JAK/STAT3信号通路调控肿瘤及其相关生物功能的研究进展

JAK/STAT3信号通路是细胞信号通路中重要的信号传导通路之一,通过影响下游多种效应分子的活化状态,对细胞凋亡和增殖起着关键的作用,并且还诱导胚胎发育、肝脏再生、糖酵解和炎性反应、上皮间质转化和血管再生等一系列生物发生过程,与人类肿瘤的发生发展密切相关。     

白血病形成中JAK/STAT信号通路的持续激活

JAK/STAT通路是细胞因子、生长因子、激素等广泛应用的信号转导通路,白血病形成中普遍存在JAK/STAT通路的持续激活。白血病融合蛋白的表达、酪氨酸激酶过度表达或激活突变及某些病毒感染可导致JAK/STAT通路的持续激活和调节异常,并引起细胞的转化和白血病形成。了解白血病形成中JAK/STAT通路的异常调节有助于开发靶向JAK/STAT通路的治疗策略。     

JAK／STAT信号通路对RA调控作用的研究进展

JAK／STAT信号通路是近年发现的重要的信号转导通路,参与调控人体多种器官和组织的发育、生长和分化。研究证实,在RA起病和关节破坏过程中,JAK／STAT信号通路发挥着重要的调控作用。JAK／STAT信号通路通过多种途径参与炎性反应,与RA关系密切。闪此,了解JAK／STAT信号通路对RA的调控层次关系,能为开发新的抗RA药物提供新的际遇。     

JAK/STAT信号转导通路在树突状细胞分化成熟过程中的作用

树突状细胞(DC)是目前发现的效能最高的专职性抗原提呈细胞,其分化成熟过程对机体免疫功能的发挥起着至关重要的作用.大量研究表明JAK/STAT信号转导通路与DC分化成熟密切相关.JAK/STAT是一种多效联级的信号转导通路,是大量细胞因子和生长因子传递信号的主要途径,参与细胞生长发育繁殖凋亡等过程的调节.多种肿瘤病人体内DC分化成熟障碍可能与JAK/STAT通路的异常表达有关.     

JAK2/STAT3 pathway mediating inflammatory responses in heatstroke-induced rats

Heatstroke not only directly induces cell injury, but also causes large amounts of inflammatory mediators release and cells with extensive biological activities to induce a systemic inflammatory response and immune dysfunction. This study aimed to observe the effects of JAK2 inhibitor AG490 on the brain injury and inflammatory responses of rats with systemic heatstroke. Under the light microscope, the hippocampus tissues of rat with heatstroke were edema and apoptotic rate was increased. Up-regulation of malondialdehyde (MDA), nitric oxide synthase (iNOS), reactive oxygen species (ROS) and down-regulation of superoxide dismutase (SOD) were also found after heatstroke in rats, which compared with that of the control group. Heatstroke induced inflammation factors secretions and up-regulated levels of matrix metallopeptidase 2 and 9 (MMP2 and MMP-9) and systemic inflammatory response molecules including intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-beta 1 (TNF-β1) and cyclooxygenase-2 (COX-2). However, the JAK2 inhibitor AG490 was significantly attenuated the brain injury and inflammatory responses induced by heatstroke in rats. The survival time of heatstroke rats showed that AG490 notably lived longer than heatstroke rats without AG490 treatment. These findings suggest that AG490 may prevent the occurrence of heatstroke via inhibiting the JAK2/STAT3 pathway and the systemic inflammatory responses.     

异丙酚通过抑制JAK/STAT通路减轻肝冷缺血再灌注大鼠肾损伤

目的:探讨JAK/STAT信号通路在异丙酚减轻大鼠肝冷缺血再灌注后肾损伤中的作用。方法:SD大鼠随机分为4组(n=8):假手术组(sham组);肝冷缺血再灌注模型组(I/R组);异丙酚组(Pro组),于再灌注前5 min经右侧股静脉给予异丙酚20 mg·kg~(-1)·h~(-1)持续泵注30 min;JAK2抑制剂AG490组(AG490组),于建立模型前30 min腹腔注射AG490 10 mg/kg。再灌注6 h后处死大鼠,采集血样和肾组织标本,检测血清肌酐(Cr)、尿素氮(BUN)、白细胞介素-6(IL-6)和肿瘤坏死因子-α(TNF-α)的浓度及肾组织超氧化物歧化酶(SOD)和丙二醛(MDA)的水平;观察肾组织的病理学改变,并进行肾小管损伤评分;检测肾组织细胞凋亡并计算凋亡指数(AI);检测p-JAK2、p-STAT_1和p-STAT_3的蛋白水平。结果:与sham组比较,I/R组血清的Cr和BUN浓度、肾组织的MDA含量、肾小管损伤评分及AI均明显升高,SOD活性降低,p-JAK2、p-STAT_1和p-STAT_3的蛋白水平显著上调(P0.05)。与I/R组相比,Pro组和AG490组的血清BUN和Cr浓度、肾组织的MDA含量、AI和肾小管损伤评分降低,SOD活性升高,p-JAK2、p-STAT_1和p-STAT_3蛋白水平显著下调(P0.05)。结论:异丙酚可减轻肝冷缺血再灌注后肾损伤,其机制可能与抑制JAK/STAT信号通路激活有关。     

JAK/STAT信号通路在高糖诱导人脐静脉内皮细胞损伤中的作用

 目的: 探讨Janus激酶/信号转导子及转录激活子(JAK/STAT)信号通路是否介导高糖诱导的人脐静脉内皮细胞(HUVECs)损伤。方法: CCK-8检测细胞存活率;Western blot法检测内皮细胞JAK2、STAT3、caspase-9和内皮型一氧化氮合酶(eNOS)的表达水平;DCFH-DA染色荧光显微镜照相法检测内皮细胞内活性氧簇(ROS)水平;罗丹明123染色荧光显微镜照相法测定线粒体膜电位(MMP)。结果: 高糖(40 mmol/L葡萄糖)处理HUVECs 6~12 h能上调JAK2的磷酸化,于9 h达最高峰;高糖处理HUVECs 6~12 h能上调p-STAT3水平,其中12 h表达最多;JAK/STAT通路抑制剂AG490预处理1 h可显著抑制由高糖引起的内皮细胞损伤,表现为细胞存活率升高、凋亡相关蛋白caspase-9表达和胞内ROS生成减少、MMP及eNOS表达升高。结论: JAK/STAT信号通路参与了高糖诱导的人脐静脉内皮细胞损伤过程。     

miR-153靶向PRDM2基因并通过JAK/STAT信号通路影响膀胱癌的侵袭和迁移

目的:研究微小RNA(miR)-153是否靶向正性调控域锌指蛋白2(PRDM2)基因并通过调控JAK/STAT信号通路影响膀胱癌细胞的侵袭和迁移。方法:运用q PCR检测miR-153在膀胱癌组织中的表达;运用免疫组化检测PRDM2在正常组织和膀胱癌组织中的表达;Western blot检测不同膀胱癌细胞株中PRDM2的表达情况;双萤光素酶报告基因系统检测miR-153对PRDM2转录活性的影响;Transwell侵袭实验检测miR-153过表达对膀胱癌细胞RT4侵袭能力的影响;划痕实验检测miR-153过表达对膀胱癌细胞RT4迁移能力的影响;Western blot实验检测过表达miR-153后JAK/STAT信号通路蛋白的水平。结果:和正常组织比较,PRDM2蛋白在膀胱癌中表达较高(P0.05);miR-153的表达水平在膀胱癌组织中较低(P0.05);双荧光素酶报告基因系统检测结果显示,miR-153可以调控PRDM2的表达水平;过表达miR-153后,膀胱癌细胞株RT4的侵袭和迁移能力明显降低,p-JAK2和p-STAT3的蛋白水平下调。结论:miR-153靶向PRDM2,并通过JAK/STAT信号通路调控膀胱癌细胞的侵袭和迁移能力。     

Up-regulation of MARVEL domain-containing protein 1 (MARVELD1) accelerated the malignant phenotype of glioma cancer cells via mediating JAK/STAT signaling pathway

This work aimed to research the function of MARVEL domain-containing protein 1 (MARVELD1) in glioma as well as its functioning mode. Bioinformatics analysis was utilized to assess the MARVELD1 expression in glioma tissues and its relationship with grade and prognosis, based on The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Chinese Glioma Genome Atlas (CGGA) databases. Cell Counting Kit-8 (CCK-8), colony formation, and Transwell assays were carried out to determine the impact of MARVELD1 on malignant biological behavior of glioma, such as proliferation, invasion, and migration. qRT-PCR was carried out to test the mRNA level of MARVELD1. Western blot assay was performed to measure the protein expression of MARVELD1 and JAK/STAT pathway-related proteins. MARVELD1 was expressed at high levels in glioma tissues and cell lines. Kaplan-Meier survival analysis revealed that the higher MARVELD1 expression, the shorter the survival time of patients with glioma. Also, the MARVELD1 expression in WHO IV was significantly enhanced compared to that in WHO II and WHO III. Furthermore, the functional analysis of MARVELD1 in vitro revealed that knockdown of MARVELD1 in U251 cells restrained cell proliferation, migration, and invasion, while up-regulation of MARVELD1 in U87 cells presented opposite outcomes. Finally, we found that JAK/STAT signaling pathway mediated the function of MARVELD1 in glioma. MARVELD1 contributed to promoting the malignant progression of glioma, which is the key driver of activation of JAK/STAT signaling pathway in gliomas.     

黄角颗粒对脑缺血再灌注损伤大鼠JAK2/STAT3信号通路的影响

目的:研究黄角颗粒对脑缺血再灌注损伤大鼠JAK2/STAT3信号通路的影响。方法:采用线栓法构建大鼠脑缺血再灌注损伤模型,取30只健康雄性SD大鼠随机分为假手术组、模型组和黄角颗粒组,并按分组给予相应处理。采用Zea Longa评分法对各组大鼠进行神经功能评分,TTC染色检测各组大鼠脑梗死体积百分比,HE染色观察各组大鼠脑组织病理形态,TUNEL染色法检测各组大鼠脑细胞凋亡率,Western blot检测各组大鼠脑组织中p-JAK2和p-STAT3的蛋白水平。结果:与假手术组相比,模型组大鼠的神经功能缺损程度和神经细胞损伤程度明显加重(P0.05);脑梗死体积百分比和脑细胞凋亡率显著上升(P0.05);脑组织中p-JAK2和p-STAT3的蛋白水平显著上调(P0.05)。与模型组相比,黄角颗粒组大鼠的神经功能缺损程度和神经细胞损伤程度明显减轻(P0.05);脑梗死体积百分比和脑细胞凋亡率显著下降(P0.05);脑组织中p-JAK2和p-STAT3的蛋白水平显著下调(P0.05)。结论:黄角颗粒对脑缺血再灌注损伤大鼠的保护作用可能与抑制JAK2/STAT3信号通路的激活相关。     

胃癌患者血清IL-1的升高和癌组织JAK2/STAT3信号通路的激活

目的 探讨胃癌患者血清中白细胞介素1(IL-1)含量升高及癌组织中JAK2/STAT3信号通路激活在胃癌生长过程中的作用.方法 选取甘肃省武威肿瘤医院胃癌手术患者及同期健康体检者各30例;酶联免疫吸附法(ELISA)检测样本血清中IL-1和IL-10的含量;免疫组化和Western blot分别检测各组织中Bcl-2、...     

miR-135a靶向调节SP1对人骨肉瘤细胞增殖和凋亡的影响

目的探讨miR-135a通过靶向调节SP1对人骨肉瘤(osteosarcoma,OS)细胞增殖和凋亡的影响。方法收集人正常成骨组织和OS组织,培养正常成骨细胞(h FOB1.19)和OS细胞(MG-63),Real-time PCR法检测miR-135a和SP1的表达,Western blot法检测SP1表达。转染miR-135a mimics和inhibitor,MTT法和Brd U-ELISA法检测OS细胞增殖变化,Western blot法检测凋亡蛋白Bax、BCL-2和Caspase 3的表达。双荧光素酶报告基因检测miR-135a与SP1的靶定关系。Western blot法检测miR-135a对OS细胞中SP1表达的影响。Western blot法检测miR-135a对OS细胞中JAK2/STAT3表达的影响。结果 OS组织和细胞中miR-135a表达均显著降低,SP1表达均显著升高。转染miR-135a mimics可降低OS细胞活性,减少Brd U阳性标记率。同时,miR-135a mimics增加OS细胞Bax和Caspase 3的表达,减少BCL-2的表达。miR-135a mimics降低荧光素酶报告基因的荧光强度,结合位点突变后荧光素酶活性升高。上调miR-135a显著降低SP1的表达并降低JAK2和STAT3的磷酸化水平。miR-135a inhibitor作用均与mimics相反。结论 miR-135a可通过靶向调节SP1抑制人OS细胞增殖,诱导OS细胞凋亡,并下调JAK2/STAT3活化。     

The immediate early protein WSV187 can influence viral replication via regulation of JAK/STAT pathway in Drosophila

The world production of shrimp is seriously affected by the white spot syndrome virus (WSSV). Viral immediate-early (IE) genes encode regulatory proteins critical for the viral lifecycle. In spite of their importance, only five out of the 21 identified WSSV IE genes are functionally characterized. Here, we report the use of Drosophila melanogaster as a model to explore the role of WSSV IE gene wsv187. In vivo expression of WSV187 in transgenic flies show WSV187 localized in the cytoplasm. Overexpression of wsv187 results wing defects consistent with phenotypes observed in JAK/STAT exacerbated flies. After artificial infection of the DCV virus, the flies expressing wsv187 showed a lower viral load, a higher survival rate and an up-regulated STAT92E expression. These data demonstrate wsv187 plays a role in the controlling of virus replication by activating host JAK/STAT pathway.     

Regulation of airway inflammation and remodeling in asthmatic mice by TLR3/TRIF signal pathway

This paper aims to investigate the effect of Toll-like receptors 3 (TLR3)/TIR-domain-containing adapter-inducing interferon-β (TRIF) signal pathway on the airway inflammation and remodeling in asthmatic mice. C57BL/6 and TLR3^−/− mice were randomly divided into three groups (10 mice per group), including Control group (mice inhaled phosphate buffer saline (PBS)), Asthma group (mice inhaled ovalbumin (OVA)) and polyriboinosinic-ribocytidylic acid (poly (I: C)) group (asthmatic mice were injected intraperitoneally with TLR3 agonist poly (I: C)). Hematoxylin-eosin (HE) staining, Wright-Giemsa staining, Enzyme-linked immunosorbent assay (ELISA), Immunohistochemistry, Hydroxyproline assay, quantitative real time polymerase chain reaction (qRT-PCR) and Western blot were used to assess for the indices of airway inflammation and remodeling. In terms of WT mice, all asthma groups with or without the addition of poly (I: C) showed exaggerated inflammation and remodeling in the airways as compared to Control group, which were more seriously in poly (I: C) group than Asthma group. Furthermore, we observed the significant inhibition of airway inflammation and remodeling in the TLR3^−/− mice in both Asthma no matter with or without addition of poly (I: C) than the WT mice. TLR3 knockout could obviously relieve the airway inflammation and remodeling in asthma through inhibiting TLR3/TRIF signaling pathway.     

Targeting JAK/STAT signalling in inflammatory skin diseases with small molecule inhibitors

For most inflammatory skin diseases topical glucocorticosteroids and traditional oral immunosuppressive drugs remain the principle treatment choices, but this has started to change. A deeper understanding in individual disease pathogenesis, basic immune mechanisms and molecular signalling pathways, together with advances in pharmaceutical drug development, allow us to interfere more precisely with disease‐related factors. Some examples of inflammation‐controlling interventions include antibodies neutralizing disease‐associated cytokines, and small molecules targeting intracellular pathways relevant to cytokine production or cytokine signalling. So far, this is best established for psoriasis, an inflammatory skin disease dominated by Th17 cytokines. In this review, we focus on chronic inflammatory skin diseases where cytokines using type I/II cytokine receptors play a dominant role in disease pathogenesis and where novel treatments with inhibitors of the JAK/STAT pathway are already under clinical investigation. To better understand the rationale of using JAK/STAT inhibitors in the discussed skin diseases, we give an overview of important genetic and immunological associations with the JAK/STAT pathway and summarize the stage of clinical development of small molecular inhibitors. JAK/STAT inhibitors will presumably find wide application in dermatology, since they can be applied not only systematically but also topically for the treatment of inflammatory skin diseases.     

血管紧张素(1-7)通过抑制JAK/STAT信号通路对抗高糖诱导的人脐静脉内皮细胞损伤

目的:研究血管紧张素(1-7)[Ang-(1-7)]能否通过抑制JAK/STAT信号通路对抗高糖诱导的人脐静脉内皮细胞(HUVECs)损伤。方法:CCK-8检测细胞存活率;Western blot法检测内皮细胞JAK2、STAT3、pJAK2、p-STAT3、cleaved caspase-3和内皮型一氧化氮合酶(e NOS)的蛋白水平;Hoechst 33258染色荧光显微镜照相法检测内皮细胞凋亡数量;DCFH-DA染色荧光显微镜照相法检测内皮细胞内活性氧簇(ROS)的水平。结果:应用高糖(40 mmol/L)处理HUVECs 12~48 h能明显上调JAK2的磷酸化水平,于24 h达最高峰;在24~48 h能明显上调STAT3的磷酸化水平,于36 h最高;在12~24 h能明显上调cleaved caspase-3的表达,在3~48 h随着时间延长,e NOS的表达逐渐降低。2μmol/L的Ang-(1-7)或20μmol/L的JAK/STAT通路抑制剂AG490预处理0.5 h可显著抑制由高糖引起的内皮细胞损伤,表现为p-STAT3、p-JAK2及cleaved caspase-3蛋白水平降低、细胞存活率及e NOS表达升高,细胞凋亡数量和胞内ROS生成减少。结论:Ang-(1-7)能通过抑制JAK/STAT通路对抗高糖诱导的人脐静脉内皮细胞损伤。     

PI3K/Akt和JAK2/STAT3信号转导通路在SO_2抗大鼠肢体缺血再灌注致急性肺损伤中的作用

目的:探讨PI3K/Akt和JAK2/STAT3信号转导通路在二氧化硫(SO2)抗肢体缺血再灌注(I/R)致急性肺损伤中的作用。方法:应用双大腿根部绑扎止血带复制大鼠双后肢缺血再灌注肺损伤模型。在再灌注前20 min腹腔注射Na2SO3/Na HSO3;在再灌注前1 h静脉注射Stattic或LY294002。应用TUNEL、ELISA、Western blot等方法检测细胞凋亡、细胞因子表达及相关信号通路蛋白表达的情况。结果:与对照组相比,I/R组的MDA及MPO含量、肺系数、细胞凋亡指数、细胞因子表达以及p-STAT3、p-Akt蛋白的水平均显著增高;当应用Na2SO3/Na HSO3后,上述反映肺损伤的各项指标均下降。Western blot检测结果显示I/R后,肺组织中p-STAT3和p-Akt蛋白的水平均明显增加。而应用Na2SO3/Na HSO3后,p-Akt蛋白的水平继续增加,但p-STAT3蛋白的水平却减少(P0.05)。结论:JAK2/STAT3和PI3K/Akt信号通路都参与了SO2抗肢体缺血再灌注致急性肺损伤的作用。JAK2/STAT3通路的活化,能够使I/R损伤加重;相反,PI3K/Akt信号通路的活化,可以使I/R损伤减弱。此外,JAK2/STAT3和PI3K/Akt信号通路之间存在交互作用。     

抑制G蛋白偶联受体40通过RhoA/ROCK1信号通路缓解小鼠过敏性哮喘

目的:探究抑制G蛋白偶联受体40(GPR40)减轻过敏性哮喘小鼠症状的作用及机制.方法:将28只雄性C57BL/6小鼠随机分为正常对照组、哮喘模型组(用卵清蛋白建立过敏性哮喘模型)、低剂量GPR40抑制剂DC260126干预组(3 mg/kg DC260126组)和高剂量DC260126干预组(10 mg/kg DC2...     

Anticancer effect of salidroside on colon cancer through inhibiting JAK2/STAT3 signaling pathway

Salidroside is considered to have anti-tumor properties. We investigate its effects on colon carcinoma SW1116 cells. Cell viability was assessed by CCK-8. Propidium iodide (PI) staining was used to determine the cell cycle by flow cytometry. The migration and invasion were detected by Transwell. Western blot was used to detect the expression of STAT3 signal related proteins. As the result, high concentrations of salidroside (10, 20. 50 μg/ml) significantly inhibited proliferation of SW1116 cells in a parallelly, cell cycle arrest was increased at the G0/G1 phase after salidroside treatment. Furthermore, salidroside inhibited migration and invasion of SW1116 cells. Salidroside treatment decreased proteins expression of phosphorylation levels in JAK2/STAT3 signaling, while MMP-2 and MMP-9 proteins levels were decreased and protein expression of VEGF and VEGFR-2 were down-regulated. In Conclusion, salidroside inhibited proliferation, decreased the migration and invasion of SW1116 cells in JAK2/STAT3-dependent pathway, the specific mechanisms need further study.