NDRG1的功能及其与癌症的关系

细胞生长、分化和多种应激的情况都可以影响NDRGI（N-myc downstream-rvgulatcd gene 1）蛋白的表达水平。NDRG1在许多细胞的正常生理功能中起着重要作用。NDRG1的缺乏可能导致多种疾病,如．碡D型CMTD（夏-马-图三氏病进行性神经性肌萎缩,Charcot-Marie-Toothdisease）的发生与施万细胞中NDRG1的缺失有关。在多种癌细胞系中。NDRG1的转录和翻译与肿瘤的分化和转移有关。在缺氧环境中。NDRG1的表达水平上调,而且在许多肿瘤细胞中都存在缺氧的现象,这使得NDRG1与缺氧和癌症之间存在着复杂的关系。NDRGI与癌症的关系使得NDRG1可能作为肿瘤演进的标识和癌症诊断的辅助工具。     

紫杉醇对人肝癌SMMC7721细胞NDRG1表达及增值的影响

旨在探索紫杉醇对人肝癌SMMC7721细胞NDRG1表达的影响,及紫杉醇对肝癌SMMC7721细胞系增殖的抑制作用。分别提取紫杉醇处理前后SMMC7721细胞的RNA,进行逆转录-聚合酶链反应(RT-PCR),判断紫杉醇处理前后肝癌细胞中NDRG1表达的情况;采用蛋白印迹技术(Western blotting)分析紫杉醇处理前后肝癌细胞中NDRG1蛋白表达的情况;应用不同浓度紫杉醇处理肝癌细胞,以MTT法检测处理前后肝癌细胞的抑制率,流式细胞术(FCM)观察细胞周期变化的况。结果表明紫杉醇处理后的肝癌SMMC7721细胞中NDRG1表达下降,紫杉醇浓度越高,NDRG1表达水平越低,具有浓度依赖性。以MTT法观察紫杉醇对肝癌细胞的抑制作用,试验结果表明不同浓度的紫杉醇处理肝癌SMMC7721细胞后,癌细胞被明显抑制;以流式细胞术观察紫杉醇作用后肝癌SMMC7721细胞周期的变化,结果显示G2-M期细胞比例升高的程度随浓度增高而升高,细胞越来越多地被阻滞在G2-M期,不能继续分裂增殖。分化相关基因NDRG1的表达可能是肝癌的发病机制之一,紫杉醇可抑制肝癌SMMC 7721细胞中NDRG1的表达;同时紫杉醇能使肝癌SMMC7721细胞的生长阻滞在G2-M期,从而显著抑制SMMC7721细胞的增殖,并且具有剂量、时间依赖效应。     

N-myc下游调节基因1在乳腺癌中表达的临床病理意义

目的:探讨N-myc下游调节基因1(N-myc downstream-regulated gene 1,NDRG1)在乳腺癌中表达。方法:收集乳腺癌病例及相应的临床资料包括随访资料,应用免疫组织化学技术检测良性病变(BBD)47例,无淋巴结转移乳腺癌(NMBC)83例,有淋巴结转移乳腺癌(MBC)107例及配对淋巴结转移灶(PLNM)107例中NDRG1的表达,分析NDRG1表达与乳腺癌临床病理指标间(患者年龄、肿块大小、临床分期、组织学类型和分级、淋巴结转移、雌孕激素受体和c-erb B2水平、绝经史)及生存状态的关系。结果:通过免疫组化技术检测乳腺癌中NDRG1的表达,结果显示阳性表达率分别为BBD(95.7%,45/47),NMBC(96.4%,80/83),MBC(98.1%,105/107),PMLN(90.7%,97/107),MBC组织中NDRG1阳性表达率显著高于PMLN中阳性表达率(P=0.021)。NDRG1与组织学分级相关(P=0.041),即分化越差的癌表达NDRG1越强。NDRG1的表达状态与乳腺癌患者的生存预后无显著性相关(P=0.196)。结论:NDRG1表达与乳腺癌淋巴结转移和分化有一定关系。     

抑癌基因OVCA1的研究进展

随着肿瘤分子生物学技术及学科的发展,人们认识到癌症是一种基因疾病,肿瘤的发生发展是多种基因参与的复杂过程,包括癌基因的异常激活和肿瘤抑制基因失活。新近分离鉴定的重要的肿瘤抑制基因——卵巢癌基因1(OVCA1)在多种肿瘤中存在高频率的缺失和突变,对多种癌细胞增殖有明显的抑制作用,可能作用于肿瘤发生的早期阶段,在哺乳动物中高度保守,提示在细胞中具有重要作用;OVCA1可能具有调控细胞周期、翻译、DNA损伤及胚胎发育等生物功能,具体作用机制尚不明确;体外研究显示,OVCA1的缺失表达导致肿瘤发生可能与周期蛋白D1上调表达、P16下调表达相关,与p53基因突变可能存在相互作用;OVCA1的缺失表达与卵巢癌发生发展及预后密切相关,与宫颈癌及人乳头瘤病毒感染、乳腺癌等恶性肿瘤的关系尚在研究中。我们简要综述了OVCA1基因的国内外研究进展,为卵巢癌等恶性肿瘤进行基因水平的诊治提供理论依据。     

NDRG2基因启动子甲基化与肺腺癌细胞中mRNA表达相关性的实验研究

目的:探讨肺腺癌细胞中NDRG2基因启动子甲基化状态及其与基因表达的关系。方法:甲基化焦磷酸测序技术检测启动子区域甲基化状态,荧光定量PCR技术检测不同药物浓度下培养细胞中NDRG2基因mRNA的表达水平,分析启动子区域甲基化与基因表达之间的关系。结果:在体外培养细胞中检测到NDRG2基因启动子区域呈现不同程度的甲基化,甲基化频率分别为肺癌A549细胞71.8%、GLC-82细胞86.1%、人脐静脉内皮ECV-304细胞36.8%、胃上皮GES-1细胞42.9%。NDRG2基因mRNA表达与其启动子甲基化程度成反比,甲基转移酶抑制剂5-杂氮-2-脱氧胞苷(5-Aza-CdR)作用于细胞后,A549和GLC-82细胞中NDRG2基因的mRNA转录明显上调,至72 h差异显著(P0.05)。结论:肺腺癌细胞中NDRG2基因启动子CpG岛存在高甲基化,甲基化程度与该基因的表达具有负相关性,5-Aza-CdR能在一定程度上提高NDRG2的转录水平。     

NDRG—1基因表达的影响因素

恶性肿瘤细胞迁移是一个非常重要的临床问题,也是导致癌症患者死亡的主要原因之一。N—myc下游调节基因1（NDRG—J）是近年发现的与细胞分化相关的基因,在阻止肿瘤细胞入侵和迁移,尤其是抑制肿瘤组织生长的过程中扮演着非常重要的角色。该基因可以被多种分化调节剂诱导表达。我们就影响其表达的几个典型因素做简要综述。     

MAT2A与NDRG2基因在结直肠癌中表达情况及临床意义的研究

目的研究MAT2A(甲硫氨酸腺苷转移酶2A)和NDRG2(N-Myc下游调节基因-2)基因在结直肠癌组织中的表达及两者的相关性,为结直肠癌的研究及治疗提供重要参考。方法选取68例术中切除结直肠癌组织及相应的癌旁组织标本,应用RT-PCR(逆转录-聚合酶链式反应)和Western blotting(蛋白质印迹法)检测结直肠癌中MAT2A和NDRG2表达水平。结果结直肠癌中MAT2A和NDRG2mRNA表达情况:MAT2A阳性表达率(66.2%,45/68)高于癌旁组织(7.4%,5/68);NDRG2阳性表达率(36.8%,25/68)低于癌旁组织(91.2%,62/68);两者的表达与患者年龄、性别、肿瘤生长位置等因素均无关,与癌肿临床分期、分化水平及淋巴结转移密切相关。癌肿组织中MAT2A蛋白表达量相较于癌旁组织明显增多(t=39.1152,P=0.0000),而癌肿组织中NDRG2蛋白表达量较癌旁组织明显降低(t=46.5103,P=0.0000);且在结直肠癌组织中两基因的表达可能有相关性(χ~2=7.41,P=0.009)。结论在结直肠癌组织中MAT2A表达增高,NDRG2表达下降,两者与肿瘤的发生发展具有一定相关性,推测可能与DNA甲基化异常有关,但具体机制仍待进一步研究。     

PIWIL1在不同肿瘤细胞中的差异性表达

PIWI作为AGO蛋白家族的成员,在睾丸中特异表达,在精子形成过程中扮演着重要角色.已有文献报道,PIWIL2也广泛存在于多种肿瘤中,与肿瘤的发生相关.本文旨在确定PIWL1在不同肿瘤细胞中的表达差异性,进而初步探讨PIWIL1的表达差异与肿瘤发生发展的关系.半定量RT-PCR和Western 印迹检测多种肿瘤细胞中,PIWIL1在mRNA水平及蛋白水平的表达情况,进一步用免疫组化和免疫荧光检测PIWIL1在细胞中的表达及定位.PIWIL1在多种肿瘤细胞中的表达存在差异,其中一些肿瘤细胞中的表达水平较高,包括卵巢癌,前列腺癌,肝癌,胃癌等细胞.对于肿瘤细胞而言,PIWIL1定位于细胞浆中.因此,PIWIL1在多种肿瘤细胞中的表达差异性可能为肿瘤发生发展的研究提供新的线索.     

NDRG2与癌基因c-Myc和抑癌基因p53的关系

NDRG2基因在多种肿瘤中均低表达或不表达,而过表达NDRG2则能降低肿瘤的恶性程度,这些研究结果表明NDRG2具有肿瘤抑制作用,但是其确切的作用机制尚不是十分清晰。本文通过综述NDRG2与c-Myc和p53的关系,为探究NDRG2抑制肿瘤的确切机制提供线索。     

膜联蛋白A1及其与肿瘤关系的研究进展

膜联蛋白A1 (Annexin A1,ANXA1)是一种来源于脊柱(哺乳)动物的钙依赖性磷脂结合蛋白,是介导细胞内糖皮质激素抗炎作用的效应分子,在组织中广泛表达,参与细胞生长周期的各个阶段.其既可以可溶性形式存在,也可稳定或可逆结合于细胞骨架蛋白,调控细胞与细胞外基质的相互作用.大量的研究发现,AnnexinA1的表达在不同肿瘤组织中有差异,并且同一肿瘤不同类型中表达也不一样,其异常表达及细胞内定位改变可能跟多种恶性肿瘤的分化及转移相关.Annexin A1与肿瘤的密切关系,或许可使其发展为一个新的肿瘤标志物,为肿瘤的早期诊断、治疗及预后提供新的判断标准.因此,探讨Annexin A1与肿瘤的关系极具临床应用前景.     

Differential expression patterns of NDRG family proteins in the central nervous system.

The N-myc downstream-regulated gene (NDRG) family consists of four proteins: NDRG1, NDRG2, NDRG3, and NDRG4 in mammals. NDRG1 has been thoroughly studied as an intracellular protein associated with stress response, cell growth, and differentiation. A nonsense mutation in the NDRG1 gene causes hereditary motor and sensory neuropathy, Charcot-Marie-Tooth disease type 4D. We previously generated Ndrg1-deficient mice and found that they exhibited peripheral nerve degeneration caused by severe demyelination, but that the complicated motor abilities were retained. These results implied that other NDRG family proteins may compensate for the NDRG1 deficiency in the central nervous system. In this study we raised specific antibodies against each member of the NDRG protein family and examined their cellular expression patterns in the mouse brain. In the cerebrum, NDRG1 and NDRG2 were localized in oligodendrocytes and astrocytes, respectively, whereas NDRG3 and NDRG4 were ubiquitous. In the cerebellum, NDRG1 and NDRG4 were localized in Purkinje cells and NDRG2 in Bergmann glial cells. NDRG3 was detected in the nuclei in most cells. These expression patterns demonstrated the cell type-specific and ubiquitous localization of the NDRG family proteins. Each NDRG may play a partially redundant role in specific cells in the brain.     

Association of NDRG1 Gene Promoter Methylation with Reduced NDRG1 Expression in Gastric Cancer Cells and Tissue Specimens

NDRG1 (N-myc downstream-regulated gene 1) plays a role in cell differentiation and suppression of tumor metastasis. This study aims to determine the expression of NDRG1 mRNA and protein in gastric cancer cell lines and tissue specimens and then assess the possible cause of its aberrant expression. Six gastric cancer cell lines and 20 pairs of normal and gastric cancer tissue samples were used to assess NDRG1 expression using Real-time PCR and Western blot. High-resolution melting analysis (HRM) and methylation-specific PCR (MSP) were performed to detect gene mutation and methylation, respectively, in cell lines and tissues samples. Expression of NDRG1 mRNA and protein was downregulated in gastric cancer cell lines and tissues. Specifically, expression of NDRG1 mRNA and protein was lower in all six gastric cancer cell lines than that of normal gastric cells, while 15 out of 20 cases of gastric cancer tissues had the reduced levels of NDRG1 mRNA and protein. HRM data showed that there was no mutation in NDRG1 gene, but MSP data showed high levels of NDRG1 gene promoter methylation in the CpG islands in both cell lines and tissue samples. Moreover, treatment with the DNA methyltransferase inhibitor 5-Aza-2′-deoxycytidine upregulated NDRG1 expression in gastric cancer HGC27 cells, but not in the histone deacetylase inhibitor trichostatin A-treated HGC27 cells. In conclusion, this study has shown that expression of NDRG1 mRNA and protein was reduced in gastric cancer cell lines and tissues, which is due to methylation of NDRG1 gene promoter. Further study will unearth the clinical significance of the reduced NDRG1 protein in gastric cancer.     

NDRG2: a Myc-repressed gene involved in cancer and cell stress

As a master switch for cell proliferation and differentiation, Myc exerts its biological functions mainly through transcrip-tional regulation of its target genes, which are involved in cells' interaction and communication with their external environment. The N-Myc downstream-regulated gene ( NDRG ) family is composed of NDRG1, NDRG2, NDRG3 and NDRG4 , which are important in cell proliferation and differentiation. This review summarizes the recent studies on the structure, tissue distribution and functions of NDRG2 that try to show its significance in studying cancer and its therapeutic potential.     

N-myc down-regulated gene 1 modulates the response of term human trophoblasts to hypoxic injury

The placenta is susceptible to diverse insults during human pregnancy. The expression of the protein N-myc down-regulated gene 1 (NDRG1) is regulated during cell proliferation, differentiation, and in response to stress. Nevertheless, the function of this protein in humans remains unknown. We tested the hypothesis that NDRG1 is up-regulated in hypoxic primary human trophoblasts and that NDRG1 modulates trophoblast response to hypoxia. We initially demonstrated that the expression of NDRG1 is enhanced in primary human trophoblasts exposed to hypoxia. Importantly, we found a similar increase in NDRG1 expression in placental samples derived from either singleton gestations complicated by intrauterine growth restriction or from dizygotic twin gestation where one twin exhibited growth restriction. Having established efficient lentivirus-mediated transfection of primary human trophoblasts, we overexpressed NDRG1 in trophoblasts, which resulted in enhanced trophoblast differentiation. In contrast, lentivirus-driven short interfering RNA-mediated silencing of NDRG1 diminished trophoblast viability and differentiation. Consistent with these results, NDRG1 reduced the expression level of p53 in trophoblasts cultured in standard or hypoxic conditions. Furthermore, NDRG1 expression was regulated by the activity of SIRT1 (Sir2-like protein 1), which promotes cell survival. Together, our data indicate that NDRG1 interacts with SIRT1/p53 signaling to attenuate hypoxic injury in human trophoblasts.     

Ndrg1-deficient mice exhibit a progressive demyelinating disorder of peripheral nerves

NDRG1 is an intracellular protein that is induced under a number of stress and pathological conditions, and it is thought to be associated with cell growth and differentiation. Recently, human NDRG1 was identified as a gene responsible for hereditary motor and sensory neuropathy-Lom (classified as Charcot-Marie-Tooth disease type 4D), which is characterized by early-onset peripheral neuropathy, leading to severe disability in adulthood. In this study, we generated mice lacking Ndrg1 to analyze its function and elucidate the pathogenesis of Charcot-Marie-Tooth disease type 4D. Histological analysis showed that the sciatic nerve of Ndrg1-deficient mice degenerated with demyelination at about 5 weeks of age. However, myelination of Schwann cells in the sciatic nerve was normal for 2 weeks after birth. Ndrg1-deficient mice showed muscle weakness, especially in the hind limbs, but complicated motor skills were retained. In wild-type mice, NDRG1 was abundantly expressed in the cytoplasm of Schwann cells rather than the myelin sheath. These results indicate that NDRG1 deficiency leads to Schwann cell dysfunction, suggesting that NDRG1 is essential for maintenance of the myelin sheaths in peripheral nerves. These mice will be used for future analyses of the mechanisms of myelin maintenance.     

Prognostic significance of NDRG1 expression in oral and oropharyngeal squamous cell carcinoma

Human N-myc downstream-regulated gene 1 (NDRG1) is a metastasis suppressor gene with several potential functions, including cell differentiation, cell cycle regulation and response to hormones, nickel and stress. The purpose of this study was to investigate the immunoexpression of NDRG1 in oral and oropharyngeal squamous cell carcinomas searching for its role in the clinical course of these tumors. We investigated immunohistochemical expression of NDRG1 protein in 412 tissue microarray cores of tumor samples from 103 patients with oral and oropharyngeal squamous cell carcinomas and in 110 paraffin-embedded surgical margin sections. The results showed NDRG1 up-regulation in 101/103 (98.1?%) tumor samples, but no expression in any normal tissue sample. Western blot assays confirmed the immunohistochemical findings, suggesting that lower levels of NDRG1 are associated with a high mortality rate. NDRG1 overexpression was related to long-term specific survival (HR?=?0.38; p?=?0.009), whereas the presence of lymph-node metastasis showed the opposite association with survival (HR?=?2.45; p?=?0.013). Our findings reinforce the idea that NDRG1 plays a metastasis suppressor role in oral and oropharyngeal squamous cell carcinomas and may be a useful marker for these tumors.     

Global Gene Expression Analysis Reveals a Link between NDRG1 and Vesicle Transport

N-myc downstream-regulated gene 1 (NDRG1) is induced by cellular stress such as hypoxia and DNA damage, and in humans, germ line mutations cause Charcot-Marie-Tooth disease. However, the cellular roles of NDRG1 are not fully understood. Previously, NDRG1 was shown to mediate doxorubicin resistance under hypoxia, suggesting a role for NDRG1 in cell survival under these conditions. We found decreased apoptosis in doxorubicin-treated cells expressing NDRG1 shRNAs under normoxia, demonstrating a requirement for NDRG1 in apoptosis in breast epithelial cells under normal oxygen pressure. Also, different cellular stress regimens, such as hypoxia and doxorubicin treatment, induced NDRG1 through different stress signalling pathways. We further compared expression profiles in human breast epithelial cells ectopically over-expressing NDRG1 with cells expressing NDRG1 shRNAs in order to identify biological pathways where NDRG1 is involved. The results suggest that NDRG1 may have roles connected to vesicle transport.