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sonic hedgehog signaling during nervous system development

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Neural Regeneration Research 2008年第7期3卷 782-785页

作者： Qin Yang Peng Xie Department of Neurology First Affiliated Hospital Chongqing Medical University Chongqing 400016 China

The hedgehog signaling pathway plays a key role in embryonic development and organ formation. sonic hedgehog signaling participates in nervous system development, regulates proliferation and differentiation of neural stem cells, controls growth and targeting of axons, and contributes to specialization of oligodendrocytes. For further studies of the sonic hedgehog signaling pathway and for the development of new drugs in the treatment of nervous system diseases, it is beneficial to understand these mechanisms.

关键词： development nervous system review sonic hedgehog

Activation of sonic hedgehog signaling pathway is an independent potential prognosis predictor in human hepatocellular carcinoma patients

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Chinese Journal of Cancer Research 2012年第4期24卷 323-331页

作者： Li Che Yan-Hua Yuan Jun Jia Jun Ren Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education) Department of Medical OncologyPeking University Cancer Hospital & Institute

Objective： The activation of hedgehog （HH） pathway is implicated in the development of human malignancies including hepatocellular carcinoma （HCC）. However, the clinical impact of HH activation in HCC patients is still unclear. This study was conducted to confirm whether the expression of HH pathway components was associated with HCC progression and clinical outcome. Methods： This study was a sample-expanded and prolonged follow up of one of our previous studies. It included 46 HCC patients who underwent surgical treatment from 2002 to 2005. The expression of sonic HH （SHIq）, patched-1 （PTCHI）, smoothened （SMOH） and glioma-associated oncogene-1 （GLI1） genes in tumor and adjacent normal tissues extracted from the patients were examined by reverse transcription- polymerase chain reaction （RT-PCR） to explore the relationship between these genes and the clinical prognosis of HCC. Results： The expression levels ofSHH, PTCH1, SMOH and GLI1 in HCC tissues were 60.87%, 50.00%, 32.61% and 54.35%, respectively. The expression levels of SHH-related molecules were relatively intense in cancer tissue, but insignificantly correlated with any clinicopathological factors of tumor. Transcriptional factor GLI1 was the only molecule associated with poor prognosis among the HCC patients. The expression of GLI1 gene in tumor tissues was significantly related with disease-free survival （DFS）（P=0.042） and overall survival （OS）（P=0.030）. The simultaneous expression of GLI1 in tumor and adjacent normal liver tissues correlated with DFS （P〈0.029） and OS （P〈0.025）. Conclusions： HH signaling activation is an important event in the development of human HCC. The expression of GLI1 in SHH pathway is possibly involved in HCC progression, which may be a useful prognostic indicator of HCC.

关键词： Hepatocellular carcinoma hedgehog GLII sonic hedgehog patched smoothened prognosis

Changes in expression and secretion patterns of fibroblast growth factor 8 and sonic hedgehog signaling pathway molecules during murine neural stem/progenitor cell differentiation in vitro

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Neural Regeneration Research 2012年第22期7卷 1688-1694页

作者： Jiang Lu Kehuan Lu Dongsheng Li State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources Guangxi University Nanning 530004 Guangxi Zhuang Autonomous Region China Department of Anesthesiology Taihe Hospital Hubei University of Medicine Shiyan 442000 Hubei Province China Hubei Key Laboratory of Embryonic Stem Cell Research Taihe Hospital Hubei University of Medicine Shiyan 442000 Hubei Province China

In the present study, we investigated the dynamic expression of fibroblast growth factor 8 and sonic hedgehog signaling pathway related factors in the process of in vitro hippocampal neural stem/progenitor cell differentiation from embryonic Sprague-Dawley rats or embryonic Kunming species mice, using fluorescent quantitative reverse transcription-PCR and western blot analyses. Results demonstrated that the dynamic expression of fibroblast growth factor 8 was similar to fibroblast growth factor receptor 1 expression but not to other fibroblast growth factor receptors. Enzyme-linked immunosorbent assay demonstrated that fibroblast growth factor 8 and sonic hedgehog signaling pathway protein factors were secreted by neural cells into the intercellular niche. Our experimental findings indicate that fibroblast growth factor 8 and sonic hedgehog expression may be related to the differentiation of neural stem/progenitor cells.

关键词： neural stem cells neural progenitor cells fibroblast growth factor 8 sonic hedgehog signalpathway secretion dynamic differentiation neurons neural regeneration

Blockade of sonic hedgehog signal pathway enhances antiproliferative effect of EGFR inhibitor in pancreatic cancer cells

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Acta Pharmacologica Sinica 2007年第8期28卷 1224-1230页

作者： Wei-guo HU Tao LIU Jiong-xin XIONG Chun-you WANG~2 Pancreatic Surgery Center,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China Pancreatic Surgery Center Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China

Aim:To investigate the expression of sonic hedgehog(SHH)and epidermal growthfactor receptor(EGFR)signal molecules in pancreatic cancer cells,and to assessthe inhibitory effects through the blockade of the SHH and EGFR signaling path-ways by cyclopamine and Iressa,respectively.Methods:The expression of SHHand EGFR in pancreatic cancer cell lines(PANC-I,SUIT-2,and ASPC-1)was de-tected by RT-PCR and Western blot analysis.After treatment with different con-centrations of cyclopamine,alone or in combination with Iressa,the antiproliferativeeffect on pancreatic cancer cells was analyzed by methyl thiazolyl tetrazoliumassays.A flow cytometry analysis was used to detect the cellular cycle distribu-tion and apoptosis of pancreatic cancer cells.Results:All of the 3 pancreaticcancer cell lines expressed SHH,Smoothened(SMO),and EGFR.Cyclopaminecould downregulate the expression of EGFR in all cell lines.Cyclopamine or Iressacould induce a growth inhibitory effect in a dose-dependent manner.Moreover,the combined use of 2.5μmol/L cyclopamine and 1μmol/L iressa induced anenhanced inhibitory effect and a greater apoptosis rate than any agent alone.Thepercentage of the cell population of the G0/G1and sub-G1phases was significantlyincreased along with the increasing dose of cyclopamine and/or Iressa.Conclusion:The blockade of the sonic hedgehog signal pathway enhances theantiproliferative effect of the EGFR inhibitor through the downregulation of itsexpression in pancreatic cancer cells.The simultaneous blockade of SHH andEGFR signaling represents possible targets of new treatment strategies for pan-creatic carcinoma.

关键词： pancreas cancer sonic hedgehog epidermal growth factor receptor inhibitor cyclopa-mine

Blockade of the sonic hedgehog Signalling Pathway Inhibits Choroidal Neovascularization in a Laser-induced Rat Model

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2010年第5期30卷 659-665页

作者：何花张虹李斌李贵刚王志涛 Department of Ophthalmology Tongji HospitalTongji Medical CollegeHuazhong University of Science and Technology

sonic hedgehog (Shh) signaling has recently been shown to be involved in the pathological angiogenesis in response to tissue hypoxia and ischemic injury.Hypoxia/ischemia is considered to play an important role in the development of choroidal neovascularization (CNV).This study was aimed to examine the effect of blockade of the Shh signaling pathway on CNV and the underlying mechanism.A total of 64 male Brown-Norway (BN) rats were used in this study.One eye of each rat underwent laser photocoagulation.The other eye served as normal control.After the laser treatment, the 64 rats were divided into four groups (n=16 in each group):Blank control group, in which no intravitreal administration was given; cyclopamine group, recombinant Shh N-terminals protein (rShh) group and phosphate-buffered saline (PBS) group, in which cyclopamine (a Shh inhibitor), rShh (a Shh activator) and PBS were intravitreally injected into the laser-treated eyes respectively every other day for a total of four intravitreal injections immediately after the laser treatment.Fourteen days after the intravitreal administration, the changes of CNV-related variables, including positive CNV lesion percentage, CNV membrane area and CNV membrane thickness, were evaluated by fluorescein anqiography, indocyanine green angiography and pathological examinations.The mRNA and protein expression of PTCH1, Gli1, HIF-1α, VEGF and DLL4 in each group on 14 days of CNV model was detected by real-time quantitative PCR and western blot analysis, and the relationship between the Shh cascade and the HIF-1α-VEGF-DLL4 cascade in CNV was analyzed.The results showed that the CNV membrane area and the CNV membrane thickness were decreased by 62.5% and 41.9% in the cyclopamine group and increased by 85.7% and 64.3% in the rShh group in comparison to those in the blank control group (P<0.01 for each).There was no significant difference in the CNV membrane area and thickness between the blank control group and PBS group (P=0.102 and P=0.063, respectively).Real-time quantita

关键词： sonic hedgehog choroidal neovascularization therapeutics hypoxia ischemia

Involvement of PI3K/Akt Pathway in the Neuroprotective Effect of sonic hedgehog on Cortical Neurons under Oxidative Stress

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2012年第6期32卷 856-860页

作者：戴若莲夏远鹏毛玲梅元武薛玉梅胡波 Department of Neurology Union Hospital Tongji Medical College Huazhong University of Science and Technology

The sonic hedgehog (SHH) signaling pathway plays a pivotal role in neurogenesis and brain damage repair. Our previous work demonstrated that the SHH signaling pathway was involved in the neuroprotection of cortical neurons against oxidative stress. The present study was aimed to further examine the underlying mechanism. The cortical neurons were obtained from one-day old Sprague-Dawley neonate rats. Hydrogen peroxide (H2O2, 100 μmol/L) was used to treat neurons for 24h to induce oxidative stress. Exogenous SHH (3μg/mL) was employed to activate the SHH pathway, and cyclopamine (20 μmol/L), a specific SHH signal inhibitor, to block SHH pathway. LY294002 (20 μmol/L) were used to pretreat the neurons 30 min before H2O2 treatment and selectively inhibit the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. The cell viability was measured by MTT and apoptosis rate by flow cytometry analysis. The expression of p38, p-p38, ERK, p-ERK, Akt, p-Akt, Bcl-2, and Bax in neurons was detected by immunoblotting. The results showed that as compared with H2O2 treatment, exogenous SHH could increase the expression of p-Akt by 20% and decrease the expression of p-ERK by 33%. SHH exerted no significant effect on p38 mitogen-activated protein kinase (p38 MAPK) pathway. Blockade of PI3K/Akt pathway by LY294002 decreased the cell viability by 17% and increased the cell apoptosis rate by 2-fold. LY294002 treatment could up-regulate the expression of the proapoptotic gene Bax by 12% and down-regulate the expression of the antiapoptotic gene Bcl-2 by 54%. In conclusion, SHH pathway may activate PI3K/Akt pathway and inhibit the activation of the ERK pathway in neurons under oxidative stress. The PI3K/Akt pathway plays a key role in the neuroprotection of SHH. SHH/PI3K/Bcl-2 pathway may be implicated in the protection of neurons against H2O2-induced apoptosis.

关键词： sonic hedgehog PI3K/Akt apoptosis oxidative stress cortical neuron

sonic hedgehog诱导人脐带间充质干细胞分化过程中成骨相关miRNA表达差异的筛选

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临床口腔医学杂志 2022年第2期38卷 71-74页

作者：青莹石琦张涵泳张志翔曹颖光宋珂华中科技大学同济医学院附属同济医院湖北武汉430030 华中科技大学同济医学院口腔医学院湖北武汉430030 口腔颌面发育与再生湖北省重点实验室湖北武汉430022

目的:检测并分析人脐带间充质干细胞(hUCMSCs)成骨分化过程中的成骨特征性miRNA表达谱,探讨其可能的靶基因和临床意义。方法:对Shh诱导hUCMSCs成骨分化过程中表达的miRNA进行高通量测序分析,检测其表达量的变化,并验证成骨相关miRNA的... 详细信息

目的:检测并分析人脐带间充质干细胞(hUCMSCs)成骨分化过程中的成骨特征性miRNA表达谱,探讨其可能的靶基因和临床意义。方法:对Shh诱导hUCMSCs成骨分化过程中表达的miRNA进行高通量测序分析,检测其表达量的变化,并验证成骨相关miRNA的表达差异。结果:通过miRNA高通量测序和RT-qPCR验证,预测miRNA-342-3p可能作为关键因子,通过靶向Sufu调控Shh信号通路,进而调控hUCMSCs的成骨分化。结论:筛选出新的调控因子miRNA-342-3p作为Shh信号通路的靶分子,对成骨分化过程进行精准调控,为种植义齿骨组织工程提供新的治疗思路。

关键词： miRNA测序 sonic hedgehog 成骨分化人脐带间充质干细胞

慢性肾脏病患者血浆中sonic hedgehog的表达及临床意义

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慢性肾脏病患者血浆中Sonic Hedgehog的表达及临床意义

作者：周鹏华西安医学院

学位级别：硕士

目的:通过实验比较正常体检者和慢性肾脏病(Chronic Kidney Disease,CKD)患者之间、慢性肾脏病各期患者之间血浆中音猬因子(sonic hedgehog,SHH)的表达水平差异,探讨SHH在CKD患者中的表达及临床意义。方法:选取陕西省人民医院肾病血透... 详细信息

目的:通过实验比较正常体检者和慢性肾脏病(Chronic Kidney Disease,CKD)患者之间、慢性肾脏病各期患者之间血浆中音猬因子(sonic hedgehog,SHH)的表达水平差异,探讨SHH在CKD患者中的表达及临床意义。方法:选取陕西省人民医院肾病血透中心收治的54例CKD患者作为实验组,选择同期的健康体检者20例作为对照组。采用酶联免疫吸附试验(Enzyme Linked Immunosorbent Assay,ELISA)-双抗体夹心法测定两组被试血浆SHH水平,比较两组被试血浆SHH水平的差异;依据估算肾小球滤过率(Estimation of glomerular filtration rate,e GFR)将CKD患者进行分期,比较不同分期患者血浆SHH的水平;并探讨其与收缩压、舒张压、血肌酐(Serum creatinine,Scr)、尿素氮(Blood ureanitrogen,BUN)、尿酸(Uric acid,UA)、胱抑素C(Cystatin C,Cys C)、血红蛋白(Hemoglobin,Hb)、白蛋白(Albumin,Alb)、甘油三酯(Triglyceride,TG)、总胆固醇(Total cholesterol,TC)、高密度脂蛋白胆固醇(Highdensity lipoprotein-cholesterol,HDL-C)、低密度脂蛋白胆固醇(Low density lipoprotein-cholesterol,LDL-C)、血钙、血磷、甲状旁腺激素(Parathyoid hormone,PTH)、B型N-端脑钠尿肽(Type B N-terminal brain natriuretic peptide,BNP)、e GFR之间的相关性。全部数据采用SPSS 20.0统计软件进行分析,P0.05);CKD组患者收缩压、Scr、BUN、UA、Cys C、24小时尿蛋白定量均显著高于对照组,而Hb、Alb、e GFR均显著低于对照组,差异具有统计学意义(P0.05),与收缩压、UA、Scr、BUN、Cys C呈显著正相关,血浆SHH水平与e GFR、Hb呈显著负相关(P<0.05)。4.血浆SHH水平与e GFR呈显著负相关,即随着CKD疾病进展,由CKD1期到CKD5期,随着CKD患者肾脏损伤程度越重、e GFR值越小,血浆SHH水平反而越高。结论:CKD患者血浆中SHH的水平比对照组明显高,其血浆SHH水平与e GFR呈显著负相关,即随着CKD疾病进展,由CKD1期到CKD5期,随着CKD患者肾脏损伤程度越重,e GFR值越小,血浆SHH水平反而越高。上述结论也证实了SHH水平与CKD的发生、发展及进程有关,可能成为检测CKD患者早期肾功能损伤的一个新的生物标记物。

关键词：慢性肾脏病 sonic hedgehog 生物标记物

sonic hedgehog信号通路中Smoothened的跨膜域对其在原纤毛中定位的机制研究

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Sonic hedgehog信号通路中Smoothened的跨膜域对其在原纤毛中定位...

作者：濮晓红南京医科大学

学位级别：硕士

sonic hedgehog (Shh)是哺乳动物调控组织形态发生和细胞定向分化的主要形态发生因子(morphogen)。在人类及其他高等哺乳动物中,Shh的功能与肢芽、中枢神经、骨胳、心肺、消化、生殖、及皮肤等各种组织器官系统的形成都有着至关重要的... 详细信息

sonic hedgehog (Shh)是哺乳动物调控组织形态发生和细胞定向分化的主要形态发生因子(morphogen)。在人类及其他高等哺乳动物中,Shh的功能与肢芽、中枢神经、骨胳、心肺、消化、生殖、及皮肤等各种组织器官系统的形成都有着至关重要的关系。由基因突变造成的Shh通路异常激活会导致很多肿瘤的产生。当Shh配基不与其受体Patched(Ptch)结合时,Ptch对G蛋白偶联受体(GPCR) Smoothened (Smo)起抑制作用。这时,Smo下游全长的Gli转录激活子(Gli activator, GliA)被蛋白酶体剪切成截短的转录抑制子形式(Glirepressor, GliR),进入细胞核,抑制Shh靶基因转录。Ptch与Shh配基结合后,它对Smo的抑制作用被解除。Smo向原纤毛迁移,调控suppressor of fused (Sufu)与Gli的蛋白复合体向原纤毛顶端转运,进而阻断转录激活子GliA被蛋白酶体剪切成Gli R。GliA进入细胞核,激活靶基因转录。在由于Shh信号通路异常激活而形成的人类肿瘤中,40%的散发性基底细胞癌和25%的早期的神经外胚层的肿瘤是由于Ptch功能缺失或是Smo的过度激活所导致的。近年来的研究已经从天然植物中发现了一大类能够抑制Smo活性的类固醇类生物碱(steroidal alkaloid)包括环多胺(cyclopamine)。目前针对Smo的环多胺药物已经作为抗皮肤基底细胞癌和小脑延髓癌的实验药物进入了临床试验阶段。Smo是一个七次跨膜蛋白,主要包括3个结构域：N端胞外域、七次跨膜域和C端胞内域。目前,关于Smo的研究主要集中在其C端结构域,认为C端结构域是Smo的主要磷酸化区域,磷酸化后Smo构象发生改变,由无活性的单体形成2个C端相互结合的二聚体。然后该二聚体被转运进入原纤毛(primary cilia),在其中Smo活化并激活下游信号。并且Smo的C端结构域也是Smo发挥功能的主要结构域,因为Smo的活性与其保留的C端结构域长短呈正相关。但目前为止,关于Smo的七次跨膜域的功能以及七次跨膜域调节Smo在原纤毛中定位的机制尚不清楚。为了解决以上的疑问,我们首先研究了Smo七次跨膜域对其蛋白稳定性的影响。我们构建了切除Smo不同跨膜域的质粒,命名为SDTm,并在C端标记了Flag和GFP的标签。结果发现只保留了Smo第7个跨膜域的Smo(SDTm1-6)在蛋白稳定性上与全长的Smo存在差异,而其它的截断的Smo在蛋白稳定性上与全长的Smo并无差异。进一步分析我们发现SDTm1-6蛋白不稳定是由于被截的太短,使之被蛋白酶体降解造成的。既然其它的SDTm在蛋白稳定性上与全长的Smo并无差异,那么我们进而研究了Smo的七次跨膜域对下游信号传导的影响。在融合了Gli的荧光素酶报告基因的3T3细胞(Gli-Luc3T3)中,报告基因检测发现这些SDTm能与内源性的Smo协同使得下游靶基因Glil的表达量上调,说明SDTm能与内源性的Smo协同作用激活下游信号。通过进一步研究,我们用发现用病毒Ad-Cre-GFP感染Smofl/fl细胞,敲低了内源性的Smo时,下游靶基因Gli1的读值仍然有不同程度的上调,说明Smo的七次跨膜域对其下游信号传导并无显著的影响。最后,我们研究了Smo的七次跨膜域对其在原纤毛中定位的影响,发现当切除Smo的1-2号跨膜域时,Smo仍然可以在原纤毛中定位,而当切除6-7号跨膜域时,Smo不能在原纤毛中定位,说明Smo的七次跨膜域对其在原纤毛中定位起着重要的调节作用。综上所述,我们认为Smo的七次跨膜域对其蛋白稳定性和下游的信号传导并无显著的影响,而对其在原纤毛中的定位却至关重要。我们的研究阐明了Smo的七次跨膜域调节其在原纤毛中定位的部分机制,对进一步阐明Shh信号传导的机制具有深远的意义。

关键词： sonic hedgehog Smo SDTm 原纤毛