IGF系统的生物学功能及其与肿瘤的关系

胰岛素样生长因子（insulin-like growth factor,IGF)是体内重要的生长因子。它对组织细胞的增殖。分化,凋亡,机体的生长发育及肿瘤的发生发展起重要的调节作用。IGF系统的组成包括;IGF-Ⅰ,IGF-Ⅱ,IGF-ⅠR,IGF-ⅡR,IGFBP家族,IGF促增殖,促生长的活性主要由IGF-IR介导;IGF-ⅡR的主要作用是清除游离IGF-Ⅱ,调节IGF-Ⅱ的水平,IGFBP1-6是IGFs活性的调节因子。近年的研究表明它们也有不依赖IGF的生物活性。     

牙鲆变态中IGF-I基因表达及甲状腺激素对其的调节作用

胰岛素样生长因子(Insulin-like growth factors,IGFs)是一类具有胰岛素样代谢和促有丝分裂功能的蛋白质,参与脊椎动物的胚胎发育、生长和生殖。IGF系统包括两个配体(IGF-Ⅰ、IGF-Ⅱ)、IGF受体(IGF-I receptor,IGF-I R;IGF-II receptor,IGF-ⅡR)以及IGF结合蛋白(IGF binding     

IGF-Ⅱ、IGF-1R、IGFBP-3在结直肠癌中的表达及诊断价值研究

目的：探讨结直肠癌中IGF-Ⅱ、IGF-1R以及IGFBP-3等的阳性表达及诊断价值。方法：收集我院45例结直肠癌、33例炎性息肉、40例腺瘤以及35例正常肠粘膜组织予以免疫组织化学SP法进行IGF—Ⅱ、IGF—1R以及IGFBP-3检测,并统计结直肠腺瘤不同组织类型和结直肠癌不同Dukes分期的阳性表达差异。结果：结直肠癌组织中IGF—Ⅱ、IGF—1R以及IGFBP-3表达均呈高阳性率,并且显著高于其他3组（P〈0．05）。结直肠腺瘤管状、混合型、绒毛状等不同组织类型IGF-Ⅱ、IGF—1R以及IGFBP-3表达阳性率呈逐渐增高趋势,绒毛状腺瘤显著高于其他两型（P〈0．05）。45例结直肠癌中,Dukes分期A、B两期显著低于C期和D期,比较差异具有显著性（P〈0．05）。结论：IGF—Ⅱ、IGF-1R以及IGFBP-3可能在结直肠腺瘤发生、发展及进展为结直肠癌的过程中起一定作用,对结直肠癌早期诊断具有一定价值。     

叶酸缺乏致胎鼠宫内发育迟缓及肝脏胰岛素生长因子 系统表达变化

目的：叶酸是一种水溶性B 族维生素,在体内氨基酸与核苷酸代谢中起重要作用, 是胎儿生长发育所必须的营养素。本文通 过建立叶酸缺乏的孕鼠模型,探讨叶酸缺乏对胎鼠宫内发育的影响,并研究胎鼠肝脏组织中胰岛素生长因子（IGF）系统的表达变 化。方法：雌性C57BL/6J 小鼠叶酸缺乏组6 只、正常对照组6 只,分别饲以不含叶酸和含2 mg 叶酸/kg 的纯合饲料。四周后与雄 鼠交配,于怀孕第13.5 天（13.5 dpc）对孕鼠剖腹取胎,观察和评价胎鼠发育指标,并对宫内发育迟缓（IUGR）比率进行统计。用 Real-time PCR 法检测胎鼠肝脏组织中胰岛素生长因子Ⅰ（IGFⅠ）、胰岛素生长因子Ⅰ受体（IGFⅠ R）、胰岛素生长因子Ⅱ（IGF Ⅱ）、胰岛素生长因子Ⅱ受体（IGFⅡR）、胰岛素生长因子结合蛋白1（IGFBP-1）和胰岛素生长因子结合蛋白3（IGFBP-3）mRNA的 相对表达水平。结果：叶酸缺乏组雌鼠合笼前每日体重增长量降低,13.5 dpc胎鼠吸收胎和死胎比率升高,胎重下降,IUGR 比率显 著升高,差异有统计学意义（P<0.05）;叶酸缺乏组胎鼠肝脏组织中IGFⅡ和IGFⅡR mRNA 的相对表达水平均低于正常对照组 （P<0.05）,IGFⅠ、IGFⅠR、IGFBP-1 和IGFBP-3 mRNA的相对表达水平两组间没有差异（P>0.05）。结论：叶酸缺乏会导致小鼠孕 中期胎鼠IUGR 比率升高及胎肝IGFⅡ和IGFⅡR mRNA 的表达水平降低,提示叶酸缺乏对IGF系统基因的调控,可能与胎鼠IUGR 发生机制有关。     

低氧调节大鼠前额叶皮层IGFs家族基因的表达

目的：探讨急性和慢性低氧对胰岛素样生长因子（IGFs）家族中IGF-I,IGF一Ⅱ,IGF-1R和IGFBPlmRNA表达变化的调节。方法：我们利用低压低氧舱模拟5km低氧环境,研究大鼠暴露于急性和慢性低氧后的前额叶皮层IGF家族基因的表达变化。结果：急性和慢性连续低氧暴露后,大鼠前额叶皮层中IGF-I,IGF-II,IGF-1R和IGFBPlmRNA对低氧应激表现出明显不同的变化模式。急性低氧时,IGF-I和IGFBPlmRNA表达显著升高。而在慢性连续低氧暴露5～15d后,IGF-I和IGFBPlmRNA表达量逐渐回复到对照水平。但IGF-1R的表达仍然保持较高水平。结论：急性低氧上调IGF基因表达可能参与皮层神经元的保护,而慢性低氧升高的IGF-1R基因表达可能参与慢性低氧损伤的适应过程。     

胰岛素样生长因子IGF系统与鱼类性腺的研究进展

IGFs系统包含3个配体(IGF-1、IGF-2、IGF-3)、2个受体(IGF-1R、IGF-2R)和6个IGF结合蛋白(IGFBP).生殖和生长是生物体最基本的特征,两者既密切相关又相互区别,胰岛素样生长因子(IGFs)是生长轴和生殖轴相交联的关键因子.最近研究表明:鱼类性腺的发育及成熟伴随着细胞分化和组织生长,传统的生长因子IGF-1、IGF-2和最近发现的IGF-3,对鱼类性腺发挥着重要作用.本文重点介绍鱼类特有的配体IGF-3的结构,鱼类IGFs系统的信号通路及其与鱼类性腺的相关性研究进展.     

IGF-Ⅰ对卵巢的作用及其调节

IGF-Ⅰ能刺激卵泡颗粒细胞的代谢、增生、分化,甾体激素的生成及受体的诱导。卵泡内IGF-Ⅰ的分泌受促性腺激素,雌二醇及卵泡大小的调节。 1976年Rinderknecht和Humbel从血清中具有胰岛素样活性但不同胰岛素抗体反应的物质中分离出两种肽类,由于这两种肽类是依赖于生长激素,并具有促进生长的特性,因此被定名为胰岛素样生长因子(Insulin-like growth factor,简称IGF)。IGF又由于其组成肽类的氨基酸不同而被皮分为IGF-Ⅰ和IGF-Ⅱ。IGF-Ⅰ分子量约7000道尔顿,包括70个氨基     

IGF—Ⅱ异常表达机制与肝细胞癌变的关系

肝细胞癌变过程中，IGF—Ⅱ常呈过量表达状态并与肝细胞的恶性转化关系密切。近年研究表明，IGF—Ⅱ异常表达与基因组印记失调、肝细胞恶性转化过程中局部缺氧、乙型及丙型肝炎病毒感染以及饮食中黄曲霉毒素B1暴露等因素密切相关。本文对IGF—Ⅱ异常过量表达与肝细胞癌变的分子机制作一简要综述。     

人胰岛素样生长因子－ⅡcDNA的PCR扩增及序列分析

人胰岛素样生长因子(Human insulin-like growth factor,简称 h IGF)是一类既有细胞分化和增殖活性,又有胰岛素样作用的多肽,包括IGF-Ⅰ和IGF-Ⅱ两种。其中IGF-Ⅰ的功能比较清楚,而IGF-Ⅱ的作用正在研究中,可能在胎儿的生长发育及脑组织和神经系统中起重要作用。IGF-Ⅱ能刺激一些细胞系的生长,对不同的肿瘤起自分泌和旁分泌生长因子的作用。最近又发现IGF-Ⅱ能刺激神经及肌肉的再生。由于天然IGF-Ⅱ的分离困难,我们利用基因工程方法克隆表达IGF-Ⅱc DNA,以获得大量重组蛋白,为研究和应用打下基础。     

人胰岛素样生长因子－ⅡcDNA的PCR扩增及序列分析

人胰岛素样生长因子(Hurman insulin-1ike growth factor,简称h IGF)是一类既有细胞分化和增殖活性,又有胰岛索样作用的多肽,包括IGF—Ⅰ和IGF—Ⅱ两种。其中IGF—Ⅰ的功能比较清楚。而IGF—Ⅱ的作用正在研究中,可能在胎儿的生长发育及脑组织和神经系统中起重要作用。IGF－Ⅱ能刺激一些细胞系的生长,对不同的肿瘤起自分泌和旁分泌生长因子的作用〔1－6〕,最近又发现IGF—Ⅱ能刺激神经及肌肉的再生。由于天然IGF—Ⅱ的分离困难,我们利用基因工程方法克隆表达IGF—Ⅱ c DNA,以获得大量重组蛋白,为研究和应用打下基础。     

Alteration of the insulin-like growth factor axis during in vitro differentiation of the human osteosarcoma cell line HOS 58

The insulin-like growth factors I and II (IGF-I, IGF-II), their receptors, and high affinity binding proteins (IGFBPs) represent a family of cellular modulators that play essential roles in the development and differentiation of cells and tissues including the skeleton. Recently, the human osteosarcoma cell line HOS 58 cells were used as an in vitro model of osteoblast differentiation characterized by (i) a rapid proliferation rate in low-density cells that decreased continuously with time of culture and (ii) an increasing secretion of matrix proteins during their in vitro differentiation. In the present paper, HOS 58 cells with low cell density at early time points of the in vitro differentiation (i) displayed a low expression of IGF-I and -II; (ii) synthesized low levels of IGFBP-2, -3, -4, and -5, but (iii) showed high expression levels of both the type I and II IGF receptors. During the in vitro differentiation of HOS 58 cells, IGF-I and -II expressions increased continuously in parallel with an upregulation of IGFBP-2, -3, -4, and -5 whereas the IGF-I receptor and IGF-II/M6P receptor mRNA were downregulated. In conclusion, the high proliferative activity in low cell density HOS 58 cells was associated with high mRNA levels of the IGF-IR, but low concentrations of IGFBP-2. The rate of proliferation of HOS 58 cells continuously decreased during cultivation in parallel with a decline in IGF-IR expression, but increase of mitoinhibitory IGFBP-2. These data are indicative for a role of the IGF axis during the in vitro differentiation of HOS 58 cells.     

IGF1调控区微卫星座位对金华猪生长性能的影响

类胰岛素生长因子IGF1及其相关结合蛋白和跨膜受体IGFR在哺乳动物的生长过程中扮演着重要角色。本文基于最小二乘法分析了IGF1 5′ 调控序列微卫星座位对金华猪初生重, 断奶重, 120日龄重, 180日龄重和出生窝重等生长性状的影响。结果表明: 286/286基因型对金华猪初生重有显著影响(P<0.05); 280/286基因型对金华猪开产后出生窝重影响显著(P<0.05), 进一步通过等位基因平均替代效应分析发现274 bp和286 bp等位基因有利于提高初生重, 280 bp等位基因有利于第二胎出生窝重的提高。同时通过相关性分析发现金华猪开产母猪出生窝重、总产仔数和产活仔数间的相关性极显著(P<0.01), 因此出生窝重的增加有利于提高金华猪的产仔性能。     

猪IGF2基因外显子4b的遗传多态性及其遗传效应

采用PCR-SSCP方法检测猪胰岛素样生长因子2(insulin-like growth factor 2,IGF2)基因外显子4b的多态性,并分析其对初生重、断奶重、6月龄重和背膘厚的遗传效应。根据猪IGF2基因的DNA序列(AY044828)设计引物,在exon4b上发现了一个多态性位点,并对纯合子进行测序,发现13位C→A转换,且存在3种基因型(AA、AB、BB)。统计结果表明,3种基因型在各品种中的分布不一致,长白猪与大白猪比较,莱芜猪与大薄莲猪比较,沂蒙黑猪和里岔黑猪比较差异不显著(P>0.05);其他猪种间基因型分布的差异均显著(P<0.05)。固定效应模型分析结果表明,初生重,断奶重和背膘厚基因型间差异显著(P<0.05),而6月龄重基因型间差异不显著(P>0.05)。最小二乘分析结果表明,BB基因型个体同AA和AB、基因型个体比较初生重和断奶重的差异显著(P<0.05),3种基因型在初生重和断奶重的大小排列顺序为AA>AB>BB;AA基因型个体同AB和BB基因型个体比较背膘厚的差异显著(P<0.05),3种基因型在背膘厚的大小排列顺序为BB>AB>AA。因此,推测IGF2基因对个体的生长速度和胴体瘦肉率存在一定的影响,将IGF2基因应用于猪育种过程中的标记辅助选择可以加快猪的育种进程。     

卵巢中的胰岛素样生长因子系统

本文详细阐述了胰岛素样生长因子（IGFs)系统各个成员的结构及其在卵巢中的表达和作用机制。IGFs是这一系统的中间环节,与IGFs受体作用刺激卵巢细胞中类固醇激素的生产和DNA合成,能够介导和扩大促性腺激素对卵巢功能的作用。IGFs与胰岛素样生长因子结合蛋白（IGFBPs)发生高亲和性结合,卵巢中自由的IGFs的水平受IGFBPs的调节。而IGFBPs蛋白酶能够降低IGFBPs和IGFs的亲和性,从而参与调节IGFs在卵巢中的作用。深入的研究这一系统,对于进一步了解卵巢卵泡生长发育、分化以及闭锁,卵泡细胞的增殖和凋亡的内在机制,以及提高动物的繁殖力有重要意义。     

Differential expression of the two GH genes during embryonic development of rainbow trout Oncorhynchus mykiss in relation with the IGFs system

The Growth hormone (GH)/insulin-like growth factor (IGF) system promotes embryonic growth in higher vertebrates. Such a system exists in salmonids, but exhibits an additional level of complexity resulting from a recent whole genome tetraploidisation. Thus, two nonallelic GH genes are present in the trout genome. Although the two GH genes are similar, the possibility remains that the two genes have evolved separately, acquiring a distinct expression pattern. In this study, using whole mounted in situ hybridisation, we observed a one stage delay between the appearance of GH-2 (Stage 22) and GH-1 (Stage 23) soon after pituitary formation (Stage 21). In addition, by double in situ hybridisation, we clearly evidenced two types of somatotroph, one expressing only GH-2 and the other type both GH-1 and GH-2 at Stage 24. Consequently, at this stage more cells expressed GH-2 than GH-1 as confirmed by quantitative RT-PCR. However at hatching, as in adult, the difference between the expression of the two GH genes was no longer observed. In addition, our immunohistochemical studies did not show any delay between the expression of the mRNA and its translation as a protein at Stage 24. A comparison of the expression pattern of the IGF system components (IGF-1, IGF-2, and the receptor type I) determined by real time RT-PCR, have shown an IGF-1 mRNA increase concomitantly to the appearance of GH expression. On the whole, our results demonstrate a differential regulation of GH-1 and GH-2 genes in rainbow trout embryo. The relationship observed between the expression of different component of the GH/IGF system seems to indicate that this system could be functional early on during embryonic development.     

Effects of insulin-like growth factor-binding protein 2 and an IGF-type I receptor-blocking antibody on apoptosis in human teratocarcinoma cells in vitro

Human teratocarcinoma cells (Tera-2) deprived of serum undergo programmed cell death which can be counteracted by simultaneous addition of IGF-I or IGF-II. This protective effect of IGFs was specific in the sense that both addition of IGF-binding protein-2, and blocking of the IGF-type I receptor by a specific antibody, both resulted in an increased apoptotic rate.     

Insulin‐like growth factor axis targeting in cancer and tumour angiogenesis – the missing link

Numerous molecular players in the process of tumour angiogenesis have been shown to offer potential for therapeutic targeting. Initially denoted to be involved in malignant transformation and tumour progression, the insulin‐like growth factor (IGF) signalling axis has been subject to therapeutic interference, albeit with limited clinical success. More recently, IGFs and their receptors have received attention for their contribution to tumour angiogenesis, which offers novel therapeutic opportunities. Here we review the contribution of this signalling axis to tumour angiogenesis, the mechanisms of resistance to therapy and the interplay with other pro‐angiogenic pathways, to offer insight in the renewed interest in the application of IGF axis targeting agents in anti‐cancer combination therapies.     

Regulation of Ligand and Shear Stress-induced Insulin-like Growth Factor 1 (IGF1) Signaling by the Integrin Pathway

Mechanical loading of the skeleton, as achieved during daily movement and exercise, preserves bone mass and stimulates bone formation, whereas skeletal unloading from prolonged immobilization leads to bone loss. A functional interplay between the insulin-like growth factor 1 receptor (IGF1R), a major player in skeletal development, and integrins, mechanosensors, is thought to regulate the anabolic response of osteogenic cells to mechanical load. The mechanistic basis for this cross-talk is unclear. Here we report that integrin signaling regulates activation of IGF1R and downstream targets in response to both IGF1 and a mechanical stimulus. In addition, integrins potentiate responsiveness of IGF1R to IGF1 and mechanical forces. We demonstrate that integrin-associated kinases, Rous sarcoma oncogene (SRC) and focal adhesion kinase (FAK), display distinct actions on IGF1 signaling; FAK regulates IGF1R activation and its downstream effectors, AKT and ERK, whereas SRC controls signaling downstream of IGF1R. These findings linked to our observation that IGF1 assembles the formation of a heterocomplex between IGF1R and integrin β3 subunit indicate that the regulation of IGF1 signaling by integrins proceeds by direct receptor-receptor interaction as a possible means to translate biomechanical forces into osteoanabolic signals.