The potential values of insulin-like growth factor binding protein 3 in disease diagnosis and risk assessment

doi:10.3969/j.issn.2095-4344.2014.38.025

Abstract

Abstract:

BACKGROUND: Insulin-like growth factor 1 (IGF1) plays an important role in cell growth, proliferation and differentiation. Insulin-like growth factor binding protein 3 (IGFBP-3), as the main binding protein of IGF1, is involved in the regulation of IGF1.
OBJECTIVE: To attempt to analyze the relation of IGFBP-3 and various diseases, and to explore the potential values of IGFBP-3 in disease diagnosis and risk assessment.
METHODS: Databases of PubMed, Science Direct and Wanfang database were retrieved with key words of “insulin-like growth factors 1; IGFBP-3; cancer; growth hormone deficiency; diabetes; osteoporosis” in English and Chinese, respectively, by screening titles and abstracts to search papers related to IGFBP-3 structure and function as well as relationship of IGFBP-3 with cancer, growth hormone deficiency, diabetes, osteoporosis. Finally, 43 articles were summarized according to inclusion criteria.
RESULTS AND CONCLUSION: In recent years, the relationship between gene of IGFBP-3 and risk of cancer is becoming a hot research topic. The results show that IGFBP-3 is a protective agent of cancer risk, and it is an important factor in evaluating the risk of cancer, exhibiting a potential application value. IGFBP-3 is also associated with growth hormone deficiency and diabetes. In addition, IGFBP-3 can assist IGF-1 to play the regulatory role in bone growth and differentiation, which is closely linked with osteoporosis. Therefore, IGFBP-3 can be a potential predictor for osteoporosis.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

全文链接：

Key words: insulin-like growth factor I, diabetes mellitus, carcinoma

CLC Number:

R318

Zhang Zhi-fang, Xiao Wei-hua, Zhou Wei-ai. The potential values of insulin-like growth factor binding protein 3 in disease diagnosis and risk assessment[J]. Chinese Journal of Tissue Engineering Research, 2014, 18(38): 6210-6215.

Figures/Tables 1

2.1 IGFBP-3的结构 IGFBP-3即胰岛素样生长因子结合蛋白3，人体的IGFBP-3是由264个氨基酸组成的相对分子质量为28.700 0的蛋白质，在血液、细胞外基质、细胞内发挥着重要作用[3]。 IGFBP-3结构主要由3个大致相等的不同区域组成，发挥着不同的功能。第一区域为保守的氨基端区域，IGFBP-3一共有18个半胱氨酸，12个在此区域，与胰岛素样生长因子结合的重要氨基酸残基也在此区域。第二区域为变化多样的中间区域，此区域包含了95个氨基酸，将氨基端和羧基端区域分隔开。而且IGFBP-3只在中间区域进行翻译后修饰(糖基化、磷酸化)。糖基化可以影响细胞间的相互作用，磷酸化可以影响胰岛素样生长因子与蛋白酶结合的敏感性和亲和力。第三区域为保守的羧基端区域，此区域有6个半胱氨酸，3个二硫键。羧基端的18个残基单位可与肝素结合，同时也可和其他黏多糖及细胞表面聚糖结合。此外，羧基端区域的其他氨基酸残基可与细胞表面、细胞基质及细胞核上的运输蛋白β等蛋白质结合[3]。 2.2 IGFBP-3的功能 2.2.1 调节胰岛素样生长因子1的作用 IGFBP-3是胰岛素样生长因子1主要的结合载体，在由IGFBP-3、酸不变性蛋白亚单位和胰岛素样生长因子组成的复合体中结合了75%-90%的胰岛素样生长因子1，延长了胰岛素样生长因子1的半衰期[3]。在IGFBP-3的协助下，胰岛素样生长因子1和胰岛素样生长因子1型受体结合，产生了不同的细胞生物学效应，包括细胞增殖和分化，增强了代谢活动和细胞的抗凋亡活动[3]。此外，IGFBP-3可抑制和促进胰岛素样生长因子1功能活动，调节胰岛素样生长因子1和细胞表面受体的相互作用[7]。 2.2.2 诱导细胞凋亡研究显示，IGFBP-3可作为细胞凋亡的调节剂。类视黄醇X受体(retinoid X receptor-α，RXRα)是IGFBP-3与细胞核结合的一部分，IGFBP-3与其结合后可介导细胞凋亡。近期研究发现，IGFBP-3与RXR配基VTP194204结合，可抑制前列腺癌细胞的生长，介导肿瘤细胞凋亡[8]。然而有研究表明IGFBP-3可以一种独立于胰岛素样生长因子的方式，无需在细胞核上聚集都可介导细胞凋亡[9]。此外，IGFBP-3可增强干扰素γ介导的细胞凋亡和抑制细胞分化的作用，间接促进肿瘤细胞凋亡[10]。 2.2.3 对生长、血糖及骨的作用研究显示，IGFBP-3过度表达的转基因小鼠出生时体质量、身长及以后的生长与正常对照组相比没有降低，但是脑质量却降低了[11]。提示IGFBP-3过度表达对身体的部分生长发育是不利的。人体的IGFBP-3在小鼠中过度表达会使小鼠空腹血糖升高。对该转基因小鼠进行糖耐量测试，发现葡萄糖降低幅度减慢。在胰岛素耐量测试中发现胰岛素降低速度减慢。总之，IGFBP-3在体内的过度表达会延长胰岛素的清除率，降低葡萄糖刺激胰岛素分泌[12]。 IGFBP-3在体内过度表达会导致骨量减少。人体的IGFBP-3cDNA在转基因小鼠中过度表达，使得此种转基因小鼠骨密度、骨钙等降低[5]。IGFBP-3缺乏会导致骨的体积分数(BV/TV)降低，破骨细胞分化因子增加，这些都不利于骨的生长。IGFBP-3的缺乏同时会导致血液中胰岛素样生长因子1的大幅度降低，胰岛素样生长因子1的降低影响了骨细胞的增殖和分化、成熟，间接影响了骨的生长发育[6]。 2.3 IGFBP-3和癌症 2.3.1 IGFBP-3水平变化和癌症 IGFBP-3是一种肿瘤抑制剂，可抑制胰岛素样生长因子和其受体结合，从而阻碍了胰岛素样生长因子促进肿瘤细胞有丝分裂功能活动，同时可通过独立胰岛素样生长因子方式促进细胞凋亡[13]。无论是实验研究还是流行病学研究都证实IGFBP-3是一种癌症风险的保护剂。它是一种评估癌症风险的重要因子。大多数研究表明，高水平的胰岛素样生长因子1和低水平的IGFBP-3与癌症的高风险有密切的关系。 Chen等[14]学者对前列腺癌患者进行了9年的跟踪研究，发现IGFBP-3水平的增加会相应降低前列腺癌的风险。Weiss等[15]学者发现，胰岛素样生长因子1/IGFBP-3的摩尔比率增加和肥胖男性的前列腺癌患病风险增加显著相关。 Rinaldi等[16]对1 081例患有浸润性乳腺癌的女性做了相关研究，发现胰岛素样生长因子1浓度增加和乳腺癌风险增加显著相关，在2年内IGFBP-3的增加与癌症诊断风险降低相关。此种相关性仅限于50岁以上的女性，而在年轻女性中没有发现这两种因子和乳腺癌风险的关系。Vatten等[17]对挪威小于50岁的患有乳腺癌的女性生理指标进行了分析，发现乳腺癌女性的胰岛素样生长因子1浓度显著高于正常对照组。通过校正胰岛素样生长因子1、年龄和血液收集的时间，发现IGFBP-3水平变化与乳腺癌风险呈负相关关联。而且胰岛素样生长因子1水平最高而IGFBP-3水平最低时，乳腺癌风险最高。Duggan等[18]研究发现，高水平胰岛素样生长因子1和高胰岛素样生长因子1/IGFBP-3比率会增加乳腺癌女性死亡率风险。 Unsala等[19]发现肺癌患者的IGFBP-3水平相对正常对照组较低。 Yagyu等[20]的研究显示IGFBP-3水平和胆囊癌及胆道癌风险呈负相关关系。 2.3.2 IGFBP-3基因多样性与癌症近年来，很多学者已经深入到微观水平研究IGFBP-3与癌症的关系。研究已经证实IGFBP-3基因多样性的变化和癌症风险具有一定的相关性。最常见的是IGFBP-3-202位置单核苷酸序列的多样性。研究显示，癌症的高风险和AA基因型及CC基因型紧密相关。一些研究显示AA基因型的癌症风险较高；而另一些研究则表明CC基因型的癌症风险较高。 Han等[13]学者对韩国肺癌患者IGFBP-3基因进行了监测分析，发现IGFBP-3 A-C单体基因型和女性增高的肺癌风险显著相关。IGFBP-3启动子多样性(-1590C>A和-202A>C)可能是一种和肺癌相关的基因风险因子。Moon等[21]在非小细胞肺癌患者中发现这种癌症的风险和IGFBP-3-202AA基因型显著相关。相比CC基因型，携有AC或AA基因有较高的非小细胞肺癌风险。Safarinejad[22]的研究显示，肾细胞癌患者的IGFBP-3AA基因的频率相对健康对照组显著增加。 Hernandez等[23]发现患有前列腺癌的非裔美国人的IGFBP-3-202CC及AC与IGFBP-3低水平有显著相关性。在前列腺癌发展进程中携有CC基因型的患者的癌症风险明显增加。Safarinejad[24]在膀胱癌患者中发现，IGFBP-3AA基因型和癌症风险显著降低相关，携有CC基因型的患者IGFBP-3水平相对其他基因型水平是最低的，癌症风险最高。吴琛等[25]将所构建的真核分泌型表达载体(pSectag-IGFBP3)转染人肾癌细胞786-O细胞后，检测细胞凋亡情况，结果显示，转染IGFBP-3的细胞凋亡率明显高于对照组正常细胞和转染空载体细胞的凋亡率，表明分泌表达的IGFBP-3可明显促进786-O细胞的凋亡。综上所述，IGFBP-3水平变化及基因的差异和癌症风险具有密切关系。IGFBP-3水平降低，癌症风险会相应升高。IGFBP-3-202A/C基因类型和癌症风险显著相关。因此，IGFBP-3在癌症风险预测中可作为一种潜在的评定指标。 2.4 IGFBP-3与生长激素缺乏症生长激素是胰岛素样生长因子1主要的调节因子，可介导肝脏及局部组织的胰岛素样生长因子1的表达，同时可直接或者间接地促进IGFBP-3的分泌[3]。Mauras等[26]在研究生长激素缺乏症患者从青春期到成年阶段生长激素治疗的效果时，发现生长激素缺乏症患者的IGFBP-3平均值相对正常组要偏低。Westwood[27]研究不同剂量生长激素对生长激素缺乏的侏儒大鼠胰岛素样生长因子轴和躯体及骨的生长影响时，发现经过生长激素治疗的大鼠，血清胰岛素样生长因子1、IGFBP-3水平增加。Jaffe等[28]学者对生长激素缺乏症的患者进行生长激素注射和生长激素丸药摄入干预后，发现胰岛素样生长因子1、IGFBP-3水平高于空白对照组。以上研究说明，生长激素的缺乏会造成IGFBP-3水平的降低，经过生长激素治疗，IGFBP-3水平会升高。生长激素和IGFBP-3之间的密切关系提示IGFBP-3可能作为对生长激素缺乏的辅助测量指标。Stanley学者认为在儿童时期生长激素缺乏症的诊断具有挑战性，因为在一定程度上缺乏检测此病的金标准，诊断儿童时期生长激素缺乏症需要多种因素，如身体成分、青春期状态、生长激素测试。此外胰岛素样生长因子1和IGFBP-3的测量不能单独应用诊断此病，而结合其他指标对于诊断是有益的[29]。Quigley[30]对73个生长激素缺乏症患者的身体指标进行了评估，意在探究生长激素缺乏症潜在敏感的预测指标。研究显示，IGFBP-3平均标准差值对于长期生长激素缺乏症患者(先天生长激素缺乏症家族遗传史)来说，是很好的预测指标。AliA等[31]研究人员对52个身材矮小的儿童进行了测试，探究胰岛素样生长因子1、IGFBP-3在生长激素缺乏症矮小儿童中的评估价值，研究表明胰岛素样生长因子1和IGFBP-3在检测儿童生长激素缺乏症时有较高的敏感性和精确性，可作为一种相对的有价值的测量指标来辅助生长激素测试。 2.5 IGFBP-3与糖尿病研究表明，在肝外组织的IGFBP-3的表达及生物活性的变化可影响碳水化合物的代谢，IGFBP-3表达的变化会直接或间接影响胰岛素分泌和功能活动[6]。IGFBP-3还可结合细胞蛋白质调节葡萄糖代谢，如和9-顺式视黄酸核受体-α结合，同时也诱导肝胰岛素抵抗，使得肌肉葡萄糖摄取降低[32]。一些研究已经证实IGFBP-3与1型和2型糖尿病指标存在一定的相关性。 Lee等[33]学者的研究发现胰岛素样生长因子1和IGFBP-3在2型糖尿病青少年中显著升高，空腹血糖、胆固醇、三酰甘油和低密度脂蛋白也相应增加。而且IGFBP-3水平和这些指标之间的相关性显著。因此，Lee认为IGFBP-3可能作为青少年2型糖尿病评价血糖控制和血脂异常发展的标志。Rajpathak[32]研究了女性2型糖尿病风险和胰岛素样生长因子轴的相关性，发现IGFBP-3和胰岛素在2型糖尿病女性中显著升高，IGFBP-3和2型糖尿病的发展紧密相关，IGFBP-3水平增加，糖尿病风险也会相应升高。 Bideci等[34]发现1型糖尿病受试者的IGFBP-3水平相对对照组显著降低。同时Leger等[35]发现患有1型糖尿病儿童的胰岛素样生长因子1、IGFBP-3的平均值相比健康对照组较低。Capoluongo等[36]针对1型糖尿病的血压和胰岛素样生长因子1及IGFBP-3关系进行了研究，发现IGFBP-3水平降低，收缩压增加，IGFBP-3与收缩压之间呈负相关的关系。该研究认为IGFBP-3可作为一种预测1型糖尿病风险的检测标志。Kim等[37]发现1型糖尿病的IGFBP-3与糖化血红蛋白、总胆固醇、低密度脂蛋白呈显著正相关关系。以上的一些研究显示，1型糖尿病和2型糖尿病的IGFBP-3变化不同，2型糖尿患者IGFBP-3水平升高，而1型糖尿病则相反，这可能和2种糖尿病的发病机制不同有关。鉴于IGFBP-3与糖尿病患者血糖、血压、血脂等的相关性及和此病风险的关系，它可能作为一种预测和诊断糖尿病的潜在指标。 2.6 IGFBP-3与骨质疏松 2.6.1 IGFBP-3对骨生长发育等代谢的作用胰岛素样生长因子1可介导成骨细胞分化，促进成骨细胞功能成熟[38]。在血液中，胰岛素样生长因子1与IGFBPs结合，主要是和IGFBP-3结合[2]。胰岛素样生长因子1与IGFBP-3结合的复合体再与胰岛素样生长因子1R受体(一种酪氨酸激酶受体)结合而发挥生物学效应[39]。IGFBP-3可抑制和促进胰岛素样生长因子1功能活动，调节胰岛素样生长因子1和细胞表面受体相互作用[7]。因而IGFBP-3可间接对骨的生长发育产生影响。然而，IGFBP-3在体内过度表达会导致骨量减少。人体的IGFBP-3cDNA在转基因小鼠中过度表达，使得此种转基因小鼠骨密度、骨钙等骨的增值指标降低，而尿脱氧吡啶诺林、破骨细胞周边组织等骨的再吸收指标显著增加。这些表明过度表达的IGFBP-3增加了破骨细胞数量和骨的再吸收，破坏了骨增值，对骨的形成具有显著负面影响[10]。此外，也有研究显示，IGFBP-3的过度表达增加了破骨细胞的数量和骨吸收，破坏了骨的增值，对骨的形成具有负面影响[40]。IGFBP-3缺乏也会对骨造成一定影响，在IGFBP3KO小鼠中，骨的体积分数(BV/TV)降低，破骨细胞分化因子增加，这些都不利于骨的生长。IGFBP-3的缺乏同时会导致血液中胰岛素样生长因子1的大幅度降低。胰岛素样生长因子1的降低影响了骨细胞的增值和分化、成熟[11]。所以，IGFBP-3缺乏和过度表达对骨的形成起到了负面效应。 2.6.2 IGFBP-3可作为骨质疏松评定的潜在指标许多研究发现IGFBP-3水平降低和骨密度减少有密切关系，提示IGFBP-3可作为骨质疏松的评定的潜在指标。Amin等[41]发现在男性和绝经后妇女中，低水平的胰岛素样生长因子1、IGFBP-3和低骨密度密切相关。Sittadjody[42]发现绝经后女性的IGFBP-3水平降低了，而且跟骨密度也相应降低。IGFBP-3水平和跟骨密度呈正相关关系。Koutroubakis[43]炎症性肠病的骨质疏松患者的IGFBP-3降低，颈椎和腰椎的骨密度也相应降低，IGFBP-3与颈椎和腰椎骨密度呈显著正相关关系。"

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