or central amygdala (CeA) produces elevated anxiety. Optogenetic stimulation of Hoxb8 microglia in the ventral CA1 region of the hippocampus (vCA1) induces both behaviors as well as freezing. In vitro we directly demonstrate that optogenetic stimulation of Hoxb8 microglia in specific regions of the brain activate neighboring neural activity through the induction of the c-fos-immediate early response. These experiments connect outputs from optogenetically stimulated Hoxb8 microglia, within specific regions of the brain, to the activation of neurons and neural circuits that in turn enable induction of these behaviors. These experiments suggest that Hoxb8 microglia are likely to be among, or the main, first responders to signals that evoke these behaviors. The same regions of the brain (DMS, mPFC, BLA, CeA and vCA1) have previously been defined at the neuronal level, by optogenetics, to control anxiety in mice. Intriguingly, the optogenetic experiments in microglia suggest that the two populations of microglia, canonical non-Hoxb8 and Hoxb8 microglia, function in opposition rather than in parallel to each other, providing a biological reason for the presence of two microglial subpopulations in mice.

2024-02-01·Poultry Science

Transcriptome-based comparison reveals key genes regulating allometry growth of forelimb and hindlimb bone in duck embryos

Article

作者: Li, Liang ; Tang, Qian ; Xi, Yang ; Liu, Hehe ; Qi, Jingjing ; Yang, Qinglan ; Hu, Jiwei ; Wu, Qifan ; Wang, Rui

Allometric growth of the forelimb and hindlimb is a widespread phenomenon observed in vertebrates. As a typical precocial bird, ducks exhibit more advanced development of their hindlimbs compared to their forelimbs, enabling them to walk shortly after hatching. This phenomenon is closely associated with the development of long bones in the embryonic stage. However, the molecular mechanism governing the allometric growth of duck forelimb and hindlimb bones is remains elusive. In this study, we employed phenotypic, histological, and gene expression analyses to investigate developmental differences between the humerus (forelimb bone) and tibia/femur (hindlimb bones) in duck embryos. Our results revealed a gradual increase in weight and length disparity between the tibia and humerus from E12 to E28 (embryo age). At E12, endochondral ossification was observed solely in the tibia but not in the humerus. The number of differentially expressed genes (DEGs) gradually increased at H12 vs. T12, H20 vs. T20, and H28 vs. T28 stages consistent with phenotypic variations. A total of 38 DEGs were found across all 3 stages. Protein-protein interaction network analysis demonstrated strong interactions among members of HOXD gene family (HOXD3/8/9/10/11/12), HOXB gene family (HOXB8/9), TBX gene family (TBX4/5/20), HOXA11, SHOX2, and MEIS2. Gene expression profiling indicated higher expression levels for all HOXD genes in the humerus compared to tibia while opposite trends were observed for HOXA/HOXB genes with low or no expression detected in the humerus. These findings suggest distinct roles played by different clusters within HOX gene family during skeletal development regulation of duck embryo's forelimbs versus hind limbs. Notably, TBX4 exhibited high expression levels specifically in tibia whereas TBX5 showed similar patterns exclusively within humerus as seen previously across other species' studies. In summary, this study identified key regulatory genes involved in allometric growth of duck forelimb and hindlimb bones during embryonic development. Skeletal development is a complex physiological process, and further research is needed to elucidate the regulatory role of candidate genes in endochondral ossification.

项与 HOXB8 相关的新闻（医药）

2024-09-01

·生物探索

Nature Cancer | 赵蔚/李杰团队： “黑神化”HDAC6以“相分离”调控三阴性乳腺癌三维基因组

引言三阴性乳腺癌（TNBC）是一种高度异质性的疾病，展现出极高的侵袭性【1】，常规的内分泌治疗或化疗对此类癌症通常无效【2】。之前的基因组、转录组和蛋白质组分析发现TNBC缺乏有效的生物标志物来指导治疗决策和预测治疗反应【3】，因此从新的角度深入理解TNBC病理生物学特性尤为重要。三维染色质结构指的是染色质在细胞核中的空间排列，包括染色质区域如何折叠、聚集以及它们如何与核小体和其他核内结构相互作用。在肿瘤中，染色质结构的异常重组可能导致染色质可及性变化，进而使原本静默的致癌基因被激活，或者抑癌基因被抑制。染色质结构的改变也可以影响染色体上的表观遗传标记，进而影响基因表达。尽管三维染色质结构对肿瘤表型的影响非常关键，但TNBC染色质结构的调控机制仍知之甚少。 2024年8月28日，广东省人民医院、中山大学、广州市妇女儿童中心、桂林医科大学附属医院及顺德医院的联合科研团队，以赵蔚和李杰两位教授为通讯作者，在Nature Cancer上发表了题为Phase separation of phospho-HDAC6 drives aberrant chromatin architecture in triple-negative breast cancer的论文。该研究发现磷酸化形式的HDAC6蛋白在TNBC细胞的核内转录活跃区域形成了液液相分离（LLPS）凝聚体，而在非TNBC中这种现象较少见。研究还鉴定出Nexturastat A作为磷酸化HDAC6 LLPS抑制剂，显示出能够导致染色质结构重塑和转录谱改变，有效抑制TNBC的肿瘤生长。该论文首次揭示了TNBC中存在磷酸化形式的HDAC6蛋白，并且干预磷酸化HDAC6的相分离可能为开发TNBC的治疗的新策略。该研究显示与非TNBC及相邻非癌组织相比，TNBC中HDAC6在细胞核表达显著增加，且主要以磷酸化形式存在。通过对HDAC6的潜在磷酸化位点进行突变分析，发现特定位点Ser22的磷酸化对其核内定位至关重要，这种磷酸化状态与肿瘤的分期及转移显著相关，并与患者的总生存期负相关。超分辨率显微镜观察发现，TNBC细胞中磷酸化HDAC6倾向于在细胞核中形成LLPS的凝聚体，这些凝聚体主要分布在活跃的染色质区域，并与转录活跃相关的标记物共定位。此外，实验还观察到表皮生长因子（EGF）能通过特定的激酶GRK2显著增加磷酸化HDAC6的水平和凝聚体形成。接下来，研究团队探讨了HDAC6的两个主要固有无序区域（IDRs）在相分离作用。研究发现，HDAC6的第一个无序区域（IDR1）的删除显著减少了磷酸化HDAC6的相分离，而第二个无序区域（IDR2）的删除则对相分离没有显著影响。此外，IDR1内Ser22位点的磷酸化状态对其相分离能力有重要影响。进一步的实验表明，HDAC6的特定结构域，如核输出信号（NES）域的删除，显著增强了HDAC6在核内的定位和相分离能力。探究肿瘤中异常LLPS凝聚体形成的机制不仅有助于理解染色质结构在基因表达调控中的角色，而且可能为开发新的治疗策略提供线索。例如，NUP98-HOXA9的LLPS有助于形成广泛的超级增强子（SE）样结合模式，从而促进白血病基因的转录激活4。此外，赵蔚团队之前的研究发现，HOXB8和FOSL1在染色质的SE位点形成的LLPS导致了骨肉瘤中转录的失调5。尽管LLPS在癌症中具有重要作用，但如何特异性破坏癌症中LLPS凝聚体仍有待探索。研究团队通过基于相分离蛋白的筛选，发现了一种名为Nexturastat A的HDAC6抑制剂，该抑制剂能有效地抑制TNBC中磷酸化HDAC6凝聚体的形成。相比之下，另一种HDAC6抑制剂HPOB则未能达到相同的效果。实验表明，Nexturastat A通过降低磷酸化HDAC6的LLPS，从而抑制TNBC细胞的增殖、瘤球形成能力和侵袭性，同时促进细胞凋亡。Nexturastat A在体内显著抑制了TNBC的生长。此外，Nexturastat A显示出极低的非癌细胞毒性，表明其具有良好的安全性。 Nexturastat A能够显著改变HDAC6与其相互作用蛋白之间的互作，尤其是降低与14-3-3θ的结合，后者是已知的LLPS的潜在参与因子。Nexturastat A的处理还减少了磷酸化HDAC6与进出核运输蛋白Importin β的相互作用，这一过程依赖于HDAC6的S22位点。此外，研究还揭示了NUP153在磷酸化HDAC6进入细胞核过程中的关键作用。随后，研究团队详细探讨了Nexturastat A对TNBC染色质结构的影响。通过Hi-C分析发现，Nexturastat A处理后，TNBC细胞的全基因组染色质相互作用发生了显著变化，特别是在开放和封闭染色质区域的重新分布。此外，Nexturastat A的治疗还促进了新的染色质环结构的形成，这些新环结构富含RNA聚合酶II（Pol II）特异性DNA结合和免疫系统过程通路，显示出Nexturastat A对染色质动态具有深远的影响。通过对Nexturastat A处理的TNBC细胞进行RNA-seq和Pol II ChIP-seq分析，揭示了Nexturastat A处理主要导致染色质结构的变化和转录模式的重新编程，这体现在染色质的增加可及性和Pol II的增加结合。此外，通过ATAC-seq研究发现Nexturastat A处理能够促使肿瘤抑制基因的表达上调，原癌基因表达下调，并且激活了与免疫反应相关的基因。最后，Nexturastat A通过改变HDAC6的结合模式和H3全乙酰化修饰，显著影响了染色质结构，尤其是在转录起始位点（TSS）周围。特别地，研究团队识别出一组基因显示HDAC6结合和H3全乙酰化的一致变化，这些基因主要富集在内质网应激和TP53信号通路中，包括肿瘤抑制基因ATF3。此外，ATF3敲减实验表明，ATF3是HDAC6的一个重要下游靶标，其敲减降低了细胞对Nexturastat A治疗的敏感性，影响了细胞的生存和侵袭能力。综上，本研究揭示了磷酸化HDAC6在TNBC中的全新作用，特别是它在转录活跃区域形成的相分离凝聚体对染色质结构的影响。通过与14-3-3θ共凝聚，磷酸化HDAC6不仅改变了染色质的物理结构，还促进了特定的组蛋白乙酰化修饰和转录谱的重编程，从而推动了TNBC的恶性表型发展。这一发现不仅为我们提供了对TNBC中染色质动态复杂性的更深层理解，还可能指明了新的治疗策略，即通过调控磷酸化HDAC6来干预TNBC的染色质结构和细胞命运。参考文献 1. Shi, Y., Jin, J., Ji, W. & Guan, X. Therapeutic landscape in mutational triple negative breast cancer. Mol Cancer 17, 99 (2018). 2. Garrido-Castro, A.C., Lin, N.U. & Polyak, K. Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment. Cancer Discov 9, 176-198 (2019). 3. Derakhshan, F. & Reis-Filho, J.S. Pathogenesis of Triple-Negative Breast Cancer. Annu Rev Pathol 17, 181-204 (2022). 4. Ahn, J.H. et al. Phase separation drives aberrant chromatin looping and cancer development. Nature 595, 591-595 (2021). 5. Lu, B. et al. Pharmacological Inhibition of Core Regulatory Circuitry Liquid-liquid Phase Separation Suppresses Metastasis and Chemoresistance in Osteosarcoma. Adv Sci (Weinh) 8, e2101895 (2021). https://www.nature.com/articles/s43018-024-00816-y 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

引进/卖出

2022-09-05

·生物谷

BMC cancer: lncRNA如何促进神经内分泌分化结直肠癌进展？

近段时间，来自中山大学的一个团队针对IncRNA展开了相关研究，以探索其在神经内分泌分化CRC中的功能和机制。结直肠癌（CRC）细胞中的神经内分泌分化（NED）已经存在了几十年，大量研究表明，患有神经内分泌分化的CRC患者的5年生存率较低。近年来，越来越多的研究发现，外泌体来源的长链非编码RNA（lncRNA）在癌症进展和转移中起着重要作用。然而，外泌体来源的lncRNA在CRC中伴神经内分泌分化的功能和机制尚不完全清楚。近段时间，来自中山大学的一个团队针对IncRNA展开了相关研究，以探索其在神经内分泌分化CRC中的功能和机制。该回顾性研究共纳入了105 名患者，对受试者进行下一代测序和生物信息学分析，选择lnc-HOXB8-1：2进行进一步研究。采用免疫组化、qRT–PCR、免疫印迹、转井检测、免疫荧光测定、荧光原位杂交测定和双荧光素酶报告基因测定，测定了外泌体衍生的 lnc-HOXB8-1：2 在 NED 结直肠癌中的致癌作用。还探讨了 lnc-HOXB8-1：2/hsa-miR-6825-5p/CXCR3 轴的机制。 NED是CRC进展和死亡的危险因素。该研究表明lnc-HOXB8-1：2来源于神经内分泌分化结肠癌细胞分泌的外泌体。M2巨噬细胞的比例以及肿瘤相关巨噬细胞（TAM）的迁移和侵袭能力在加入神经内分泌分化的CRC细胞衍生外泌体后显着增加。更令人兴奋的是，lnc-HOXB8-1：2的表达和CXCR3的蛋白水平在TAMs中也上调。lnc-HOXB8-1：2/hsa-miR-6825-5p/CXCR3轴通过miRanda软件预测，并通过双荧光素酶报告基因检测法得到了证实。此外，lnc-HOXB8-1：2的表达增加伴随着has-miR-6825-5p表达的下调和CXCR3蛋白水平的上调。has-miR-6825-5p的过表达也降低了CXCR3的表达。肿瘤相关巨噬细胞(CD68染色)围绕神经内分泌分化细胞(CgA染色)聚集与非NED组相比，NED组中含有CD68染色的肿瘤相关巨噬细胞比例显著增加总之，来自神经内分泌分化CRC细胞的外泌体中的lcc-HOXB8-1：2充当ceRNA竞争性结合has-miR-6825-5p以上调CXCR3表达并导致TAM浸润和M2极化，从而促进神经内分泌分化CRC进展。原始出处：Li X, Lan Q, et al. Exosome-derived lnc-HOXB8-1:2 induces tumor-associated macrophage infiltration to promote neuroendocrine differentiated colorectal cancer progression by sponging hsa-miR-6825-5p. BMC Cancer. 2022 Aug 27;22(1):928. doi: 10.1186/s12885-022-09926-1. PMID: 36030223; PMCID: PMC9419355.