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更新于：2025-05-07

FZD10

更新于：2025-05-07

基本信息

别名

CD350、frizzled (Drosophila) homolog 10、frizzled 10, seven transmembrane spanning receptor

+ [8]

简介

Receptor for Wnt proteins. Functions in the canonical Wnt/beta-catenin signaling pathway (By similarity). The canonical Wnt/beta-catenin signaling pathway leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues (Probable).

关联

项与 FZD10 相关的药物

225Ac-OTSA101

靶点

FZD10

作用机制

FZD10拮抗剂

在研机构

OncoTherapy Science, Inc.

原研机构

OncoTherapy Science, Inc.

在研适应症

滑膜肉瘤

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

211At-OTSA101

靶点

FZD10

作用机制

FZD10拮抗剂

在研机构-

原研机构-

在研适应症-

非在研适应症

滑膜肉瘤

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

(90)Y-MAb 92-13

靶点

FZD10

作用机制

FZD10拮抗剂

在研机构-

原研机构

University of Tokyo

在研适应症-

非在研适应症

滑膜肉瘤

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 FZD10 相关的临床结果

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100 项与 FZD10 相关的转化医学

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0 项与 FZD10 相关的专利（医药）

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141

项与 FZD10 相关的文献（医药）

2024-12-31·mAbs

Coactivation of Tie2 and Wnt signaling using an antibody–R-spondin fusion potentiates therapeutic angiogenesis and vessel stabilization in hindlimb ischemia

Article

作者: Park, Jong-Gil ; Cho, Young-Lai ; Min, Jeong-Ki ; Lee, Dong Gwang ; Jeon, Min-Young ; Jang, Ju-Hong ; Noh, Ji-Hun ; Yang, Wonjun ; Lee, Jangwook ; Lee, Nam-Kyung ; Hwang, Byungtae

Therapeutic angiogenesis by intentional formation of blood vessels is essential for treating various ischemic diseases, including limb ischemia. Because Wnt/β-catenin and angiopoietin-1/Tie2 signaling play important roles in endothelial survival and vascular stability, coactivation of these signaling pathways can potentially achieve therapeutic angiogenesis. In this study, we developed a bifunctional antibody fusion, consisting of a Tie2-agonistic antibody and the Furin domains of R-spondin 3 (RSPO3), to simultaneously activate Tie2 and Wnt/β-catenin signaling. We identified a Tie2-agonistic antibody T11 that cross-reacted with the extracellular domain of human and mouse Tie2, and evaluated its ability to increase endothelial cell survival and tube formation. We generated a bifunctional T11-RF12 by fusing T11 with the Furin-1 and -2 domains of RSPO3. T11-RF12 could bind not only to Tie2, but also to LGR5 and ZNRF3, which are counterparts of the Furin-1 and -2 domains. T11-RF12 significantly increased Wnt/β-catenin signaling, as well as the formation of capillary-like endothelial tubes, regardless of the presence of Wnt ligands. Coactivation of Tie2 and Wnt/β-catenin signaling by T11-RF12 increased the blood flow, and thereby reduced foot necrosis in a mouse hindlimb ischemia model. In particular, T11-RF12 induced therapeutic angiogenesis by promoting vessel stabilization through pericyte coverage and retaining endothelial expression of Frizzled 10 and active β-catenin. These results indicate that the agonistic synergism of Tie2 and Wnt/β-catenin signaling achieved using T11-RF12 is a novel therapeutic option with potential for treating limb ischemia and other ischemic diseases.

2024-09-01·Non-coding RNA Research

DNA methylation of microRNA-365-1 induces apoptosis of hair follicle stem cells by targeting DAP3

Article

作者: Liu, Xin ; Du, Xinran ; Zhu, Jianyong ; Li, Fulun ; Yan, Ge ; Wang, Yi ; Liu, Te ; Cheng, Linyan ; Xi, Ruofan

BackgroundDNA methylation is a crucial epigenetic alteration involved in diverse biological processes and diseases. Nevertheless, the precise role of DNA methylation in chemotherapeutic drug-induced alopecia remains unclear. This study examined the role and novel processes of DNA methylation in regulating of chemotherapeutic drug-induced alopecia.MethodsA mouse model of cyclophosphamide (CTX)-induced alopecia was established. Hematoxylin-eosin staining and immunohistochemical staining for the Ki67 proportion and a mitochondrial membrane potential assay (JC-1) were performed to assess the structural integrity and proliferative efficiency of the hair follicle stem cells (HFSCs). Immunofluorescence staining and real-time fluorescence quantitative PCR (RT-qPCR) were performed to determine the expression levels of key HFSC markers, namely Lgr5, CD49f, Sox9, CD200, and FZD10. Differential DNA methylation levels between the normal and CTX-induced model groups were determined through simple methylation sequencing and analyzed using bioinformatics tools. The expression levels of miR-365-1, apoptosis markers, and DAP3 were detected through RT-qPCR and western blotting. In parallel, primary mouse HFSCs were extracted and used as a cell model, which was constructed using 4-hydroperoxycyclophosphamide. The luciferase reporter gene assay was conducted to confirm miR-365-1 binding to DAP3. To measure the expression of relevant indicators, superoxide dismutase (SOD) and malondialdehyde (MDA) kits were used. Methylation-specific PCR (MS-PCR) was performed to determine DNA methylation levels. The regulatory relationship within HFSCs was confirmed through plasmid overexpression of miR-365-1 and DAP3.ResultIn the alopecia areata model, a substantial number of apoptotic cells were observed within the hair follicles on the mouse backs. Immunofluorescence staining revealed that the expression of HFSC markers significantly reduced in the CTX group. Both RT-qPCR and western blotting demonstrated a noteworthy difference in DNA methyltransferase expression. Simple methylation sequencing unveiled that DNA methylation substantially increased within the dorsal skin of the CTX group. Subsequent screening identified miR-365-1 as the most differentially expressed miRNA. miR-365-1 was predicted and confirmed to bind to the target gene DAP3. In the CTX group, SOD and ATP expression markedly reduced, whereas MDA levels were significantly elevated. Cellular investigations revealed 4-HC-induced cell cycle arrest and decreased expression of HFSC markers. MS-PCR indicated hypermethylation modification of miR-365-1 in the 4-HC-induced HFSCs. The luciferase reporter gene experiment confirmed the binding of miR-365-1 to the DAP3 promoter region. miR-365-1 overexpression dramatically reduced apoptotic protein expression in the HFSCs. However, this effect was slightly reversed after DAP3 overexpression in lentivirus.ConclusionThis study explored the occurrence of miR-365-1 DNA methylation in chemotherapeutic drug-induced alopecia. The results unveiled that miR-365-1 reduces cell apoptosis by targeting DAP3 in HFSCs, thereby revealing the role of DNA methylation of the miR-365-1 promoter in chemotherapeutic drug-induced alopecia.

2024-08-01·Gene

Investigating age-related differences in muscles of Kazakh horse through transcriptome analysis

Article

作者: Wang, Jianwen ; Yao, Xinkui ; Meng, Jun ; Ren, Wanlu ; Sun, Zhiwen ; Zeng, Yaqi ; Wang, Tongliang

This study conducted transcriptome sequencing on the skeletal muscles of three different anatomical locations across various growth stages to investigate the impact of ages on crucial candidate genes and molecular mechanisms associated with muscle development in Kazakh horses. Sixteen Kazakh horses were selected, and they were divided into four age groups, each with four biological replicates. Tissue samples from the longest dorsal muscle, abdominal muscle, and diaphragm muscle were collected for analysis. The results revealed differential mRNA expression in the longest dorsal muscle between the eight-month group (Group O) and the 10-year group (Group F), with 434 up-regulated and 322 down-regulated genes. In the abdominal muscle, there were 125 up-regulated and 127 down-regulated genes, while in the diaphragm muscle, there were 73 up-regulated and 70 down-regulated genes. In this study, GO enrichment analysis focused on biological processes. KEGG pathway analysis highlighted the Oxidative Phosphorylation pathway for the longest dorsal muscle, annotating 37 differentially expressed genes (DEGs), including ATP5PF, NDUFB8, and ATP5MG, all of which were down-regulated. For the abdominal muscle, the ECM-receptor interaction pathway was enriched, annotating 7 DEGs such as COL4A2, COL4A1, and ITGA5. In the diaphragm muscle, the Hippo signaling pathway was enriched, annotating 6 DEGs, including SERPINE1, RASSF1, and FZD10. This study provides robust data support and a theoretical foundation for a comprehensive understanding of the influence of age on skeletal muscle development in horses.

项与 FZD10 相关的新闻（医药）

2023-03-13

·生物谷

《胃肠病学》：中国科学家破解肝癌对仑伐替尼耐药之谜，并发现肝癌治疗新靶点！

本研究发现在肝癌CSCs中高表达的FZD10一方面可以通过激活β-catenin和YAP1促进肝脏CSCs的自我更新、肿瘤发生和转移，另一方面可以通过c-Jun/MEK/ERK通路导致肝癌细胞对仑伐替肝细胞癌（HCC）是世界上第六大常见恶性肿瘤，也是癌症相关死亡的第四大主要原因[1]。中国肝癌患者中，HBV感染患者和中晚期患者占比较高，患者预后差，5年生存率仅12.1%。虽然仑伐替尼已被批准用于晚期HCC的一线治疗，但大多数HCC患者在接受治疗后几个月内仍会出现病情进展。总体而言，耐药是目前HCC相关死亡的主要原因之一，但对其背后的机制仍知之甚少。近日，同济大学医学院附属东方医院、海军军医大学第三附属医院和上海长海医院的研究人员，在胃肠疾病领域权威期刊Gastroenterology发表了最新研究成果[2]。在该研究中，他们发现FZD10在肝癌肿瘤干细胞（CSCs）中表达上调，并在肝癌细胞自我更新、致瘤性、转移和仑伐替尼耐药中发挥重要作用，提示FZD10是一种新的肝CSCs生物标志物，有望成为对仑伐替尼耐药HCC治疗的潜在靶点。论文首页截图 CSCs是具有长期致瘤能力的肿瘤细胞的一个小亚群，是肿瘤内具有持续分裂、分化能力的一群细胞。通常这类的细胞被认为有形成肿瘤，发展成癌症的潜力，在癌症的发展和治疗耐药性中起着关键作用。在HCC患者中，大量CSCs的存在预示着较差的临床结果。然而，肝脏CSCs增殖的潜在机制仍不清楚。因此，研究人员首先利用转录组学分析筛选出了可能与HCC中CSCs特性相关的潜在靶点，在所有上调的379个基因中，FZD10是上调倍数最多的，而且其表达水平与肝脏CSCs标记物EpCAM和CD24呈正相关。随着连续传代，FZD10的表达水平在原发性HCC球形细胞中逐渐升高。考虑到肝CSCs与HCC复发、转移和化疗耐药密切相关，研究人员比较了FZD10在复发、转移和化疗耐药HCC组织中的表达。结果发现与原发病灶相比，FZD10在复发HCC、HCC转移灶中的表达显著上调。此外，仑伐替尼耐药HCC患者组织中FZD10的表达明显高于仑伐替尼敏感HCC患者组织。总的来说，上述结果表明肝癌干细胞中FZD10表达上调，预示HCC患者预后不良。 FZD10在肝脏CSCs中表达上调，预示着HCC预后不良为了研究FZD10的临床意义，研究人员进一步分析了HCC患者FZD10的表达情况。相关回归分析显示，HCC组织中FZD10的高表达与侵袭性临床特征相关。Kaplan-Meier生存分析显示，HCC中FZD10的高表达与较短的无病生存期和总生存期相关。随后，研究人员使用敲低、过表达实验探究了FZD10在肝脏CSCs中的潜在作用。结果发现FZD10敲低后，HCC的多能转录因子表达减少、球体形成受损、肝脏CSCs比例降低；相反，FZD10过表达则增加了HCC多能转录因子的数量、增强了HCC球体的形成能力、导致HCC细胞中CSCs比例增加，说明FZD10促进了肝脏CSCs的扩增。此外，他们还注意到敲低FZD10削弱了HCC细胞的迁移和侵袭能力、显著降低肿瘤发生率，而FZD10的过表达则增强了细胞的迁移和侵袭能力，增加了肿瘤发病率，在小鼠中形成了更多的肺转移病灶。 FZD10促进肝脏CSCs的扩增为了阐明FZD10促进肝脏CSCs扩增的机制，研究人员使用RNA测序分析了FZD10过表达的HCC细胞中的基因表达情况。 KEGG信号通路富集分析显示，在过表达FZD10的HCC细胞中，MAPK、WNT/β-catenin和Hippo是前三大富集信号通路。鉴于已有研究报道WNT/β-catenin/TCF和Hippo信号通路在调控CSCs扩增中发挥重要作用，因此研究人员重点着眼于FZD10对WNT/β-catenin和Hippo信号通路的调控。研究结果显示，FZD10敲除的HCC细胞中β-catenin的转录活性明显下调，核β-catenin的水平及其下游靶基因的表达均显著降低；而在FZD10过表达的HCC细胞中β-catenin的转录活性上调，核β-catenin的水平及其下游靶基因的表达明显增加。与之类似，过表达FZD10的HCC中YAP1核易位和靶基因表达上调，而FZD10敲除则观察到相反的结果。此外，HCC患者的数据也进一步佐证了上述结果。在HCC患者中，FZD10的表达水平与核β-catenin和YAP1的水平呈正相关，β-catenin、YAP1高表达对应肝癌患者较短的生存期。因此，上述实验结果表明，在肝癌患者肿瘤干细胞中高表达的FZD10通过WNT/β-catenin和Hippo通路增强了肝脏CSCs的特性，促进了肝脏CSCs的自我更新，最终导致肿瘤的发生和转移。越来越多的证据表明，肝脏CSCs与耐药性密切相关[3]，基于上述研究结果，研究人员自然而然地想到，既然HCC中高表达的FZD10可以促进肝脏CSCs的特性，它是否也与肝癌患者对仑伐替尼的治疗耐受相关呢？ Kaplan-Meier分析显示，FZD10低表达的HCC患者在仑伐替尼治疗后存活时间更长，而FZD10高表达的患者对仑伐替尼治疗表现出较强的耐药性。与之相对应，FZD10过表达导致肝癌细胞抵抗仑伐替尼诱导的生长抑制和细胞凋亡。进一步，研究人员利用患者源性肿瘤类器官（PDOs）和患者源性异种移植（PDXs）模型，验证了FZD10表达水平与仑伐替尼耐药性之间的相关性。结果发现FZD10表达水平较高的原发性HCC衍生的PDOs对仑伐替尼治疗具有耐药性，而FZD10表达水平较低的原发性HCC衍生的PDXs对仑伐替尼治疗极为敏感，仑伐替尼可以几乎完全阻断FZD10表达水平较低的PDXs的生长。上述结果表明，FZD10低表达的HCC患者可能对仑伐替尼的治疗更为敏感，提示肝癌患者肿瘤中的FZD10水平，可以作为推断其对仑伐替尼反应性的可靠预测因子。 FZD10表达水平与HCC患者仑伐替尼的治疗耐药性相关研究人员还探究了FZD10高表达导致仑伐替尼耐药的机制。根据已有文献报道，MAPK信号通路异常激活与仑伐替尼耐药密切相关[4]。与先前的研究结果相一致，本研究的RNA-seq数据显示MAPK信号通路在过表达FZD10的HCC细胞中富集。相比于对仑伐替尼仑伐替尼治疗敏感的HCC细胞系，对仑伐替尼耐药的HCC细胞系中MAPK信号通路之一c-Jun/MEK/ERK通路的表达水平显著上调，在仑伐替尼耐药的PDXs和仑伐替尼治疗后的临床复发肿瘤中，FZD10和c-Jun/MEK/ERK通路的表达水平也明显上调。这表明c-Jun/MEK/ERK的激活与仑伐替尼耐药有关，肝癌中高表达的FZD10通过c-Jun/MEK/ERK通路导致HCC对仑伐替尼产生耐药性。最后，研究人员评估了以FZD10为靶点对仑伐替尼耐药HCC的治疗潜力。他们发现使用FZD10抑制剂可以恢复HCC对仑伐替尼治疗的敏感性，说明FZD10有望成为治疗仑伐替尼耐药HCC的潜在靶点。靶向FZD10可恢复HCC对仑伐替尼的敏感性总的来说，本研究发现在肝癌CSCs中高表达的FZD10一方面可以通过激活β-catenin和YAP1促进肝脏CSCs的自我更新、肿瘤发生和转移，另一方面可以通过c-Jun/MEK/ERK通路导致肝癌细胞对仑伐替尼治疗产生耐药性。机制示意图好消息是，靶向FZD10可以恢复HCC对仑伐替尼的治疗敏感性，提高其临床治疗效果，这也意味着FZD10可以作为一种新的肝癌预后生物标志物和仑伐替尼耐药HCC的治疗靶点。参考文献： [1] Siegel RL, Miller KD, Fuchs HE, et al. Cancer Statistics, 2021. CA Cancer J Clin 2021;71:7-33. [2] Wang J, Yu H, Dong W, Zhang C, Hu M, Ma W, Jiang X, Li H, Yang P, Xiang D. M6A-mediated upregulation of FZD10 regulates liver cancer stem cells properties and lenvatinib resistance through WNT/β-catenin and Hippo signaling pathways. Gastroenterology. 2023 Feb 8:S0016-5085(23)00114-2. [3] Han T, Zhang Y, Yang X, et al. miR-552 Regulates Liver Tumor-Initiating Cell Expansion and Sorafenib Resistance. Mol Ther Nucleic Acids 2020;19:1073-1085. [4] Jin H, Shi Y, Lv Y, et al. EGFR activation limits the response of liver cancer to lenvatinib. Nature 2021.