更新于：2024-09-05

SLIT2

更新于：2024-09-05

基本信息

别名

SLIL3、slit guidance ligand 2、Slit homolog 2 protein

+ [4]

简介

Thought to act as molecular guidance cue in cellular migration, and function appears to be mediated by interaction with roundabout homolog receptors. During neural development involved in axonal navigation at the ventral midline of the neural tube and projection of axons to different regions. SLIT1 and SLIT2 seem to be essential for midline guidance in the forebrain by acting as repulsive signal preventing inappropriate midline crossing by axons projecting from the olfactory bulb. In spinal cord development may play a role in guiding commissural axons once they reached the floor plate by modulating the response to netrin. In vitro, silences the attractive effect of NTN1 but not its growth-stimulatory effect and silencing requires the formation of a ROBO1-DCC complex. May be implicated in spinal cord midline post-crossing axon repulsion. In vitro, only commissural axons that crossed the midline responded to SLIT2. In the developing visual system appears to function as repellent for retinal ganglion axons by providing a repulsion that directs these axons along their appropriate paths prior to, and after passage through, the optic chiasm. In vitro, collapses and repels retinal ganglion cell growth cones. Seems to play a role in branching and arborization of CNS sensory axons, and in neuronal cell migration. In vitro, Slit homolog 2 protein N-product, but not Slit homolog 2 protein C-product, repels olfactory bulb (OB) but not dorsal root ganglia (DRG) axons, induces OB growth cones collapse and induces branching of DRG axons. Seems to be involved in regulating leukocyte migration.

关联

100 项与 SLIT2 相关的临床结果

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100 项与 SLIT2 相关的转化医学

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0 项与 SLIT2 相关的专利（医药）

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696

项与 SLIT2 相关的文献（医药）

2024-02-11·The Science of the total environment

Reprogramming of DNA methylation patterns mediates perfluorooctane sulfonate-induced fetal cardiac dysplasia.

Article

作者: Min Qiu ; Jing Chen ; Mingqin Liu ; Yan Shi ; Zhiqiang Nie ; Guanghui Dong ; Xiaohong Li ; Jimei Chen ; Yanqiu Ou ; Jian Zhuang

Prenatal exposure to perfluorooctane sulfonate (PFOS) is associated with adverse health effects, including congenital heart disease, yet the underlying mechanisms remain elusive. Herein, we aimed to evaluate the embryotoxicity of PFOS using C57BL/6 J mice to characterize fetal heart defects after PFOS exposure, with the induction of human embryonic stem cells (hESC) into cardiomyocytes (CMs) as a model of early-stage heart development. We also performed DNA methylation analysis to clarify potential underlying mechanisms and identify targets of PFOS. Our results revealed that PFOS caused septal defects and excessive ventricular trabeculation cardiomyopathy at 5 mg/kg/day in embryonic mice and inhibited the proliferation and pluripotency of ESCs at concentrations >20 μM. Moreover, it decreased the beating rate and the population of CMs during cardiac differentiation. Decreases were observed in the abundances of NPPA+ trabecular and HEY2+ compact CMs. Additionally, DNA methyl transferases and ten-eleven translocation (TET) dioxygenases were regulated dynamically by PFOS, with TETs inhibitor treatment inducing significant decreases similar as PFOS. 850 K DNA methylation analysis combined with expression analysis revealed several potential targets of PFOS, including SORBS2, FHOD1, SLIT2, SLIT3, ADCY9, and HDAC9. In conclusion, PFOS may reprogram DNA methylation, especially demethylation, to induce cardiac toxicity, causing ventricular defects in vivo and abnormal cardiac differentiation in vitro.

2024-02-05·bioRxiv : the preprint server for biology

A TBX5-dependent compartment boundary patterns the cardiac interventricular septum.

作者: Irfan S Kathiriya ; Martin H Dominguez ; Kavitha S Rao ; Jonathon M Muncie-Vasic ; W Patrick Devine ; Kevin M Hu ; Swetansu K Hota ; Bayardo I Garay ; Diego Quintero ; Piyush Goyal ; Megan N Matthews ; Reuben Thomas ; Tatyana Sukonnik ; Dario Miguel-Perez ; Sarah Winchester ; Emily F Brower ; André Forjaz ; Pei-Hsun Wu ; Denis Wirtz ; Ashley L Kiemen ; Benoit G Bruneau

Failure of septation of the interventricular septum (IVS) is the most common congenital heart defect (CHD), but mechanisms for patterning the IVS are largely unknown. We show that a Tbx5 ⁺ /Mef2cAHF ⁺ progenitor lineage forms a compartment boundary bisecting the IVS. This coordinated population originates at a first- and second heart field interface, subsequently forming a morphogenetic nexus. Ablation of Tbx5 ⁺ /Mef2cAHF ⁺ progenitors cause IVS disorganization, right ventricular hypoplasia, and mixing of IVS lineages. Reduced dosage of the CHD transcription factor TBX5 disrupts boundary position and integrity, resulting in ventricular septation defects (VSDs) and patterning defects including Slit2 and Ntn1 misexpression. Reducing NTN1 dosage partly rescues cardiac defects in Tbx5 mutant embryos. Loss of Slit2 or Ntn1 causes VSDs and perturbed septal lineage distributions. Thus, we identify essential cues that direct progenitors to pattern a compartment boundary for proper cardiac septation, revealing new mechanisms for cardiac birth defects.

2024-01-10·Biomedicines

Unraveling the Role of miR-200b-3p in Attention-Deficit/Hyperactivity Disorder (ADHD) and Its Therapeutic Potential in Spontaneously Hypertensive Rats (SHR).

Article

作者: Tung-Ming Chang ; Hsiu-Ling Lin ; Chih-Chen Tzang ; Ju-An Liang ; Tsai-Ching Hsu ; Bor-Show Tzang

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder in children with unknown etiology. Impaired learning ability was commonly reported in ADHD patients and has been associated with dopamine uptake in the striatum of an animal model. Another evidence also indicated that micro-RNA (miR)-200b-3p is associated with learning ability in various animal models. However, the association between miR-200b-3p and ADHD-related symptoms remains unclear. Therefore, the current study investigated the role of miR-200b-3p in ADHD-related symptoms such as inattention and striatal inflammatory cytokines. To verify the influence of miR-200b-3p in ADHD-related symptoms, striatal stereotaxic injection of miR-200b-3p antagomir (AT) was performed on spontaneously hypertensive rats (SHR). The antioxidant activity and expressions of miR-200b-3p, slit guidance ligand 2 (Slit2), and inflammatory cytokines in the striatum of SHR were measured using quantitative real-time polymerase chain reaction (RT-qPCR), immunohistochemistry (IHC), immunoblotting, and enzyme-linked immunosorbent assay (ELISA). The spontaneous alternation of SHR was tested using a three-arm Y-shaped maze. The administration of miR-200b-3p AT or taurine significantly decreased striatal tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in SHR, along with increased super-oxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and significantly higher spontaneous alternation. In this paper, we show that miR-200b-3p AT and taurine alleviates ADHD-related symptoms in SHR. These findings provide insights into ADHD's molecular basis and suggest miR-200b-3p as a potential therapeutic target. Concurrently, this study also suggests broad implications for treating neurodevelopmental disorders affecting learning activity such as ADHD.

项与 SLIT2 相关的新闻（医药）

2023-08-29

·生物谷

第四军医大学研究者们揭示了胃癌潜在的生物标志物和治疗靶点

肿瘤的发生、发展和转移在宿主组织中引起广泛的动态变化，导致形成复杂的肿瘤间质，也称为肿瘤微环境(TME)。显然，细胞骨架重塑相关基因的激活和失活失去平衡是肿瘤转移的关键步骤。肿瘤的发生、发展和转移在宿主组织中引起广泛的动态变化，导致形成复杂的肿瘤间质，也称为肿瘤微环境(TME)。显然，细胞骨架重塑相关基因的激活和失活失去平衡是肿瘤转移的关键步骤。然而，癌症的进展和转移并不完全依赖于癌细胞自主缺陷，来自TME的刺激触发或增强了这一过程，创造了一个局部微环境，使癌细胞能够获得过度的运动性，迁移到远处并形成转移的壁龛。图片来源：https://doi.org/10.1038/s41419-023-05965-z 近日，来自第四军医大学的研究者们在Cell Death and Disease杂志上发表了题为“Cancer associated fibroblast derived SLIT2 drives gastric cancer cell metastasis by activating NEK9”的文章，该研究揭示了肿瘤相关成纤维细胞来源的SLIT2通过激活NEK9促进胃癌细胞转移。肿瘤相关成纤维细胞(CAF)的分泌特性在形成有利于转移的肿瘤微环境中起着主要作用。本研究证实了由CAF产生的轴突引导蛋白Slit2通过与迂回引导受体1(Robo1)结合而促进两种胃癌细胞系(AGS和MKN45)的转移。质谱分析表明，Robo1可以与丝氨酸/苏氨酸激酶NEK9相互作用。Slit2进一步增强了它们的相互结合活性。结构域分析表明，在AGS和MKN45细胞中，NEK9的激酶结构域在其与Robo1的胞内区(ICD)的相互作用中是关键的，它还直接磷酸化了含有28(TRIM28)和皮质蛋白(CTTN)的三聚体基序。 TRIM28是一种转录延伸因子，直接促进CTTN的激活。此外，生物信息学分析和实验验证证实了STAT3和NF-κB p1 0在转录水平上受T R I M 2 8的调控，在AGS和MKN 4 5中也观察到了STAT3和NF-κB p10 0对CTTN的转录调控。因此，CaF来源的Slit2上调CTTN的表达和磷酸化水平，从而诱导细胞骨架重组和GC细胞转移。转移性胃癌组织中NEK9、TRIM28和CTTN的表达水平同时高于配对的非癌组织和原发癌组织。对一组GC患者的数据分析表明，NEK9、TRIM28和CTTN水平的增加与总体存活率的下降有关。 Slit2/Robo1/NEK9信号通路在胃癌中的模型图片来源：https://doi.org/10.1038/s41419-023-05965-z 综上所述，本研究发现，CAF来源的Slit2通过增强Robo1和NEK9之间的相互作用而促进胃癌转移。NEK9通过靶向TRIM28和CTTn的磷酸化而发挥激酶的作用，并触发IL-6/STAT3和NF-κB通路的激活。NEK9连接了CAF和炎症信号通路的刺激，形成了一种独特的TME，用于细胞骨架重组和癌症转移。这些发现可能有助于更好地理解TME在胃癌转移中的作用。（生物谷 Bioon.com）参考文献 Guofang Lu et al. Cancer associated fibroblast derived SLIT2 drives gastric cancer cell metastasis by activating NEK9. Cell Death Dis. 2023 Jul 13;14(7):421. doi: 10.1038/s41419-023-05965-z.

临床1期

2023-03-10

·生物谷

《自然·通讯》：仁济医院团队揭示“癌王”肝转移的关键分子机制

总之，这项研究通过解释SLIT2-ROBO1轴在PMN及MMN形成中的重要作用及调控机制，系统阐述了胰腺癌肝转移过程中肿瘤细胞和肝脏细胞共适应的分子机制，为胰腺癌肝转移开发了治疗新靶点及新策略。胰腺癌是最致命的恶性肿瘤之一，最主要的治疗方式仍为根治性切除联合化疗的综合治疗，然而将近80%的患者由于已并发远处转移而无法行手术切除，尤其以肝转移最为常见[1]。因此，揭示胰腺癌肝转移的分子机制，对于改善胰腺癌预后，延长生存具有重要意义。在肿瘤转移过程中，源自于原发肿瘤的播散性肿瘤细胞（DTC）和靶器官微环境存在共适应现象，即“种子与土壤”的相互适应[2,3]。因此，破译胰腺癌播散性细胞和肝脏微环境中正常细胞相互适应的关键事件，对于阐明胰腺癌肝转移的分子机制至关重要。转移前生态位（PMN）和转移后生态位（MMN）的形成是肿瘤转移的关键事件[4]。研究表明，PMN形成是肿瘤转移的第一步，且PMN形成会诱导靶器官中的正常细胞募集形成复杂肿瘤微环境（TME）所需的细胞，以更好的形成“土壤”[5,6]。因此，解析PMN及MMN形成的机制对于解决胰腺癌肝转移具有重要指导意义。近日，由上海交通大学张志刚、李军和孙勇伟领衔的研究团队在《自然·通讯》杂志发表了一项重要研究成果。这项研究发现，肿瘤表面表达的依赖性受体ROBO1与肝细胞来源的配体SLIT2之间相互作用，促进了DTC与肝脏细胞的相互适应，进而导致胰腺癌肝转移；且靶向ROBO1的中和性抗体可阻断这种共适应效应从而抑制胰腺癌肝转移[7]。总之，这项研究破译了胰腺癌肝转移过程中肿瘤细胞与肝脏细胞相互适应的机制，为胰腺癌肝转移提供了一种新型治疗策略。文章封面截图为模拟胰腺癌肝转移的PMN及MMN的形成，张志刚团队通过脾内注射KPC1199和Panc02细胞系，构建了正常肝脏、PMN（KPC1199注射后7-11天，Panc02注射后5-8天）和MMN模型（KPC1199注射后5-8天，Panc02注射后第9天），并使用小动物CT、生物发光及组织染色等技术证明构建模型的可靠性。为揭示胰腺癌肝转移过程中共适应现象的机制，他们使用转录组学检测了正常肝脏、PMN及MMN阶段肝脏细胞中差异表达的基因。结果发现，相比于正常肝脏，PMN及MMN阶段的肝脏细胞出现更明显的轴突引导途径改变，并发现SEMA3e、SLIT2 和 EFNA4三个基因在PMM及MMN中均明显上调（图1）。图1. 正常肝脏、PMN及MMN阶段肝脏细胞中的差异基因进一步的研究结果表明，SLIT2在PMN形成过程中开始出现，并持续表达到MMN阶段完成，且通过对胰腺癌肝转移患者的样本进行染色发现，SLIT2来源于肝脏细胞而不是肿瘤细胞。也就是说，SLIT2是“土壤”中的关键配体。但要介导“土壤与种子”的共适应效应，还需要肿瘤细胞中的配体。环形引导家族（ROBO）成员是SLIT2的主要受体[8]。在这里，张志刚团队发现，仅有ROBO1在转移性胰腺癌细胞中表达（图2e），且在肝脏转移的组织中ROBO1与SLIT2之间具有很强的相关性（图2h），存在直接相互作用。图2. 肿瘤细胞中ROBO1是SLIT2的受体为明确SILT2及ROBO1在胰腺癌肝转移中的作用，他们构建了SLIT2敲除鼠，并通过慢病毒注射恢复SLIT2在肝细胞中的表达，随后向脾脏中注射表达ROBO1的肿瘤细胞。结果表明，SLIT2的缺失可显著抑制胰腺癌肝转移中PMN及MMN的形成，而SLIT2恢复后这种效果出现了逆转（图3）。图3. SLIT2在胰腺癌肝转移PMN和MMN形成中的作用他们还发现，给予ROBO1中和性抗体后，可显著降低胰腺癌肝转移鼠中的PMM及MMN的形成（图4）。此外，表达ROBO1的肿瘤细胞和表达SLIT2的肝细胞可以出现协同适应现象，肿瘤微环境中SLIT2的缺失或者ROBO1的阻断，可削弱ROBO1阳性的肿瘤细胞在肝脏微环境中的竞争优势。图4. ROBO1抗体对胰腺癌肝转移的抑制作用不仅如此，张志刚团队还构建了野生型及Ig结构域缺失（ΔROBO1，删除ROBO1与SLIT2互作的片段）的ROBO1过表达肿瘤细胞系，并注射入小鼠脾脏。结果发现，过表达野生型ROBO1后可显著上调PMM及MMN形成，而过表达ΔROBO1时却无此种现象（图5）。这说明，ROBO1对胰腺癌肝转移的作用依赖于与SLIT2的相互作用。图5. ROBO1-SLIT2的相互作用在胰腺癌肝转移中的重要作用由于丝裂原活化蛋白激酶（MAPK）通路在肿瘤增殖、转移过程中发挥了重要作用，张志刚团队假设ROBO1可通过激活MAPK通路促进胰腺癌肝转移。结果确实如此。他们发现，SLIT2与ROBO1的结合显著提高了p38α MAPK的磷酸化；而使用ROBO1中和性抗体时，p38α MAPK磷酸化水平则显著降低（图8）。具体来看，ROBO1直接与p38α MAPK和MEK3/6结合，而SLIT2的结合进一步增强了p38α MAPK的磷酸化水平。简而言之，从机制上来看，SLIT2与ROBO1复合体可以增加p38α MAPK与其激酶MEK3/6相互作用进而激活下游MAPK通路，促进胰腺癌肝转移。总之，这项研究通过解释SLIT2-ROBO1轴在PMN及MMN形成中的重要作用及调控机制，系统阐述了胰腺癌肝转移过程中肿瘤细胞和肝脏细胞共适应的分子机制，为胰腺癌肝转移开发了治疗新靶点及新策略。参考文献 [1] Houg DS, Bijlsma MF. The hepatic pre-metastatic niche in pancreatic ductal adenocarcinoma. Mol Cancer. 2018 Jun 14;17(1):95. doi: 10.1186/s12943-018-0842-9. [2] Curtis M, Kenny HA, Ashcroft B, et al. Fibroblasts Mobilize Tumor Cell Glycogen to Promote Proliferation and Metastasis. Cell Metab. 2019 Jan 8;29(1):141-155.e9. doi: 10.1016/j.cmet.2018.08.007. [3] Zhang L, Zhang S, Yao J, et al. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature. 2015 Nov 5;527(7576):100-104. doi: 10.1038/nature15376. [4] Peinado H, Zhang H, Matei IR, et al. Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer. 2017 May;17(5):302-317. doi: 10.1038/nrc.2017.6. [5] Erler JT, Bennewith KL, Cox TR,et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell. 2009 Jan 6;15(1):35-44. doi: 10.1016/j.ccr.2008.11.012. [6] Lee W, Ko SY, Mohamed MS, et al. Neutrophils facilitate ovarian cancer premetastatic niche formation in the omentum. J Exp Med. 2019 Jan 7;216(1):176-194. doi: 10.1084/jem.20181170. [7] Li Q, Zhang XX, Hu LP, et al. Coadaptation fostered by the SLIT2-ROBO1 axis facilitates liver metastasis of pancreatic ductal adenocarcinoma. Nat Commun. 2023 Feb 15;14(1):861. doi: 10.1038/s41467-023-36521-0. [8] Yadav SS, Narayan G. Role of ROBO4 signalling in developmental and pathological angiogenesis. Biomed Res Int. 2014;2014:683025. doi: 10.1155/2014/683025.

临床结果

2023-02-24

·生物谷

Nat Commun丨张志刚/孙勇伟团队揭示SLIT2-ROBO1轴调控胰腺导管腺癌肝转移的进程

肿瘤由原发癌转移至靶器官继而定植和生长是一个漫长且复杂的过程。在此过程中，虽然有数量庞大的散在肿瘤细胞（Disseminated tumor Cells，DTCs）散布入血液循环中，然而仅有其中的极少肿瘤由原发癌转移至靶器官继而定植和生长是一个漫长且复杂的过程。在此过程中，虽然有数量庞大的散在肿瘤细胞（Disseminated tumor Cells，DTCs）散布入血液循环中，然而仅有其中的极少数可以顺利在靶器官定植且形成转移灶。根据肿瘤的“种子与土壤”学说，作为的“种子”肿瘤细胞需要挑选和改造作为“土壤”的转移灶微环境，而微环境也同时在影响和筛选肿瘤细胞，这是一个共同适应的过程【1】。仅在实现了共同适应的前提下，肿瘤的转移灶才得以顺利生长。依赖性受体（Dependence Receptors，DRs）是一类功能特殊的受体，其配体存在时，DRs会促进细胞的生存和增殖；在缺乏受体时，则会反过来诱导细胞的凋亡。一般认为依赖性受体的存在是机体为了维持稳态，防止细胞移动至异种器官内生长而进化出的防卫机制：细胞如果进入了缺乏对应配体的陌生微环境，其表达的DRs便会立即启动凋亡程序，将其消灭【2】。已经有多篇报道发现和探讨了DRs在肿瘤中扮演的重要角色，调控了肿瘤的发生和进展【3, 4】。 SLIT2是轴突导向因子配体家族的成员之一，它的生理功能众多且复杂，在生物发育，神经发生，肿瘤进程等过程中发挥了不可缺少的作用。SLIT2的经典受体是同为轴突导向因子的ROBO家族（ROBO1-4），该家族的分子均为单次跨膜的大蛋白，在SLIT2的结合后发挥调控细胞的迁移以及增殖等多项机能【5】。 2023年2月5日，张志刚课题组和仁济医院孙勇伟团队合作在Nature Communications杂志在线发表了标题为Coadaptation fostered by the SLIT2-ROBO1 axis facilitates liver metastasis of pancreatic ductal adenocarcinoma的研究论文。本研究阐明了ROBO1作为一个肿瘤细胞表面表达的依赖性受体，与肝细胞来源的SLIT2一同构建了胰腺导管腺癌肝脏转移前和转移后微环境的分子机制。在本研究中，作者首先构建了脾脏注射导致胰腺导管腺癌细胞肝转移的小鼠模型，并对小鼠模型的肝脏转移前微环境（Premetastatic Niche，PMN）和转移后微环境（Macro metastatic Niche，MMN）进行了取样，并与正常肝脏一起进行了RNA-seq。结果显示SLIT2在肿瘤转移的PMN和MMN时期均高表达，且经过RNAscope实验在几种动物模型以及临床样本中确认SLIT2的来源为肝细胞（Hepatocyte）。作者经过继续研究发现肿瘤细胞膜定位的ROBO1也在SLIT2高度表达的转移灶富集，且两者的表达量随着肝转移的进程均呈现正相关。之后的研究中，作者发现ROBO1具有依赖性受体的特征，在没有SLIT2时，诱导表达自己的细胞凋亡，而在有SLIT2的微环境中可以促进肿瘤细胞进一步定植和生长，即机体所进化的防止ROBO1高表达的肿瘤细胞转移的机制反而被肿瘤微环境所利用，在肝脏中ROBO1成为了肿瘤的帮凶。进一步的机制研究阐明了，ROBO1在结合SLIT2后，可以为MEK3/6提供磷酸化p38MAKP的反应支架，使得其磷酸化的效率明显上升，以此快速激活下游通路，促进肿瘤生长。而ROBO1的中和性抗体可以阻断SLIT2-ROBO1轴：在无法结合SLIT2的情况下，ROBO1不仅不能促进肿瘤细胞生长，更可以发挥依赖性受体的特性诱导肿瘤细胞凋亡。以上工作为胰腺癌肝转移的靶向治疗提供了新的思路。李庆博士、张小昕博士、胡立鹏博士和倪博博士为该论文的共同第一作者。张志刚研究员，李军副研究员和孙勇伟主任为该论文的共同通讯作者。原文链接： https://doi.org/10.1038/s41467-023-36521-0