更新于：2024-05-01

SDCBP

syndecan binding protein

更新于：2024-05-01

基本信息

别名

MDA-9、MDA9、Melanoma differentiation-associated protein 9

+ [8]

简介

Multifunctional adapter protein involved in diverse array of functions including trafficking of transmembrane proteins, neuro and immunomodulation, exosome biogenesis, and tumorigenesis (PubMed:26291527). Positively regulates TGFB1-mediated SMAD2/3 activation and TGFB1-induced epithelial-to-mesenchymal transition (EMT) and cell migration in various cell types. May increase TGFB1 signaling by enhancing cell-surface expression of TGFR1 by preventing the interaction between TGFR1 and CAV1 and subsequent CAV1-dependent internalization and degradation of TGFR1 (PubMed:25893292). In concert with SDC1/4 and PDCD6IP, regulates exosome biogenesis (PubMed:22660413). Regulates migration, growth, proliferation, and cell cycle progression in a variety of cancer types (PubMed:26539120). In adherens junctions may function to couple syndecans to cytoskeletal proteins or signaling components. Seems to couple transcription factor SOX4 to the IL-5 receptor (IL5RA) (PubMed:11498591). May also play a role in vesicular trafficking (PubMed:11179419). Seems to be required for the targeting of TGFA to the cell surface in the early secretory pathway (PubMed:10230395).

关联

MDA-9抑制（Virginia Commonwealth University）

靶点

SDCBP

作用机制

SDCBP抑制剂

在研机构

Virginia Commonwealth University

原研机构

Virginia Commonwealth University

在研适应症

肝细胞癌

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

IVMT-Rx-3

靶点

SDCBP

作用机制

SDCBP抑制剂

在研机构

University of Pittsburgh

原研机构

University of Pittsburgh

在研适应症

黑色素瘤

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

100 项与 SDCBP 相关的临床结果

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100 项与 SDCBP 相关的转化医学

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0 项与 SDCBP 相关的专利（医药）

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231

项与 SDCBP 相关的文献（医药）

2024-03-01·Biochemistry and biophysics reports

Identification of novel biomarkers and immune infiltration characteristics of ischemic stroke based on comprehensive bioinformatic analysis and machine learning

Article

作者: Hu, Shiyu ; Cai, Jingjing ; Chen, Sizhan ; Wang, Yang ; Ren, Lijie

Background:

Ischemic stroke (IS) is one of most common causes of disability in adults worldwide. However, there is still a lack of effective and reliable diagnostic markers and therapeutic targets in IS. Furthermore, immune cell dysfunction plays an important role in the pathogenesis of IS. Hence, in-depth research on immune-related targets in progressive IS is urgently needed.

Methods:

Expression profile data from patients with IS were downloaded from the Gene Expression Omnibus (GEO) database. Then, differential expression analysis and weighted gene coexpression network analysis (WGCNA) were performed to identify the significant modules and differentially expressed genes (DEGs). Key genes were obtained and used in functional enrichment analyses by overlapping module genes and DEGs. Next, hub candidate genes were identified by utilizing three machine learning algorithms: least absolute shrinkage and selection operator (LASSO), random forest, and support vector machine-recursive feature elimination (SVM-RFE). Subsequently, a diagnostic model was constructed based on the hub genes, and receiver operating characteristic (ROC) curves were constructed to validate the performances of the predictive models and candidate genes. Finally, the immune cell infiltration landscape of IS was explored with the CIBERSORT deconvolution algorithm.

Results:

A total of 40 key DEGs were identified based on the intersection of the DEGs and module genes, and we found that these genes were mainly enriched in the regulation of lipolysis in adipocytes, neutrophil extracellular trap formation and complement and coagulation cascades. Based on the results from three advanced machine learning algorithms, we obtained 7 hub candidate genes (ABCA1, ARG1, C5AR1, CKAP4, HMFN0839, SDCBP and TLN1) as diagnostic biomarkers of IS and developed a reliable nomogram with high predictive performance (AUC = 0.987). In addition, immune cell infiltration dysregulation was implicated in IS, and compared with those in the normal group, IS patients had increased fractions of gamma delta T cells, monocytes, M0 macrophages, M2 macrophages and neutrophils and clearly lower percentages of naive B cells, CD8 T cells, CD4⁺ memory T cells, follicular helper T cells, regulatory T cells (Tregs) and resting dendritic cells. Furthermore, correlation analysis indicated a significant correlation between the hub genes and immune cells in progressive IS.

Conclusion:

In conclusion, our study identified 7 hub genes as diagnostic biomarkers and established a reliable model to predict the occurrence of IS. Meanwhile, we explored the immune cell infiltration pattern and investigated the relationship between candidate genes and immune cells in the pathogenesis of IS. Hence, our study provides new insights into the diagnosis and treatment of IS.

2023-12-18·Cellular & molecular immunology

Metabolic reprogramming by Syntenin-1 directs RA FLS and endothelial cell-mediated inflammation and angiogenesis.

Article

作者: Anja Meyer ; Stephanie R Zack ; Wes Nijim ; Adel Burgos ; Vishwa Patel ; Brian Zanotti ; Michael V Volin ; M Asif Amin ; Myles J Lewis ; Costantino Pitzalis ; Shiva Arami ; Joseph A Karam ; Nadera J Sweiss ; Shiva Shahrara

A novel rheumatoid arthritis (RA) synovial fluid protein, Syntenin-1, and its receptor, Syndecan-1 (SDC-1), are colocalized on RA synovial tissue endothelial cells and fibroblast-like synoviocytes (FLS). Syntenin-1 exacerbates the inflammatory landscape of endothelial cells and RA FLS by upregulating transcription of IRF1/5/7/9, IL-1β, IL-6, and CCL2 through SDC-1 ligation and HIF1α, or mTOR activation. Mechanistically, Syntenin-1 orchestrates RA FLS and endothelial cell invasion via SDC-1 and/or mTOR signaling. In Syntenin-1 reprogrammed endothelial cells, the dynamic expression of metabolic intermediates coincides with escalated glycolysis along with unchanged oxidative factors, AMPK, PGC-1α, citrate, and inactive oxidative phosphorylation. Conversely, RA FLS rewired by Syntenin-1 displayed a modest glycolytic-ATP accompanied by a robust mitochondrial-ATP capacity. The enriched mitochondrial-ATP detected in Syntenin-1 reprogrammed RA FLS was coupled with mitochondrial fusion and fission recapitulated by escalated Mitofusin-2 and DRP1 expression. We found that VEGFR1/2 and Notch1 networks are responsible for the crosstalk between Syntenin-1 rewired endothelial cells and RA FLS, which are also represented in RA explants. Similar to RA explants, morphological and transcriptome studies authenticated the importance of VEGFR1/2, Notch1, RAPTOR, and HIF1α pathways in Syntenin-1 arthritic mice and their obstruction in SDC-1 deficient animals. Consistently, dysregulation of SDC-1, mTOR, and HIF1α negated Syntenin-1 inflammatory phenotype in RA explants, while inhibition of HIF1α impaired synovial angiogenic imprint amplified by Syntenin-1. In conclusion, since the current therapies are ineffective on Syntenin-1 and SDC-1 expression in RA synovial tissue and blood, targeting this pathway and its interconnected metabolic intermediates may provide a novel therapeutic strategy.

2023-12-04·JAMA neurology

Neuronally Derived Extracellular Vesicle α-Synuclein as a Serum Biomarker for Individuals at Risk of Developing Parkinson Disease.

Article

作者: Shijun Yan ; Cheng Jiang ; Annette Janzen ; Thomas R Barber ; Aline Seger ; Michael Sommerauer ; Jason J Davis ; Kenneth Marek ; Michele T Hu ; Wolfgang H Oertel ; George K Tofaris

IMPORTANCE:

Nonmotor symptoms of Parkinson disease (PD) often predate the movement disorder by decades. Currently, there is no blood biomarker to define this prodromal phase.

OBJECTIVE:

To investigate whether α-synuclein in neuronally derived serum-extracellular vesicles identifies individuals at risk of developing PD and related dementia.

DESIGN, SETTING, and PARTICIPANTS:

This retrospective, cross-sectional multicenter study of serum samples included the Oxford Discovery, Marburg, Cologne, and Parkinson's Progression Markers Initiative cohorts. Participants were recruited from July 2013 through August 2023 and samples were analyzed from April 2022 through September 2023. The derivation group (n = 170) included participants with isolated rapid eye movement sleep behavior disorder (iRBD) and controls. Two validation groups were used: the first (n = 122) included participants with iRBD and controls and the second (n = 263) included nonmanifest GBA1N409S gene carriers, participants with iRBD or hyposmia, and available dopamine transporter single-photon emission computed tomography, healthy controls, and patients with sporadic PD. Overall the study included 199 participants with iRBD, 20 hyposmic participants with available dopamine transporter single-photon emission computed tomography, 146 nonmanifest GBA1N409S gene carriers, 21 GBA1N409S gene carrier patients with PD, 50 patients with sporadic PD, and 140 healthy controls. In the derivation group and validation group 1, participants with polysomnographically confirmed iRBD were included. In the validation group 2, at-risk participants with available Movement Disorder Society prodromal markers and serum samples were included. Among 580 potential participants, 4 were excluded due to alternative diagnoses.

EXPOSURES:

Clinical assessments, imaging, and serum collection.

MAIN OUTCOME AND MEASURES:

L1CAM-positive extracellular vesicles (L1EV) were immunocaptured from serum. α-Synuclein and syntenin-1 were measured by electrochemiluminescence. Area under the receiver operating characteristic (ROC) curve (AUC) with 95% CIs evaluated biomarker performance. Probable prodromal PD was determined using the updated Movement Disorder Society research criteria. Multiple linear regression models assessed the association between L1EV α-synuclein and prodromal markers.

RESULTS:

Among 576 participants included, the mean (SD) age was 64.30 (8.27) years, 394 were male (68.4%), and 182 were female (31.6%). A derived threshold of serum L1EV α-synuclein distinguished participants with iRBD from controls (AUC = 0.91; 95% CI, 0.86-0.96) and those with more than 80% probability of having prodromal PD from participants with less than 5% probability (AUC = 0.80; 95% CI, 0.71-0.89). Subgroup analyses revealed that specific combinations of prodromal markers were associated with increased L1EV α-synuclein levels. Across all cohorts, L1EV α-synuclein differentiated participants with more than 80% probability of having prodromal PD from current and historic healthy control populations (AUC = 0.90; 95% CI, 0.87-0.93), irrespective of initial diagnosis. L1EV α-synuclein was increased in at-risk participants with a positive cerebrospinal fluid seed amplification assay and was above the identified threshold in 80% of cases (n = 40) that phenoconverted to PD or related dementia.

CONCLUSIONS AND RELEVANCE:

L1EV α-synuclein in combination with prodromal markers should be considered in the stratification of those at high risk of developing PD and related Lewy body diseases.

项与 SDCBP 相关的新闻（医药）

2022-11-10

·生物谷

Hepatology：一种新型抑制剂或有望治疗人类肝细胞癌

来自弗吉尼亚联邦大学等机构的科学家们通过研究揭示了利用名为MDA-9抑制剂的一类药物作为治疗侵袭性肝癌的潜在疗法选择的理论依据，相关研究结果或为科学家们进行后期研究调查新型抗癌药物提供了新的研究线索癌基因黑色素瘤分化相关基因-9/多配体聚糖结合蛋白（MDA-9/SDCBP）在很多癌症中都会发生过表达，从而促进更具侵袭性的转移性疾病发生，然而，MDA-9在调节肝细胞癌方面所扮演的关键角色，目前研究人员并未进行更好地研究。近日，一篇发表在国际杂志Hepatology上题为“Melanoma differentiation associated gene-9/syndecan binding protein promotes hepatocellular carcinoma”的研究报告中，来自弗吉尼亚联邦大学等机构的科学家们通过研究揭示了利用名为MDA-9抑制剂的一类药物作为治疗侵袭性肝癌的潜在疗法选择的理论依据，相关研究结果或为科学家们进行后期研究调查新型抗癌药物提供了新的研究线索和思路。黑色素瘤分化相关基因-9（MDA-9）是一种肿瘤驱动蛋白，其在很多侵袭性癌症中都会过量表达，并会促进快速的细胞生长和恶性疾病的进展；此前研究人员发现，MDA-9能刺激新血管的产生，并能为肿瘤细胞生存、生长和扩散提供一种支持性的环境，然而，MDA-9在肝细胞癌（一种最常见的肝癌形式）中所扮演的关键角色，研究人员并不清楚。为此，本文研究中，研究人员就设法开始研究该蛋白在肝癌中的功能。图片来源：https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.32797 研究者Sarkar说道，本文研究证实了MDA-9在肝癌的快速进展过程中扮演着重要角色，同时也确定了MDA-9的抑制（无论是单独抑制还是与其它疗法相结合）或许能作为治疗肝细胞癌的有效疗法途径。据美国癌症协会数据显示，从1980年以来肝癌的发生率增加了两倍多，2022年大约就有4.1万新发肝癌病例。肝细胞癌的主要特征就是肝脏细胞的慢性炎症，通常是由多种风险因素所引起，包括病毒性肝炎、酒精中毒和非酒精性脂肪肝等；研究人员表示，MDA-9并不会直接促进癌症生长，但相反其会激活巨噬细胞来开启引发机体炎症的一系列细胞反应。总的来讲，本文而研究与此前研究结果相结合共同建立了MDA-9或能作为一种驱动肿瘤炎症的关键激活子。此外，研究者还识别出了名为ILK的信号通路，其在促进与MDA-9相关的肝癌发生过程中也扮演着重要角色。后期研究人员还计划进一步检测MDA-9抑制剂—PDZ1i在肝细胞癌细胞中的作用效果。此前研究人员在扩散到骨骼的前列腺癌中研究了PDZ1i的疗效。综上，本文研究结果揭示了由NF-κB和Spp1所介导的MDA-9促进肝细胞癌的关键作用，并支持了使用MDA-9抑制剂来作为恶性肝细胞癌潜在疗法的理论依据。（生物谷Bioon.com）原始出处： Debashri Manna, Saranya Chidambaranathan Reghupaty, Maria Del Carmen Camarena, et al. Melanoma differentiation associated gene‐9/syndecan binding protein promotes hepatocellular carcinoma, Hepatology (2022). DOI:10.1002/hep.32797

免疫疗法小分子药物创新药

2022-11-03

·Science Daily

MDA-9 inhibitors for aggressive liver cancer?

Researchers have published new study findings that establish rationale for the use of a class of drugs known as MDA-9 inhibitors as a potential treatment option for aggressive liver cancer. Researchers at VCU Massey Cancer Center have published new study findings that establish rationale for the use of a class of drugs known as MDA-9 inhibitors as a potential treatment option for aggressive liver cancer. The findings -- recently published in Hepatology -- pave the way for future studies investigating a novel cancer drug developed by scientists at VCU. Melanoma differentiation associated gene-9 (MDA-9) is a tumor-driving protein that is overexpressed in a number of invasive cancers and promotes rapid cell growth and advanced disease. Previous research at Massey indicates that MDA-9 stimulates the generation of new blood vessels and provides a supportive environment for tumor cells to survive, grow and spread. However, the role of MDA-9 in hepatocellular carcinoma (HCC) -- the most common form of liver cancer -- has remained relatively unknown. Led by Devanand Sarkar, M.B.B.S., Ph.D., associate director for research training and education and member of the Cancer Biology research program at Massey who holds the Harrison Foundation Distinguished Professorship in Cancer Research, a team of scientists set out to understand more about this protein's function in liver cancer. "Our study confirms that MDA-9 plays an important role in the rapid progression of liver cancer, and it establishes the rationale that MDA-9 inhibition -- either alone or in combination with other therapeutics -- might be an effective treatment approach for HCC," said Sarkar, who is also the associate scientific director of cancer therapeutics at the VCU Institute of Molecular Medicine and professor in the Department of Human and Molecular Genetics at the VCU School of Medicine. Liver cancer incidence has more than tripled since 1980, with more than 41,000 new cases estimated in 2022, according to the American Cancer Society. HCC is characterized by the chronic inflammation of liver cells often instigated by a variety of risk factors, including viral hepatitis, alcoholism and non-alcoholic fatty liver disease. Sarkar and his team determined that MDA-9 does not directly contribute to cancer growth, but instead activates a specialized type of cells called macrophages that initiate a sequence of cellular reactions that lead to inflammation. "Collectively, this study combined with previous research findings establishes MDA-9 as a key activator of tumor-driving inflammation," Sarkar said. Additionally, the researchers identified a signaling pathway -- ILK -- that plays a significant role in facilitating the development of liver cancer associated with MDA-9. Further research is planned testing the use of an MDA-9 inhibitor called PDZ1i in HCC cells. PDZ1i is a novel drug developed at VIMM by Paul Fisher, M.P.H., Ph.D., the Thelma Newmeyer Corman Endowed Chair in Cancer Research at Massey and VIMM director. Researchers at Massey and VIMM have previously studied the efficacy of PDZ1i in treating prostate cancer that has spread to the bone. Sarkar collaborated on this study with Fisher, in addition to Massey researchers Jennifer Koblinski, Ph.D., Jinze Liu, Ph.D., Jolene Windle, Ph.D., Mikhail Dozmorov, Ph.D., Nitai Mukhopadhyay, Ph.D., and Rebecca Martin, Ph.D.; Xufeng Qu of the Bioinformatics Shared Resource at Massey; Debashri Manna, Ph.D., Mark Subler, Ph.D., Rachel Mendoza and Swadesh Das, Ph.D., of the VCU Department of Human and Molecular Genetics; Maria Del Carmen Camarena and Saranya Chidambaranathan Reghupaty of the VCU C. Kenneth and Dianne Wright Center for Clinical and Translational Research; and Zhao Lai, Ph.D., of UT Health San Antonio.

合作

2022-09-06

·佰傲谷BioValley

科棋药业实体瘤CAR-T申报临床

小编有话说y2010年-2019年，全球范围内，在实体瘤领域共有178种细胞基因疗法进行了491项临床试验。其中，由中国团队发起的研究数量仅次于美国，是全球实体瘤创新药研发的重要力量。根据国家药监局药品审评中心（CDE）官网，上海科棋药业科技有限公司（以下简称科棋药业）申报的“KQ-L6自体嵌合抗原受体T细胞注射液”临床试验申请，已经获得受理。KQ-L6靶点并未公开，推测KQ-L6靶点很可能是实体瘤靶点TM4SF1。根据公开资料查询，该产品的开发适应症包括肠癌、肺癌等实体瘤，并且在人体试验中取得积极的初步数据。- 2021年6月，一名肠癌患者接受了科棋药业针对L6靶点的CAR-T细胞治疗，回输前肺部存在多发转移灶，最大的病灶为14mm。回输后一个月，肺部的病灶缩小至10.8mm，CEA降至正常。回输5个月后的复查显示，病灶呈持续的缩小。- 一名直肠癌复发患者（肺转移，腋下淋巴结转移，胸壁局部复发）接受了科棋药业针对L6靶点的CAR-T细胞治疗，CAR-T细胞回输五天后，患者的胸壁癌性溃疡愈合。图片来源：中国临床试验注册中心在中国临床试验注册中心进行查询，科棋药业针对实体瘤的CAR-T项目仅有一款正在和上海市第十人民医院正在进行的“嵌合抗原受体T细胞治疗TM4SF1和EpCAM阳性的复发/难治性实体瘤安全性和有效性的初步临床研究”。再根据科医联创（科棋药业是科医联创的全资子公司）官方微信公众号，上海市第十人民医院与科棋药业合作开展一项名为“嵌合抗原受体T细胞治疗TM4SF1阳性的复发/难治性实体瘤安全性和有效性的初步临床研究”，适应症包括胃癌、食管癌、肺癌、结直肠癌、卵巢癌、间皮瘤、胰腺癌、宫颈癌、输卵管癌、肝细胞癌、胆管细胞癌、膀胱癌、三阴性乳腺癌、脑胶质瘤等实体瘤。此研究已经经过上海市第十人民医院伦理委员会批准，正在面向社会招募受试者。同时，TM4SF1是科棋药业开发的全新肿瘤干细胞靶点，并且在CAR结构中融入多种因子解除肿瘤微环境，激活自体免疫系统，杀伤肿瘤细胞，实现了在实验动物体内完全清除肿瘤的显著疗效。2018年7月，科棋药业获得了一项TM4SF1特异性嵌合抗原受体及其应用的国家专利授权。因此，推测KQ-L6很可能是科棋药业开发的TM4SF1 CAR-T。科棋药业是科医联创的全资子公司，主要针对CAR-T细胞免疫疗法的研发与临床应用。公司团队自2013年涉足精准免疫疗法领域，建立了完整的从抗体筛选到CAR-T制备的研究和生产平台，重点发展国际领先的原创性的治疗产品。目前科棋药业已经获得多项发明专利授权，包括一种TM4SF1特异性嵌合抗原受体及其应用、一种抗BCMA的单域抗体及其应用、一种靶向EpCAM的嵌合抗原受体及其应用等。TM4SF1靶点TM4SF1是Tetraspanin超家族中亚家族TM4SFs的一员，首次于1986年被鉴定，具有Tetraspanin家族典型的四次跨膜结构，胞外含两个loop区EC1和EC2，其中EC2区可通过半胱氨酸残基与整合素α5β1结合，影响细胞的黏附和运动，C端胞质区包含PDZ结合域，可与Syntenin-1和Syntenin-2蛋白相互作用介导肿瘤细胞的增殖和转移。TM4SF1在肺癌、乳腺癌、肝癌、结直肠癌及卵巢癌等细胞表面显著高表达，且能与脂质激酶、酪氨酸蛋白激酶等形成复合体，如可结合DDR1，激活PKC和JAK2-STAT3信号通路，促进细胞伪足延伸。除了参与细胞增殖和运动，TM4SF1也介导肿瘤细胞EMT转化和血管生成，还参与调节肿瘤干细胞的自我更新[6]，并且与肿瘤耐药和不良预后相关，是现下极具潜力的抗肿瘤靶点。TM4SF1的临床药物披露不多，大都处于早期研究阶段，开发药物包括单抗、ADC、以及CAR-T细胞药物等。总结基于CAR-T优异的肿瘤治疗效果，CAR-T细胞治疗被视为肿瘤治疗的下一个主力军。相较于CAR-T在血液肿瘤中取得成功，多年来针对实体瘤的CAR-T疗法开发仍鲜有进展，大部分的实体瘤CAR-T项目都还停留在早期开发阶段。主要是由于肿瘤抗原异质性、CAR-T细胞的归巢障碍、肿瘤微环境 (TME) 抑制等因素限制了CAR-T在实体瘤的进展。因此开发实体瘤特异性靶点是一个很好的突破口。目前，Claudin 18.2、GPC3、MSLN、HER2、EGFR已经成为实体瘤CAR-T开发的热门靶点。参考资料：1.科医联创官方微信公众号2.大乘医学资讯《接受CAR-T细胞治疗的福大姐最新的复查结果显示，肝上的转移灶处于持续PR的状态》《CAR-T细胞回输后五天，胸壁的癌性溃疡竟然愈合了》3.中国临床试验注册中心4.恺佧生物《免疫治疗潜力股TM4SF1》近期热门视频更多精彩视频，尽在佰傲谷视频号，欢迎关注~本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处﹀点亮在看，传递信息♥

免疫疗法细胞疗法基因疗法抗体合作