Noncanonical Wnt as a prognostic marker in prostate cancer: “you can’t always get what you Wnt”

ABSTRACT

Introduction: Wnt signaling is important for normal development, cell proliferation, and cell differentiation. However, aberrations in the pathway can lead to tumorigenesis and cancer progression. Recent genome-wide studies have demonstrated the frequent occurrence of Wnt pathway alterations in prostate cancer. Although alterations in the canonical Wnt pathway in prostate cancer may have an impact on prognosis, recent studies suggest that the noncanonical Wnt pathway also plays an important role in disease progression and treatment resistance.

Areas covered: We review the literature with regard to the potential prognostic significance of noncanonical Wnt signaling in prostate cancer. After a brief overview of the canonical and noncanonical Wnt pathways, we discuss the preclinical and clinical evidence for activation of Wnt signaling in prostate cancer. We focus on clinical evidence for noncanonical Wnt pathway components to serve as potential prognostic biomarkers.

Expert opinion: Although many therapeutic options are available for men with prostate cancer, there remains an unmet need for prognostic and predictive biomarkers to precisely guide clinical management. Early evidence suggests that components of the noncanonical Wnt pathway may serve as prognostic biomarkers. However, prospective validation studies are necessary before these biomarkers can be routinely applied in the clinic.     

Noncanonical Wnt signaling promotes apoptosis in thymocyte development

The Wnt–β-catenin signaling pathway has been shown to govern T cell development by regulating the growth and survival of progenitor T cells and immature thymocytes. We explore the role of noncanonical, Wnt–Ca²⁺ signaling in fetal T cell development by analyzing mice deficient for Wnt5a. Our findings reveal that Wnt5a produced in the thymic stromal epithelium does not alter the development of progenitor thymocytes, but regulates the survival of αβ lineage thymocytes. Loss of Wnt5a down-regulates Bax expression, promotes Bcl-2 expression, and inhibits apoptosis of CD4⁺CD8⁺ thymocytes, whereas exogenous Wnt5a increases apoptosis of fetal thymocytes in culture. Furthermore, Wnt5a overexpression increases apoptosis in T cells in vitro and increases protein kinase C (PKC) and calmodulin-dependent kinase II (CamKII) activity while inhibiting β-catenin expression and activity. Conversely, Wnt5a deficiency results in the inhibition of PKC activation, decreased CamKII activity, and elevation of β-catenin amounts in thymocytes. These results indicate that Wnt5a induction of the noncanonical Wnt–Ca²⁺ pathway alters canonical Wnt signaling and is critical for normal T cell development.     

Wnt3a转染小鼠胸腺激酶缺陷细胞及对β-连环素蛋白亚细胞分布的影响

背景:Wnt信号通路是动物胚胎发育过程中重要的调控通路,建立Wnt信号通路细胞模型对于研究该通路有重要意义.目的:以Wnt3a真核表达质粒转染小鼠胸腺激酶缺陷细胞,构建能够持续激活Wnt信号通路的体外细胞模型,观察经典Wnt信号通路对β-1连环素蛋白亚细胞分布的影响.方法:将扩增真核表达质粒pgk-Wnt3a-pcDNA3.0进行酶切鉴定.应用脂质体转染技术将真核表达质粒pgk-Wnt3a-pcDNA3.0和对照质粒pgk-neo-pcDNA3.0转染入胸腺激酶缺陷细胞,经过G418筛选后挑出细胞克隆,扩大培养.应用RT-PCR技术检测表达产物,应用间接免疫荧光技术检测Wnt3a对鼠胸腺激酶缺陷细胞β-catenin亚细胞分布的影响.结果与结论:Wnt3a质粒经过酶切鉴定证明所扩增的质粒为目的质粒.经过G418筛选3周后,挑选10个稳定转染的细胞克隆,进行RT-PCR检测,可见在L-Wnt3a细胞的cDNA产生1条长度为320 bp亮带,表明扩增产物为所需要的目的片段,Wnt3a质粒转染胸腺激酶缺陷细胞后有Wnt3a在mRNA转录水平表达.转染对照质粒的胸腺激酶缺陷细胞cDNA未扩增出目的条带.免疫荧光检测可见Wnt3a质粒转染胸腺激酶缺陷细胞后细胞浆中有Wnt3a蛋白表达,转染对照质粒组无表达.Wnt3a质粒转染胸腺激酶缺陷细胞核中可见明亮的红色荧光,提示β-连环素蛋白在胸腺激酶缺陷细胞-Wnt3a细胞聚集并进入细胞核中.转染对照质粒的胸腺激酶缺陷细胞浆未见有明显β-连环素蛋白着色,细胞核中无β-连环素蛋白的聚集.构建了能够持续激活Wnt信号通路的体外细胞模型,真核表达Wnt3a质粒转染胸腺激酶缺陷细胞能够获得稳定表达,促进胸腺激酶缺陷细胞浆中β-连环素蛋白向细胞核转移.     

体外培养大鼠骨髓间充质干细胞向神经元样细胞分化:Wnt3a信号分子的诱导作用

背景:Wnt信号通路是细胞增殖分化的关键调控环节.已有证据显示此通路参与了对神经前体细胞增殖、分化以及决定细胞命运的调控.目前有关Wnt信号通路对间充质干细胞向神经元样细胞分化的作用还少见报道.目的:寻找促进间充质干细胞向神经元样细胞分化的Wnt信号分子.方法:采用密度梯度离心法在体外分离培养SD大鼠股骨间充质干细胞并培养.传代后通过形态学和流式细胞学检测细胞表面标志物CD29、CD44、CD34、CD45,筛选并鉴定培养细胞.采用神经营养因子碱性成纤维细胞生长因子分别联合Wnt3a和Wnt5a诱导方案,通过免疫组化和RT-PCR的方法比较Wnt3a、Wnt5a在间充质干细胞向神经元样细胞分化过程中的作用,以碱性成纤维细胞生长因子单独培养为对照.结果与结论:间充质干细胞经培养、传代后,细胞贴壁生长,形态均一,呈长梭形,流式细胞学检测细胞表面标志物CD29、CD44高表达,CD34、CD45低表达.Wnt3a诱导后细胞巢蛋白、神经元特异性烯醇化酶呈阳性,胶质纤维酸性蛋白无明显表达,诱导后细胞的活力良好;Wnt5a诱导组及对照组巢蛋白呈弱阳性表达,神经元特异性烯醇化酶及胶质纤维酸性蛋白阴性.RT-PCR结果显示,Wnt3a诱导组巢蛋白在诱导前后均有表达,神经元特异性烯醇化酶在诱导后5d可见明显的扩增条带,10d后更加明显;胶质纤维酸性蛋白在诱导10d后有比较弱的扩增条带出现.结果说明Wnt3a分子能够促进体外培养的间充质干细胞向神经元样细胞分化.     

The Wnt signaling pathway regulates Nalm-16 b-cell precursor acute lymphoblastic leukemic cell line survival and etoposide resistance

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common malignancy in children. The Wnt signaling pathway has been found to be extensively involved in cancer onset and progression but its role in BCP-ALL remains controversial. We evaluate the role of the Wnt pathway in maintenance of BCP-ALL cells and resistance to chemotherapy. Gene expression profile revealed that BCP-ALL cells are potentially sensitive to modulation of Wnt pathway. Nalm-16 and Nalm-6 cell lines displayed low levels of canonical activation, as reflected by the virtually complete absence of total β-catenin in Nalm-6 and the β-catenin cell membrane distribution in Nalm-16 cell line. Canonical activation with Wnt3a induced nuclear β-catenin translocation and led to BCP-ALL cell death. Lithium chloride (LiCl) also induced a cytotoxic effect on leukemic cells. In contrast, both Wnt5a and Dkk-1 increased Nalm-16 cell survival. Also, Wnt3a enhanced the in vitro sensitivity of Nalm-16 to etoposide (VP-16) while treatment with canonical antagonists protected leukemic cells from chemotherapy-induced cell death. Overall, our results suggest that canonical activation of the Wnt pathway may exerts a tumor suppressive effect, thus its inhibition may support BCP-ALL cell survival.     

葛根素干预激素诱导骨髓间充质干细胞成脂分化的Wnt信号途径

背景：国内外学者研究证明,激素性股骨头缺血性坏死的发病机制与体内脂质代谢紊乱,尤其是大剂量激素诱导下骨髓间充质干细胞的成脂分化有关。目前葛根素抑制激素诱导骨髓间充质干细胞成脂分化的Wnt信号转导途径还未经证实。〈br〉 目的：观察葛根素干预激素诱导大鼠骨髓间充质干细胞成脂分化过程中 Wnt 信号途径相关基因及关键蛋白β-catenin表达的变化。〈br〉 方法：第3代SD大鼠骨髓间充质干细胞随机分为空白组、激素组、葛根素低、中、高剂量组,5组干预6 d后RT-PCR法检测Wnt/β-catenin信号通路主要成员Wnt10b mRNA、GSK3β mRNA、β-catenin mRNA的表达,Western blot法对β-catenin蛋白的表达进行检测分析。〈br〉 结果与结论：与激素组比较,葛根素各干预组Wnt10b mRNA、β-catenin mRNA及β-catenin蛋白的表达水平均显著升高;GSK3βmRNA的表达水平显著降低。提示葛根素对激素诱导骨髓间充质干细胞成脂分化的抑制作用可能是通过调节信号通路的Wnt10b mRNA、GSK3βmRNA、β-catenin mRNA及β-catenin蛋白的表达来实现的。葛根素防治激素性股骨头缺血坏死的机制不仅是改善股骨头局部的微循环,同时还与其抑制激素诱导下骨髓间充质干细胞的成脂分化有关。     

Wnt信号通路与常染色体显性多囊肾病发病关系的研究进展

Wnt信号通路是一条保守的信号途径,其生物学效应非常广泛,对细胞的黏附、迁移、增殖和凋亡具有调控作用,与多种疾病的发生发展均有关系。近年研究发现,在常染色体显性多囊肾病的发病过程中,Wnt信号通路扮演着非常重要的角色。本文就Wnt信号通路与常染色体显性多囊肾病发病的研究进展做一综述。     

Wnt3a促进大鼠骨髓间充质干细胞向神经元样细胞的分化

背景:Wnt信号通路是细胞增殖分化的关键调控环节,但与骨髓间充质干细胞神经分化的联系并不十分明确.目的:寻找促进骨髓间充质干细胞向神经元样细胞分化的Wnt信号分子.方法:首先体外分离培养大鼠骨髓间充质干细胞并传代,行形态学观察,并以流式细胞学方法检测细胞表型CD44,CD9,CD34和CD45.采用碱性成纤维细胞生长因子分别联合Wnt3a或Wnt5a的方案诱导分化,应用免疫组化和反转录-聚合酶链反应方法比较Wnt3a和Wnt5a对骨髓间充质干细胞向神经元样细胞分化的影响.结果与结论:骨髓间充质干细胞为长梭形,CD9,CD44高表达,CD34,CD45低表达.Wnt3a诱导组的巢蛋白和神经元特异烯醇化酶呈阳性,而胶质纤维酸性蛋白无明显表达,诱导后细胞的活力良好.Wnt5a诱导组巢蛋白呈弱阳性表达,而神经元特异烯醇化酶及胶质纤维酸性蛋白阴性.反转录-聚合酶链反应结果显示,Wnt3a诱导组巢蛋白在诱导前后均有表达,神经元特异烯醇化酶在诱导后5 d可见明显的扩增条带,10 d后更加明显.胶质纤维酸性蛋白在诱导10 d后出现较弱的扩增条带.Wnt5a组、对照组骨髓间充质干细胞在诱导后10 d巢蛋白有微弱表达,神经元特异烯醇化酶和胶质纤维酸性蛋白几乎无表达.提示Wnt3a分子能够促进体外培养的骨髓间充质干细胞向神经元样细胞分化.     

姜黄素通过新型蛋白激酶-θ亚型抑制大鼠海马神经元中通道的研究

目的探讨姜黄素对Ca2+通道电流的选择性抑制作用。方法使用10 mmol/L的钡离子作为电荷载体,利用膜片钳技术记录大鼠海马神经元的全细胞电流;免疫印迹法检测大鼠海马神经元中蛋白激酶C(PKC)的分型;进行全细胞膜片钳技术分析。结果姜黄素浓度依赖性抑制高电压门控Ca2+通道电流(IBa),姜黄素对Ca2+型通道的激活无显著影响,但能够使Ca2+通道的失活曲线向超极化方向移动;此外,在体外培养的大鼠海马神经元中,细胞内应用PKC-θ的抑制肽PKC-θ-IP,能消除黄素诱导抑制的作用;新型PKC-δ、PKC-ε和PKC-θ,但不包括PKC-η在神经元中内源性表达。结论姜黄素在大鼠海马神经元中通过新型的PKC-θ依赖途径抑制IBa,这个结论可能有利于证明姜黄素的神经保护作用。     

沉默wee1基因对卵巢癌细胞增殖、迁移和侵袭的作用机制

目的探讨沉默wee1基因对卵巢癌细胞增殖、迁移和侵袭的作用机制。方法将卵巢癌细胞分为Blank组、小干扰RNA(siRNA)阴性对照(siRNA-NC)组和携带wee1基因片段(siRNA-wee1)组,利用siRNA技术在卵巢癌细胞中沉默wee1基因,采用实时荧光定量PCR、免疫印迹法(WB)检测3组卵巢癌细胞wee1 RNA及蛋白表达水平,采用细胞划痕试验、Transwell试验观察卵巢癌细胞平板集落形成数及卵巢癌细胞迁移、侵袭能力,采用WB观察卵巢癌细胞Wnt/β-catenin信号通路相关蛋白Wnt3a、β-连环蛋白(β-catenin)、细胞周期蛋白D1(Cyclin-D1)、基质金属蛋白酶7(MMP-7)的表达情况。结果siRNA-wee1组卵巢癌细胞wee1 RNA和蛋白表达水平均低于siRNA-NC组和Blank组(P<0.05),卵巢癌细胞集落形成数少于Blank组和siRNA-NC组(P<0.05),卵巢癌细胞迁移、侵袭能力低于Blank组和siRNA-NC组(P<0.05),Wnt/β-catenin信号通路相关蛋白Wnt3a、β-catenin、Cyclin-D1和MMP-7表达水平均低于siRNA-NC组和Blank组(P<0.05)。结论沉默wee1基因可抑制Wnt/β-catenin信号通路的激活,进而抑制卵巢癌细胞增殖、迁移和侵袭能力。     

The role of Wnt signaling in skin fibrosis

Skin fibrosis is the excessive deposition of extracellular matrix in the dermis. Cutaneous fibrosis can occur following tissue injury, including burns, trauma, and surgery, resulting in scars that are disfiguring, limit movement and cause significant psychological distress for patients. Many molecular pathways have been implicated in the development of skin fibrosis, yet effective treatments to prevent or reverse scarring are unknown. The Wnt signaling pathways are known to play an important role in skin homeostasis, skin injury, and in the development of fibrotic skin diseases. This review provides a detailed overview of the role of the canonical Wnt signaling pathways in regulating skin scarring. We also discuss how Wnt signaling interacts with other known fibrotic molecular pathways to cause skin fibrosis. We further provide a summary of the different Wnt inhibitor types available for treating skin scarring. Understanding the role of the Wnt pathway in cutaneous fibrosis will accelerate the development of effective Wnt modulators for the treatment of skin fibrosis.     

Wnt信号通路在足细胞中的作用和调节机制

Wnt信号通路在细胞的分化、增殖和凋亡等生理过程中以及在细胞癌变、肿瘤侵袭等病理过程中均发挥了重要的调控作用。最近研究显示,Wnt信号通路在肾脏疾病发展和上皮细胞特化中起重要作用,在损伤等不同的疾病条件下该通路被激活。基因修饰动物模型研究表明,在足细胞中Wnt信号通路持续激活通常与蛋白尿和肾小球硬化的进展有关。本文就Wnt信号在足细胞中的作用和调节机制作一综述。     

CircKRT17与miR-485-5p互作调控Wnt/β-catenin通路影响胃癌发生发展的机制研究

目的探讨circ KRT17在胃癌中的表达水平,并对circ KRT17在胃癌中的临床意义、生物学功能及内在机制进行评价。方法 2013年5月至2018年3月获得67例临床胃癌样本和对应的癌旁正常组织标本,并采用qRTPCR检测circ KRT17在胃癌组织和不同胃癌细胞株中的表达情况;分析circ KRT17的表达与胃癌患者临床病理学特征之间的关系;CKK-8法和平板克隆实验检测circ KRT17对胃癌细胞增殖能力的影响;Transwell实验检测circ KRT17对胃癌细胞迁移和侵袭能力的影响;裸鼠成瘤实验检测circ KRT17对胃癌细胞肿瘤异种移植的影响;荧光素酶报告基因检测circ KRT17与miR-485-5p以及miR-485-5p与Wnt3a之间的相互作用。结果 circ KRT17在胃癌组织中表达上调,与肿瘤分期、转移及患者预后不良密切相关。此外,降低circ KRT17表达显著抑制了胃癌细胞的增殖、迁移和侵袭,诱导了细胞凋亡。体内实验显示,敲低circ KRT17表达抑制肿瘤生长。机制上,研究发现circ KRT17作为miR-485-5p的海绵,增加Wnt3a的表达,从而激活Wnt/β-catenin信号。结论 circ KRT17/miR-485-5p/Wnt3a/β-catenin信号对胃癌的发生、发展至关重要。     

Wnt信号通路与卵巢癌治疗新进展

Wnt通路是一条高度保守的传导通路,Wnt信号通路异常激活与肿瘤发生发展有密切关系。近年来,不少研究证明卵巢癌中存在异常激活的Wnt通路信号蛋白。该文复习了卵巢癌与Wnt通路相关的新近研究进展,对Wnt信号通路、其在卵巢癌发生发展的作用及Wnt通路中潜在的卵巢癌治疗新靶点做一综述,旨在为卵巢癌的临床治疗提供新思路。     

MCF-7 breast cancer cells transfected with protein kinase C-alpha exhibit altered expression of other protein kinase C isoforms and display a more aggressive neoplastic phenotype.

Increased protein kinase C (PKC) activity in malignant breast tissue and positive correlations between PKC activity and expression of a more aggressive phenotype in breast cancer cell lines suggest a role for this signal transduction pathway in the pathogenesis and/or progression of breast cancer. To examine the role of PKC in the progression of breast cancer, human MCF-7 breast cancer cells were transfected with PKC-alpha, and a group of heterogenous cells stably overexpressing PKC-alpha were isolated (MCF-7-PKC-alpha). MCF-7-PKC-alpha cells expressed fivefold higher levels of PKC-alpha as compared to parental or vector-transfected MCF-7 cells. MCF-7-PKC-alpha cells also displayed a substantial increase in endogenous expression of PKC-beta and decreases in expression of the novel delta- and eta-PKC isoforms. MCF-7-PKC-alpha cells displayed an enhanced proliferative rate, anchorage-independent growth, dramatic morphologic alterations including loss of an epithelioid appearance, and increased tumorigenicity in nude mice. MCF-7-PKC-alpha cells exhibited a significant reduction in estrogen receptor expression and decreases in estrogen-dependent gene expression. These findings suggest that the PKC pathway may modulate progression of breast cancer to a more aggressive neoplastic process.     

Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism

Adhesion of myeloma cells to bone marrow stromal cells is now considered to play a critical role in chemoresistance. However, little is known about the molecular mechanism governing cell adhesion-mediated drug resistance (CAM-DR) of myeloma cells. In this study, we focused our interests on the implication of the Wnt signal in CAM-DR. We first screened the expression of Wnt family in myeloma cell lines and found that Wnt3 was overexpressed in all the myeloma cells examined. KMS-5 and ARH77, which highly expressed Wnt3 protein, tightly adhered to human bone marrow stromal cells, and accumulation of beta-catenin and GTP-bounded RhoA was observed in these myeloma cell lines. Conversely, RPMI8226 and MM1S, which modestly expressed Wnt3 protein, rather weakly adhered to human bone marrow stromal. We then examined the relevance of Wnt3 expression to adhesive property to stromal cells and to CAM-DR of myeloma cells. KMS-5 and ARH-77 exhibited apparent CAM-DR against doxorubicin. This CAM-DR was significantly reduced by anti-integrin beta(1) antibody, anti-integrin alpha(6) antibody and a Wnt-receptor competitor, secreted Frizzled-related protein-1, and Rho kinase inhibitor Y27632, but not by the specific inhibitor of canonical signaling (Dickkopf-1), indicating that Wnt-mediated CAM-DR that is dependent on integrin alpha(6)/beta(1) (VLA-6)-mediated attachment to stromal cells is induced by the Wnt/RhoA/Rho kinase pathway signal. This CAM-DR was also significantly reduced by Wnt3 small interfering RNA transfer to KMS-5. These results indicate that Wnt3 contributes to VLA-6-mediated CAM-DR via the Wnt/RhoA/ROCK pathway of myeloma cells in an autocrine manner. Thus, the Wnt3 signaling pathway could be a promising molecular target to overcome CAM-DR of myeloma cells.     

Wnt信号通路在脑血管粥样硬化中的研究进展

目前,颅内动脉瘤、脑血管狭窄等脑血管疾病已经成为威胁人类健康的隐患之一。血管粥样硬化是一系列脑血管疾病的发病基础。近年来,越来越多的研究证实,Wnt信号通路广泛参与脑血管粥样硬化的发生。因此,本文对Wnt信号通路在血管内皮细胞、巨噬细胞和平滑肌细胞功能障碍中的作用进行总结,以探讨Wnt信号通路在脑血管粥样硬化发生发展中的作用机制,为脑血管疾病的研究提供新方向。     

高压氧对大鼠骨髓间充质干细胞分化和Wnt3表达的影响

背景:高压氧治疗可以促进缺氧缺血性脑损伤新生大鼠内源性神经干细胞的增殖和分化,且其机制与Wnt信号通路的活化有关,但在体外高压氧对干细胞分化的影响是否也通过Wnt信号通路起作用目前尚未见相关报道.目的:观察高压氧对大鼠骨髓间充质干细胞分化的影响,认识其相关机制.方法:全骨髓法分离培养大鼠骨髓间充质干细胞,贴壁纯化,取传至第3～5代细胞,加入含bFGF,EGF,B27的DMEM/F12培养基诱导培养24 h.诱导后细胞随机分为2组,对照组未做任何处理,高压氧组给予0.10 MPa的压力治疗,稳压时间60min,稳压期间平均氧浓度不低于90%.免疫荧光染色检测巢蛋白、NSE,GFAP,04等抗体的表达,Western-blot法检测Wnt3蛋白的表达.结果与结论:骨髓间充质干细胞用神经干细胞经典培养基诱导后巢蛋白呈阳性表达.与对照组比较,高压氧组NSE,04阳性细胞分化率均最著增加(P＜0.01),GFAP阳性细胞分化率无明显差异(P＞0.05),Wnt3蛋白的表达明显升高(P＜0.05).高压氧可以促进骨髓间充质干细胞向神经元细胞和少突胶质细胞分化,但对星形胶质细胞的分化无明显影响,其机制可能与Wnt3蛋白的活化有关.     

胶质瘤中Wnt5a介导的非经典Wnt通路的异常表达

目的探讨Wnt家族分泌性相关蛋白(Wnt5a)介导的非经典Wnt通路在胶质瘤中是否存在异常表达及其在胶质瘤中的意义,并通过在体外培养的胶质瘤细胞系中上调或下调Wnt5a的活性,观察胶质瘤细胞的增殖、侵袭等变化。方法自2009年5月至2012年9月收集手术切除的胶质瘤组织标本56例,正常脑组织8例。56例胶质瘤标本均进行HE染色,常规病理检查并进行分类,运用激光共聚焦显微镜观察Ca+内流的变化,运用RT-PCR、免疫组化、蛋白质印迹法(Western blot)检测(β-cetenin)和细胞周期蛋白D1(cyclin D1)的表达变化。结果 Wnt5a在胶质瘤中表达与正常脑组织相比差异有统计学意义(P<0.001);外源性Wnt5a能够促进胶质瘤细胞Ca+内流、显著下调胶质瘤细胞中cyclin D1的表达,差异有统计学意义(P<0.05);外源性Wnt5a能够下调胶质瘤细胞中β-cetenin的表达,但下调差异无统计学意义(P>0.05)。结论胶质瘤中Wnt5a表达有所上调,但外源性Wnt5a可以激活胶质瘤细胞的非经典Wnt通路,促进Ca+内流,进一步影响到Wnt/β-catenin途径。     

NEP1-40对缺氧缺血性脑病新生大鼠的Wnt信号通路胞增殖的调控作用

目的探讨Nogo-A受体拮抗剂NEP1-40对Wnt信号通路和神经细胞增殖的调控作用。方法 40只大鼠被均分为HIBD(缺氧缺血性脑损伤)组和HIBD+NEP1-40组,采用PCR定量、Western blot分析、细胞增殖的免疫组化试验、8-异前列腺素评估等检测分析缺氧缺血性脑病新生大鼠的修复过程中Wnt信号通路中NgR的转录因子调控与神经细胞增殖。结果NEP1-40处理后,c Jun和c-Myc的表达在蛋白水平上调,基因表达水平上调,Ki-67增加,8-异前列腺素无显著变化。结论通过抑制NgR后发现,c-Jun和c-Myc是Wnt通路的主要转录因子,同时脑室下区神经细胞的增殖增加。