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Targeting LIF/LIFR signaling in cancer

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Genes & Diseases 2022年第4期9卷 973-980页

作者： Suryavathi Viswanadhapalli Kalarickal V.Dileep Kam Y.J.Zhang Hareesh b.Nair Ratna K.Vadlamudi Department of Obstetrics and Gynecology University of Texas Health San AntonioSan AntonioTX 78229USA Laboratory for Structural bioinformatics Center for Biosystems Dynamics ResearchRIKENYokohamaKanagawa 230-0045Japan Evestra Inc.San AntonioTX 78245USA Mays Cancer Center University of Texas Health San AntonioSan AntonioTX 78229USA

Leukemia inhibitory factor (LIF), and its receptor (LIFR), are commonly over-expressed in many solid cancers and recent studies have implicated LIF/LIFR axis as a promising clinical target for cancer therapy. LIF/LIFR activate oncogenic signaling pathways including jak/STAT3 as immediate effectors and MAPK, AKT, mTOR further downstream. LIF/LIFR signaling plays a key role in tumor growth, progression, metastasis, stemness and therapy resistance. Many solid cancers show overexpression of LIF and autocrine stimulation of the LIF/LIFR axis;these are associated with a poorer relapse-free survival. LIF/LIFR signaling also plays a role in modulating multiple immune cell types present in tumor micro environment (TME). Recently, two targeted agents that target LIF (humanized anti-LIF antibody, MSC-1) and LIFR inhibitor (EC359) were under development. both agents showed effectivity in preclinical models and clinical trials using MSC-1 antibody are in progress. This article reviews the significance of LIF/LIFR pathways and inhibitors that disrupt this process for the treatment of cancer.

关键词： LIF LIFR LIFR inhibitor STAT3 Targeted therapy

Emerging agents that target signaling pathways to eradicate colorectal cancer stem cells

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Cancer Communications 2021年第12期41卷 1275-1313页

作者： Valdenizia R.Silva Luciano de S.Santos Rosane b.Dias Claudio A.Quadros Daniel P.bezerra Gonçalo Moniz Institute Oswaldo Cruz Foundation(IGM-FIOCRUZ/BA)SalvadorBahia 40296-710Brazil São Rafael Hospital Rede D’Or/São LuizSalvadorBahia 41253-190Brazil bahia State University SalvadorBahia 41150-000Brazil

Colorectal cancer(CRC)represents the third most commonly diagnosed cancer and the second leading cause of cancer death *** modern concept of cancer biology indicates that cancer is formed of a small population of cells called cancer stem cells(CSCs),which present both pluripotency and self-renewal *** cells are considered responsible for the progression of the disease,recurrence and tumor ***,some cell signaling pathways participate in CRC survival,proliferation,and selfrenewal properties,and most of them are dysregulated in CSCs,including the Wingless(Wnt)/β-catenin,Notch,Hedgehog,nuclear factor kappa b(NF-κb),Janus kinase/signal transducer and activator of transcription(jak/STAT),peroxisome proliferator-activated receptor(PPAR),phosphatidyl-inositol-3-kinase/Akt/mechanistic target of rapamycin(PI3K/Akt/mTOR),and transforming growth factor-β(TGF-β)/Smad *** this review,we summarize the strategies for eradicating CRC stem cells by modulating these dysregulated pathways,which will contribute to the study of potential therapeutic schemes,combining conventional drugs with CSC-targeting drugs,and allowing better cure rates in anti-CRC therapy.

关键词： colorectal cancer stem cells cell signaling Wnt/β-catenin pathway Notch Hedgehog NF-κb jak/STAT signaling PI3K/Akt/mTOR signaling targeted therapy

CIS controls the functional polarization of GM-CSF-derived macrophages

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Cellular & Molecular Immunology 2023年第1期20卷 65-79页

作者： Shengbo Zhang Jai Rautela Naiara G.bediaga Tatiana b.Kolesnik Yue You Junli Nie Laura F.Dagley Justin bedo Hanqing Wang Li Sun Robyn Sutherland Elliot Surgenor Nadia Iannarella Rhys Allan Fernando Souza-Fonseca-Guimaraes Yi Xie Qike Wang Yuxia Zhang Yuekang Xu Stephen L.Nutt Andrew M.Lew Nicholas D.Huntington Sandra E.Nicholson Michaël Chopin Yifan Zhan Walter and Eliza Hall Institute of Medical Research ParkvilleVICAustralia Department of Medical biology University of MelbourneParkvilleVICAustralia Department of biochemistry and Molecular biology Biomedicine Discovery InstituteMonash UniversityClaytonVICAustralia oNKo-Innate Pty Ltd Moonee PondsVICAustralia Department of Computing and Information Systems University of MelbourneParkvilleVICAustralia Department of Respiratory Medicine Guangzhou Institute of PediatricsGuangzhou Women and Children’s Medical CentreState Key Laboratory of Respiratory DiseasesGuangzhou Medical UniversityGuangzhouGuangdongChina College of biological Science Anhui Normal UniversityHefeiChina University of Queensland Diamantina Institute University of QueenslandTranslational Research InstituteBrisbaneQLDAustralia Program in Cardiovascular and Metabolic Disorders Duke-NUS Medical SchoolDukeSingapore Drug Discovery Shanghai Huaota BiopharmShanghaiChina

The cytokine granulocyte-macrophage-colony stimulating factor (GM-CSF) possesses the capacity to differentiate monocytes into macrophages (MØs) with opposing functions, namely, proinflammatory M1-like MØs and immunosuppressive M2-like MØs. Despite the importance of these opposing biological outcomes, the intrinsic mechanism that regulates the functional polarization of MØs under GM-CSF signaling remains elusive. Here, we showed that GM-CSF-induced MØ polarization resulted in the expression of cytokine-inducible SH2-containing protein (CIS) and that CIS deficiency skewed the differentiation of monocytes toward immunosuppressive M2-like MØs. CIS deficiency resulted in hyperactivation of the jak-STAT5 signaling pathway, consequently promoting downregulation of the transcription factor Interferon Regulatory Factor 8 (IRF8). Loss- and gain-of-function approaches highlighted IRF8 as a critical regulator of the M1-like polarization program. In vivo, CIS deficiency induced the differentiation of M2-like macrophages, which promoted strong Th2 immune responses characterized by the development of severe experimental asthma. Collectively, our results reveal a CIS-modulated mechanism that clarifies the opposing actions of GM-CSF in MØ differentiation and uncovers the role of GM-CSF in controlling allergic inflammation.

关键词： CIS GM-CSF Macrophage M2 M1

Macrophage-specific inhibition of the histone demethylase JMJD3 decreases STING and pathologic inflammation in diabetic wound repair

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Cellular & Molecular Immunology 2022年第11期19卷 1251-1262页

作者： Christopher O.Audu William J.Melvin Amrita D.Joshi Sonya J.Wolf Jadie Y.Moon Frank M.Davis Emily C.barrett Kevin D.Mangum Hongping Deng Xianying Xing Rachel Wasikowski Lam C.Tsoi Sriganesh b.Sharma Tyler M.bauer James Shadiow Matthew A.Corriere Andrea TObi Steven LKunkel benjamin Levi bethany bMoore Johann EGudjonsson Andrew MSmith Katherine A.Gallagher Department of Surgery Section of Vascular SurgeryUniversity of MichiganAnn ArborMIUSA Department of Microbiology and Immunology University of MichiganAnn ArborMIUSA Department of Medicinal Chemistry University of MichiganAnn ArborMIUSA Department of Surgery Section of General SurgeryUniversity of MichiganAnn ArborMIUSA Department of bioengineering University of IllinoisUrbana-ChampaignChampaignILUSA Department of Dermatology University of MichiganAnn ArborMIUSA Department of Pathology University of MichiganAnn ArborMIUSA Department of Surgery University of Texas Southwestern Medical CenterDallasTXUSA

Macrophage plasticity is critical for normal tissue repair following *** pathologic states such as diabetes,macrophage plasticity is impaired,and macrophages remain in a persistent proinflammatory state;however,the reasons for this are ***,using single-cell RNA sequencing of human diabetic wounds,we identified increased JMJD3 in diabetic wound macrophages,resulting in increased inflammatory gene ***,we report that in wound healing,JMJD3 directs early macrophage-mediated inflammation via jak1,3/STAT3 ***,in the diabetic state,we found that IL-6,a cytokine increased in diabetic wound tissue at later time points post-injury,regulates JMJD3 expression in diabetic wound macrophages via the jak1,3/STAT3 pathway and that this late increase in JMJD3 induces NFκb-mediated inflammatory gene transcription in wound macrophages via an H3K27me3 ***,RNA sequencing of wound macrophages isolated from mice with JMJD3-deficient myeloid cells(Jmjd3f/fLyz2Cre+)identified that the STING gene(Tmem173)is regulated by JMJD3 in wound *** limits inflammatory cytokine production by wound macrophages during ***,in diabetic mice,its role changes to limit wound repair and enhance *** finding is important since STING is associated with chronic inflammation,and we found STING to be elevated in human and murine diabetic wound macrophages at late time ***,we demonstrate that macrophage-specific,nanoparticle inhibition of JMJD3 in diabetic wounds significantly improves diabetic wound repair by decreasing inflammatory cytokines and *** together,this work highlights the central role of JMJD3 in tissue repair and identifies cell-specific targeting as a viable therapeutic strategy for nonhealing diabetic wounds.

关键词： wound healing epigenetics diabetes JMJD3 STING

利特替尼治疗成人和青少年斑秃患者的疗效研究

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中国临床药理学杂志 2023年第12期39卷 1712-1712页

作者：孟海峰 KING b ZHANG X HARCHA W G 不详

斑秃的特点是头皮、面部或体毛无瘢痕脱落。本课题组研究了口服选择性jak3/TEC家族激酶双抑制药利特昔替尼治疗斑秃患者的疗效。本研究为一项随机、随机、双盲、多中心、Ⅱb-Ⅲ期临床试验。研究对象为12岁以上斑秃或脱发率超过50%的患... 详细信息

斑秃的特点是头皮、面部或体毛无瘢痕脱落。本课题组研究了口服选择性jak3/TEC家族激酶双抑制药利特昔替尼治疗斑秃患者的疗效。本研究为一项随机、随机、双盲、多中心、Ⅱb-Ⅲ期临床试验。研究对象为12岁以上斑秃或脱发率超过50%的患者。将718例入组患者随机分为试验1组(利列西替尼200 mg+50 mg)、试验2组(利列西替尼200mg+30 mg 48周)、试验3组(利列西替尼50 mg 48周)、试验4组(利列西替尼30 mg 48周)、试验5组(利列西替尼10 mg 48周)、安慰剂1组(安慰剂24周+利列西替尼50 mg 24周)、安慰剂2组(安慰剂24周+利列西替尼200 mg 24周),各组均每天给药1次。主要治疗终点是在第24周时绝对脱发严重程度工具(SALT)评分≤20分,对利特昔替尼治疗有应答头皮毛发再生的患者比例。

关键词：安慰剂 Ⅲ期临床试验斑秃患者抑制药疗效研究课题组研究利列脱发

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靶向信号通路杀伤结直肠癌干细胞的新型药物

癌症 2023年第4期42卷 169-212页

在全球范围内,结直肠癌(colorectal cancer,CRC)是第三大最常见的癌症,也是第二大致死的癌症。目前癌症生物学认为,癌是由一小群肿瘤干细胞(cancer stem cells,CSCs)形成,CSCs具有多潜能和自我更新的特性。CSCs被认为是与肿瘤发展、复... 详细信息

在全球范围内,结直肠癌(colorectal cancer,CRC)是第三大最常见的癌症,也是第二大致死的癌症。目前癌症生物学认为,癌是由一小群肿瘤干细胞(cancer stem cells,CSCs)形成,CSCs具有多潜能和自我更新的特性。CSCs被认为是与肿瘤发展、复发和耐药性有关。有趣的是,一些细胞信号通路参与维持CRC的存活、增殖和自我更新的特性,其中大多数信号通路在CSCs中被异常调控,这些通路包括Wnt(Wingless)/β-catenin、Notch、Hedgehog、NF-κb(nuclear factor kappa b)、jak/STAT(Janus kinase/signal transducer and activator of transcription)、PPAR(peroxisome proliferator-activated receptor)、PI3K/Akt/mTOR(phosphatidyl-inositol-3-kinase/Akt/mechanistic target of rapamycin)和TGF-β(transforming growth factor-β)/Smad信号通路。在本综述中,我们总结了当前通过调控使这些异常信号通路来杀伤CRC干细胞的策略,这将有可能探索出联合常规药物和CSCs靶向药物的治疗方案,并将有助于提高CRC的治愈率。

关键词：结直肠肿瘤干细胞细胞信号通路 Wnt/β-catenin信号通路 Notch Hedgehog NF-κb jak/STAT信号通路 PI3K/Akt/mTOR信号通路靶向治疗

IL-12 p35 silenced dendritic cells modulate immune responses by blocking IL-12 signaling through jak-STAT pathway in T lymphocytes

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南京医科大学学报（自然科学版） 2007年第4期27卷 423-423页

作者： Xu, H. Zhang, Y. H. Hua, Y. b. Chen, T. Wang, H. Q. Wu, W. X. Nanjing Med Univ Affiliated Hosp Dept Gen Surg Nanjing 210009 Jiangsu Prov Peoples R China

长链非编码RNA RMRP通过jak2/STAT3信号通路增强胶质瘤细胞对替莫唑胺敏感性的机制研究

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中国临床药理学杂志 2018年第19期34卷 2320-2323页

作者：马飞李令兴李琳姜志平高培平泰安市中心医院静脉用药调配中心山东泰安271000 泰安市中心医院心内科山东泰安271000

目的探讨长链非编码RNA RMRP(lncRNA-RMRP)对胶质瘤替莫唑胺(TMZ)耐药的影响,并检测lncRNA-RMRP在胶质瘤细胞系(U87、U118)TMZ耐药细胞株(U87TR、U118TR)和原发胶质瘤组织、复发胶质瘤组织中的表达情况。方法用实时荧光定量聚合酶链式反... 详细信息

目的探讨长链非编码RNA RMRP(lncRNA-RMRP)对胶质瘤替莫唑胺(TMZ)耐药的影响,并检测lncRNA-RMRP在胶质瘤细胞系(U87、U118)TMZ耐药细胞株(U87TR、U118TR)和原发胶质瘤组织、复发胶质瘤组织中的表达情况。方法用实时荧光定量聚合酶链式反应(RT-q PCR)检测lncRNA-RMRP在U87、U87TR、U118、U118TR和胶质瘤组织、复发胶质瘤组织中的表达情况。U87TR、U118TR分别转染lncRNA-RMRP,并分为U87TR-RMRP组、U87TRNC组、U118TR-RMRP组和U118TR-NC组。用CCK-8方法检测400μmol·L^(-1)TMZ处理0,24,48,72,96 h后,U87、U87TR、U118、U118TR细胞的活力。用Western blotting检测jak2/STAT3相关蛋白的表达。结果 LncRNARMRP在U87、U87TR中表达量分别为(1.03±0.21)和(0.12±0.07),在U118、U118TR中表达量分别为(1.07±0.32)和(0.43±0.15),在复发胶质瘤组织和原发胶质瘤组织中表达量分别为(1.36±0.78)和(3.41±1.61),差异均有统计学意义(均Pjak2分别为(1.02±0.23)和(0.49±0.13),p-STAT3分别为(1.02±0.0.21)和(0.28±0.07),差异均有统计学意义(均Pjak2分别为(1.00±0.13)和(0.29±0.04),p-STAT3分别为(1.09±0.27)和(0.36±0.04),差异均有统计学意义(均Pjak2/STAT3信号通路增强胶质瘤细胞对TMZ敏感性。

关键词：替莫唑胺长链非编码RNA RMRP 胶质瘤耐药性

利匹韦林通过选择性STAT1介导的肝星状细胞凋亡改善肝纤维化

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临床肝胆病杂志 2020年第1期36卷 160-160页

作者：任天棋杨倩倩乔天一牛俊奇 MART■-RODRIGO A ALEGRE F MORAGREGA ■b 吉林大学第一医院感染病中心肝病科

【据《Gut》2019年9月报道】题:利匹韦林通过选择性STAT1介导的肝星状细胞凋亡改善肝纤维化(作者Martí-Rodrigo A等)。肝纤维化发病率逐年上升,缺乏具体有效的治疗措施,已经成为一个重大的公共卫生问题。大量研究结果表明,机体主要通... 详细信息

【据《Gut》2019年9月报道】题:利匹韦林通过选择性STAT1介导的肝星状细胞凋亡改善肝纤维化(作者Martí-Rodrigo A等)。肝纤维化发病率逐年上升,缺乏具体有效的治疗措施,已经成为一个重大的公共卫生问题。大量研究结果表明,机体主要通过细胞因子激活jak-STAT通路来调节肝纤维化和肝细胞再生。利匹韦林是一种临床上广泛应用的抗HIV药物,目前尚无肝毒性报道。本研究中,来自西班牙瓦伦西亚大学大学医学院药理学系的Martí-Rodrigo等主要研究了利匹韦林在几种慢性肝损伤模型中的肝脏保护作用,并研究了其作用机制:jak-STAT信号调节。研究人员利用营养性非酒精性脂肪肝、四氯化碳致肝纤维化和胆管结扎致肝纤维化三种小鼠模型,研究了利匹韦林对肝脂肪变性、炎症和纤维化的影响。并利用原代人肝星状细胞,人肝细胞株lx-2、hep3b研究了其潜在的分子机制。

关键词： STAT1 慢性肝损伤肝纤维化肝细胞再生胆管结扎非酒精性脂肪肝肝脂肪变性抗HIV药物