γ-突触核蛋白与肿瘤关系的研究进展

Synucleins家族是一种主要在神经元内表达的高度可溶性的蛋白家族。已知synucleins家族有3个成员α-synuclein(SNCA),β-synuclein(SNCB)和γ-synuclein(SNCG)。其中SNCA与SNCB参与神经递质释放过程,被认为与神经退行性变疾病密切相关,特别是在阿尔茨海默病与帕金森病中常有异常表达。近年来研究表明,SNCG在人类许多肿瘤中过表达,如乳腺癌、结直肠癌、女性生殖系统肿瘤、前列腺癌、膀胱癌等。通过研究表明γ-Synucleins异常表达机制目前包括DNA甲基化、激动蛋白-1激活、对转录因子SP1结合位点、有丝分裂检验点基因、雌激素受体影响。通过以上机制,SNCG促进上述肿瘤细胞的增殖、抑制肿瘤细胞的凋亡以及促进肿瘤细胞的转移。根据文献分析,我们提出SNCG可作为多种肿瘤预后的潜在指标的可能,同时以SNCG为切入点,探讨神经系统是否可以对肿瘤发生、发展的影响作用。     

SNCG基因与肿瘤的关系

由human γ-synuclein基因(SNCG)编码的蛋白-γ突触核蛋白(γ synuclein)为天然无折叠蛋白,是公认的乳腺癌分子标记物,且在多种肿瘤中检测到高表达.其对乳腺癌细胞有促生长和转移的作用,可干扰细胞有丝分裂开关激酶与微管启动蛋白的结合,促使肿瘤细胞耐受抗微管化疗药物.在体外试验中使用干扰γ突触核蛋白功能的多肽后,可提高化疗效果.另外还发现γ突触核蛋白能与热激蛋白(HSP)结合,进而激活雌激素受体α(ER-α)的转录活性,可能为激素相关性肿瘤增殖机制之一.     

胆管癌组织中SNCG的表达及其临床意义(英文)

目的:观察γ-synuclein(SNCG)在胆管癌和正常胆管组织中的表达,并探讨其在胆管癌发生、发展中的临床意义。方法:采用免疫组化方法检测SNCG蛋白在72例胆管癌组织及41例胆管正常组织中的表达水平,并分析其与胆管癌临床病理特征的关系。结果:SNCG蛋白在胆管癌组织中的阳性表达率为73.61%(53/72),高于其在胆管正常组织中的阳性表达率(4.88%,2/41),其差异有统计学意义(P0.01)。SNCG蛋白的表达与肿瘤的淋巴结转移相关(P0.01),但与患者的年龄、性别及肿瘤分化程度无关(P0.05)。结论:SNCG蛋白的表达与胆管癌的发生、发展正相关,并对胆管癌的浸润转移发挥重要的促进作用。对SNCG蛋白的研究将可能为胆管癌的早期诊断提供新的肿瘤标志物,并为胆管癌的预后判断和诊治提供重要理论依据。     

IAP家族分子与肿瘤靶向治疗

凋亡抑制因子(inhibitor of apoptosis proteins,IAPs)是一类高度保守的内源性抗细胞凋亡因子家族,主要通过抑制Caspase活性和参与调节核因子NF-κB的作用而抑制细胞凋亡。细胞抗凋亡机制在肿瘤发生、发展以及肿瘤耐药性形成中发挥重要作用。肿瘤细胞高表达IAPs是导致肿瘤细胞抵抗凋亡的关键。细胞凋亡调控异常与肿瘤细胞耐药密切相关,增强肿瘤细胞对化疗药物的敏感性成为近年来肿瘤治疗的重要策略之一。该文综述了IAP家族蛋白的结构、生物学特性及其作为肿瘤治疗靶点的研究进展。     

GALNT14与肿瘤

在过去的一个多世纪,许多肿瘤标志物被发现,其中包括多肽N-乙酰半乳糖胺基转移酶(polypeptide N-acetylgalactosaminyltransferase,ppGALNAc-T,简称GALNT)家族中的多个成员。GALNT家族是催化黏蛋白O-糖基化修饰的起始酶,其能够影响黏蛋白的O-糖基化,从而影响肿瘤细胞的发生、预后、增殖与迁移等。GALNT14是该家族中最新发现的成员之一,近年的研究发现,GALNT14在多种肿瘤中表达异常,并与肿瘤细胞的发生、侵袭、转移和凋亡等有关。本文主要对GALNT14蛋白的结构特点及其在肿瘤中的作用进行综述,为进一步研究GALNT14与肿瘤发病机制的关系以及作为潜在的药物靶点提供参考。     

埃兹蛋白:生物学特征及其在肿瘤转移中的作用

埃兹蛋白(ezrin)是埃兹蛋白、根蛋白和膜突蛋白(ezrin-radixin-moesin,ERM)家族成员之一,主要参与上皮细胞中细胞骨架与胞膜之间的连接,具有维持细胞形态和运动、连接黏附分子及调节信号转导等功能。近年来的研究发现,埃兹蛋白在肿瘤细胞中的表达异常,提示其在肿瘤的浸润、转移机制中发挥重要作用。     

精子相关抗原4的功能及其在疾病中的作用

精子相关抗原4(sperm associated antigen 4,SPAG4)是SUN(Sad-1,UNC-84)蛋白家族成员。近年来的研究发现,SPAG4可以维持精子头部结构的完整性,参与精子尾部发育,其功能异常可导致雄性不育。此外,SPAG4 mRNA在多种肿瘤细胞中表达,是一种潜在的肿瘤标志物。对肾透明细胞癌的最新研究发现,SPAG4表达增高将促进肿瘤细胞的增殖和侵袭,其表达受缺氧诱导因子1(hypoxia inducible factor 1,HIF-1)调控。对SPAG4功能的深入研究,将有助于阐明男性不育的分子机制并为研究肿瘤的发生发展提供新的候选靶标。     

SNCA基因在酒精依赖遗传机制中的研究进展

SNCA 基因定位于酒精依赖数量性状位点之上, 其编码的蛋白-α-synuclein 可以在多个水平上调节多巴胺的功能, 而后者是酒精依赖中重要的神经递质。研究还发现酒精依赖者SNCA 基因存在多处基因变异, 同时, 酒精依赖者SNCA 基因的表达水平也存在显著增高, 并且增高的程度与酒精依赖程度密切相关, 因此, SNCA 基因被认为参与酒精依赖的遗传机制。文章对SNCA 基因与多巴胺的关系和酒精依赖者SNCA 基因变异以及基因表达的研究进展做一综述。     

促进或抑制α-synuclein蛋白异常聚集的相互作用蛋白质

α-synuclein蛋白的异常聚集在共核蛋白病的发病过程中起到了关键性作用。与α-synuclein相互作用的蛋白质对其异常聚集起着不同的调节作用,有的蛋白质(如:蛋白synphilin-1、微管蛋白、A-β肽等)会促进α-synuclein蛋白的异常聚集,而另外一些蛋白质(如:膜联蛋白A5、基于自识别元素设计的小肽等)却能够抑制α-synuclein蛋白的异常聚集。认识与α-synuclein相互作用的蛋白,并研究其作用位点,是从分子水平上理解α-synuclein蛋白质异常聚集、揭示共核蛋白病致病机制,以及设计新药物的基础。分子动力学模拟为开展这方面研究开辟了新的途径。文章对该领域的研究进展进行了综述。     

核纤层蛋白B1的功能及其在神经系统疾病和肿瘤中的研究新进展

核纤层蛋白B1 (Lamin B1)是核纤层蛋白家族重要成员之一,其主要功能在于维持细胞核骨架完整性,并通过影响染色体分布、基因表达及DNA损伤修复等参与细胞的增殖和衰老。其表达异常与多种疾病有关,如神经系统疾病(神经管畸形,ADLD)及肿瘤(胰腺癌)等,是潜在的药物靶点和肿瘤标志物。对Lamin B1功能的深入研究,将有助于对相关神经系统疾病和肿瘤发生发展的分子机制的了解并为治疗靶点研究提供新方向。     

The Reciprocal Regulation of γ-Synuclein and IGF-I Receptor Expression Creates a Circuit That Modulates IGF-I Signaling

Insulin-like growth factor (IGF) system plays important roles in carcinogenesis and maintenance of the malignant phenotype. Signaling through the IGF-I receptor (IGF-IR) has been shown to stimulate the growth and motility of a wide range of cancer cells. γ-Synuclein (SNCG) is primarily expressed in peripheral neurons but also overexpressed in various cancer cells. Overexpression of SNCG correlates with tumor progression. In the present study we demonstrated a reciprocal regulation of IGF-I signaling and SNCG expression. IGF-I induced SNCG expression in various cancer cells. IGF-IR knockdown or IGF-IR inhibitor repressed SNCG expression. Both phosphatidylinositol 3-kinase and mitogen-activated protein kinase were involved in IGF-I induction of SNCG expression. Interestingly, SNCG knockdown led to proteasomal degradation of IGF-IR, thereby decreasing the steady-state levels of IGF-IR. Silencing of SNCG resulted in a decrease in ligand-induced phosphorylation of IGF-IR and its downstream signaling components, including insulin receptor substrate (IRS), Akt, and ERK1/2. Strikingly, SNCG physically interacted with IGF-IR and IRS-2. Silencing of IRS-2 impaired the interaction between SNCG and IGF-IR. Finally, SNCG knockdown suppressed IGF-I-induced cell proliferation and migration. These data reveal that SNCG and IGF-IR are mutually regulated by each other. SNCG blockade may suppress IGF-I-induced cell proliferation and migration. Conversely, IGF-IR inhibitors may be of utility in suppressing the aberrant expression of SNCG in cancer cells and thereby block its pro-tumor effects.     

gamma-synuclein has a dynamic intracellular localization

gamma-Synuclein is a member of the synuclein family consisting of three proteins. Within the last several years increasing attention has focused on these proteins because of their role in human diseases. alpha-Synuclein relevance to Parkinson's disease is based on mutations found in familial cases of the disease and its presence in filaments and inclusion bodies in sporadic cases. gamma-Synuclein is implicated in some forms of cancer and ocular diseases, while beta-synuclein may antagonize their pathological functions. In this paper we present data on the localization and properties of gamma-synuclein in several neuronal and nonneuronal cell cultures. We show that contrary to the current opinion, gamma-synuclein is not an exclusively cytoplasmic protein, but has a dynamic localization and can associate with subcellular structures. It is present in the perinuclear area and may be associated to centrosomes. On late steps of mitosis gamma-synuclein is not found in the centrosomes, and redistributes to the midbody in telophase. Under stress conditions a translocation of gamma-synuclein from the perinuclear area to the nucleus occurs exhibiting nucleocytoplasmic shuttling. gamma-Synuclein overexpression reduces neurite outgrowth in a greater extent then alpha-synuclein overexpression. These data support the view that gamma-synuclein may change its intracellular localization and associate with subcellular structures in response to intracellular signaling or stress.     

Proteomic analysis of membrane rafts of melanoma cells identifies protein patterns characteristic of the tumor progression stage

The molecular mechanisms controlling the progression of melanoma from a localized tumor to an invasive and metastatic disease are poorly understood. In the attempt to start defining a functional protein profile of melanoma progression, we have analyzed by LC-MS/MS the proteins associated with detergent resistant membranes (DRMs), which are enriched in cholesterol/sphingolipids-containing membrane rafts, of melanoma cell lines derived from tumors at different stages of progression. Since membrane rafts are involved in several biological processes, including signal transduction and protein trafficking, we hypothesized that the association of proteins with rafts can be regulated during melanoma development and affect protein function and disease progression. We have identified a total of 177 proteins in the DRMs of the cell lines examined. Among these, we have found groups of proteins preferentially associated with DRMs of either less malignant radial growth phase/vertical growth phase (VGP) cells, or aggressive VGP and metastatic cells suggesting that melanoma cells with different degrees of malignancy have different DRM profiles. Moreover, some proteins were found in DRMs of only some cell lines despite being expressed at similar levels in all the cell lines examined, suggesting the existence of mechanisms controlling their association with DRMs. We expect that understanding the mechanisms regulating DRM targeting and the activity of the proteins differentially associated with DRMs in relation to cell malignancy will help identify new molecular determinants of melanoma progression.     

TP53: an oncogene in disguise

The standard classification used to define the various cancer genes confines tumor protein p53 (TP53) to the role of a tumor suppressor gene. However, it is now an indisputable fact that many p53 mutants act as oncogenic proteins. This statement is based on multiple arguments including the mutation signature of the TP53 gene in human cancer, the various gains-of-function (GOFs) of the different p53 mutants and the heterogeneous phenotypes developed by knock-in mouse strains modeling several human TP53 mutations. In this review, we will shatter the classical and traditional image of tumor protein p53 (TP53) as a tumor suppressor gene by emphasizing its multiple oncogenic properties that make it a potential therapeutic target that should not be underestimated. Analysis of the data generated by the various cancer genome projects highlights the high frequency of TP53 mutations and reveals that several p53 hotspot mutants are the most common oncoprotein variants expressed in several types of tumors. The use of Muller''s classical definition of mutations based on quantitative and qualitative consequences on the protein product, such as ‘amorph'', ‘hypomorph'', ‘hypermorph'' ‘neomorph'' or ‘antimorph'', allows a more meaningful assessment of the consequences of cancer gene modifications, their potential clinical significance, and clearly demonstrates that the TP53 gene is an atypical cancer gene.     

microRNA-378 与肿瘤血管生成的研究进展

微小RNA(MicroRNAs,mi RNAs)是真核生物中一类长度约为21到23个核苷酸的非编码小分子单链RNA。mi RNA通过与靶m RNA 3′UTR(3′-untranslated region,3′非编码区)完全或不完全结合,抑制翻译或直接诱导其降解,发挥转录后负调控作用。mi RNA参与机体多种生理和病理过程,且可通过调控其靶标基因参与各种信号通路,影响血管生成。mi R-378属于诸多mi RNAs中的一种。目前已知mi R-378的研究主要集中在肿瘤发生及血管生成、心血管疾病和脑缺血等病理过程,其中与肿瘤发生及血管生成相关研究居多。mi R-378在不同肿瘤中的发挥的作用也不一样,在脑胶质瘤,肺癌,横纹肌肉瘤等肿瘤中发挥促癌基因的作用,在卵巢癌,胃癌,大肠癌等肿瘤中发挥抑癌基因的作用。但是,mi R-378调节肿瘤血管生成的作用机制还有待于深入研究。本文主要对mi R-378在四种肿瘤(脑胶质瘤、肺腺癌、卵巢癌和横纹肌肉瘤)中调控血管生成的相关性研究进展进行综述,以期为这些疾病的治疗和预防提供一种新的思路。     

CD147 与MMPs、VEGF在肿瘤发生发展中相互作用的研究进展

细胞外基质金属蛋白酶诱导因子(CD147)是一种高度糖基化的跨膜蛋白,属于免疫蛋白超家族成员。CD147 为多功能型蛋 白，可以参与人体的多种病理生理机制，其通过调节血管内皮生长因子（VEGF）和基质金属蛋白酶（MMPs）的表达参与恶性肿瘤的新生血管的生成及多重耐药性的产生。近年来随着对CD147 在肿瘤发生发展中的研究不断深入，越来越多的发现使得CD147在肿瘤进展中的作用日益凸显。已经明确了其对肿瘤的进展及治疗的作用，在多种肿瘤中高表达，并随着肿瘤的恶性程度增高而 增加，可以作为某些恶性肿瘤治疗的靶点。然而，CD147 其他的功能包括充当T 细胞的活化剂、神经识别分子和受体伴侣亲环素A的生理和病理机制还未明确。因此，有必要探索CD147 在肿瘤中的特定功能，并阐明其产生机制是至关重要的。在此研究的基础上，现就CD147 与MMPs、VEGF之间相互作用对肿瘤的转移和浸润的影响作一综述。     

Yet another polymorph of α-synuclein: solid-state sequential assignments

Parkinson’s disease is a neurological human proteinopathy, which is caused by the accumulation of protein aggregates of high molecular mass. α-Synuclein is a major component of these fibrillar, β-sheet rich, insoluble assemblies and is deposited in the form of amyloids. Structural characterization of amyloids is possible by solid-state NMR, although no atomic-resolution structure is available as of today. α-Synuclein, as many other pathology-related fibril-forming proteins, can form a number of different polymorphs that are sometimes tricky to obtain in pure form. Here, we describe the chemical shifts and secondary structure analysis of a polymorph that also adopts mainly β-sheet conformation, with a fibrillar core ranging from residues 38 to 94. In addition, residues 15–20 from the N-terminus found to be part of a rigid ordered β-sheet. The chemical shifts differ substantially from the polymorph we previously assigned.