Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors

BACKGROUND Gastrointestinal stromal tumors(GISTs)are typical gastrointestinal tract neoplasms.Imatinib is the first-line therapy for GIST patients.Drug resistance limits the long-term effectiveness of imatinib.The regulatory effect of insulin-like growth factor 2(IGF2)has been confirmed in various cancers and is related to resistance to chemotherapy and a worse prognosis.AIM To further investigate the mechanism of IGF2 specific to GISTs.METHODS IGF2 was screened and analyzed using Gene Expression Omnibus(GEO:GSE225819)data.After IGF2 knockdown or overexpression by transfection,the phenotypes(proliferation,migration,invasion,apoptosis)of GIST cells were characterized by cell counting kit 8,Transwell,and flow cytometry assays.We used western blotting to evaluate pathway-associated and epithelial-mesenchymal transition(EMT)-associated proteins.We injected transfected cells into nude mice to establish a tumor xenograft model and observed the occurrence and metastasis of GIST.RESULTS Data from the GEO indicated that IGF2 expression is high in GISTs,associated with liver metastasis,and closely related to drug resistance.GIST cells with high expression of IGF2 had increased proliferation and migration,invasiveness and EMT.Knockdown of IGF2 significantly inhibited those activities.In addition,OEIGF2 promoted GIST metastasis in vivo in nude mice.IGF2 activated IGF1R signaling in GIST cells,and IGF2/IGF1R-mediated glycolysis was required for GIST with liver metastasis.GIST cells with IGF2 knockdown were sensitive to imatinib treatment when IGF2 overexpression significantly raised imatinib resistance.Moreover,2-deoxy-D-glucose(a glycolysis inhibitor)treatment reversed IGF2 overexpressionmediated imatinib resistance in GISTs.CONCLUSION IGF2 targeting of IGF1R signaling inhibited metastasis and decreased imatinib resistance by driving glycolysis in GISTs.

Exosome-transported IncRNA H19 regulates insulin-like growth factor-1 via the H19/let-7a/insulin-like growth factor-1 receptor axis in ischemic stroke

LncRNA(long non-coding RNA) H19 is a transcript of the H19 gene that is expressed during embryogenesis.We previously discove red a role for circular lncRNA H19 in the onset and prognosis of cerebral ischemic stroke.In this study,we used serum from patients with ischemic stroke,and mouse and cell culture models to elucidate the roles of plasma and neuronal exosomes in the regulatory effect of lncRNA H19 on insulin-like growth factor-1 and its mechanism in ischemic stroke,using western blotting,quantitative real-time polymerase chain reaction,and enzyme-linked immunosorbent assays.Plasma exosomal IncRNA H19 was negatively associated with blood levels of insulin-like growth factor-1 in samples from patients with cerebral ischemic stroke.In a mouse model,levels of exosomal IncRNA H19 were positively correlated with plasma and cerebral lncRNA H19.In a cell co-culture model,we confirmed that IncRNA H19 was transported from neuro ns to astrocytes by exosomes to induce downregulation of insulin-like growth factor-1 through the H19/let-7 a/insulin-like growth factor-1 receptor axis.This study provides the first evidence for the transpo rtation of IncRNA H19 by exosomes and the relationship between IncRNA H19 and insulinlike growth factor-1.

Insulin-like growth factor-binding protein-3 inhibits IGF-1-induced proliferation of human hepatocellular carcinoma cells

OBJECTIVE Basic fibroblast growth factor(b FGF)and platelet-derived growth factor(PDGF)produced by hepatocellular carcinoma(HCC)cells are responsible for the cell growth.Accumulating evidence shows that insulin-like growth factor-binding protein-3(IGFBP-3)suppresses HCC cell proliferation in both IGF-dependent and independent manners.The present study is to investigate whether treatment with exogenous IGFBP-3 inhibits bF GF and PDGF production and the cell proliferation of HCC cells.METHODS Cell Counting Kit 8 assay were designed to detect HCC cell proliferation,transcription factor early growth response-1(EGR1)involving in IGFBP-3 regulation of b FGF and PDGF were detected by RT-PCR and Western blot assays.Western blot assay was adopted to detect the IGFBP-3 regulating insulin-like growth factor 1 receptor(IGF-1R)signaling pathway.RESULTS The present study demonstrates that IGFBP-3 suppressed IGF-1-induced b FGF and PDGF expression while it does not affect their expression in the absence of IGF-1.To delineate the underlying mechanism,Western-blot and RT-PCR assays confirmed that the transcription factor early growth response protein 1(EGR1)is involved in IGFBP-3 regulation of b FGF and PDGF.IGFBP-3 inhibition of type 1 insulin-like growth factor receptor(IGF1R),ERK and AKT activation is IGF-1-dependent.Furthermore,transient transfection with constitutively activated AKT or MEK partially blocks the IGFBP-3 inhibition of EGR1,b FGF and PDGF expression.CONCLUSION In conclusion,these findings suggest that IGFBP-3suppresses transcription of EGR1 and its target genes b FGF and PDGF through inhibiting IGF-1-dependent ERK and AKT activation.It demonstrates the importance of IGFBP-3 in the regulation of HCC cell proliferation,suggesting that IGFBP-3 could be a target for the treatment of HCC.

益气化瘀汤联合羟苯磺酸钙治疗糖尿病肾病气虚血瘀证的疗效及对VEGF,IGF-1表达水平的影响研究

【目的】观察益气化瘀汤(由黄芪、山药、茯苓、炒芡实、旱莲草、金樱子、焦山楂、女贞子、丹参、益母草等组成)联合羟苯磺酸钙治疗糖尿病肾病(DN)气虚血瘀证的临床疗效及对血管内皮生长因子(VEGF)、胰岛素样生长因子1(IGF-1)的影响。【方法】将90例DN气虚血瘀证患者随机分为观察组和对照组,每组各45例。所有患者均接受基础降糖治疗和控制血压、调节脂代谢紊乱等治疗。在此基础上,对照组患者给予羟苯磺酸钙治疗,观察组患者在对照组的基础上联合益气化瘀汤治疗,疗程为3个月。观察2组患者治疗前后中医证候积分、肾功能指标及血清VEGF、IGF-1水平的变化情况,并评价2组患者的临床疗效。【结果】(1)疗效方面,治疗3个月后,观察组的总有效率为91.11%(41/45),对照组为75.56%(34/45),组间比较(χ2检验),观察组的疗效明显优于对照组(P<0.05)。(2)中医证候积分方面,治疗1个月和3个月后,2组患者的中医证候积分均较治疗前明显降低(P<0.05),且治疗3个月后又均较治疗1个月后明显降低(P<0.05);组间比较,观察组在治疗1个月和3个月后对中医证候积分的降低作用均明显优于对照组(P<0.01)。(3)肾功能指标方面,治疗后,2组患者的血肌酐(Scr)、尿素氮(BUN)、肾小球滤过率(GFR)等肾功能指标均较治疗前明显改善(P<0.05),且观察组对各项肾功能指标的改善作用均明显优于对照组(P<0.01)。(4)血清VEGF、IGF-1水平方面,治疗后,2组患者的血清VEGF、IGF-1水平均较治疗前明显降低(P<0.05),且观察组对血清VEGF、IGF-1水平的降低作用均明显优于对照组(P<0.01)。(5)治疗过程中,2组患者均无明显不良反应发生,具有较高的安全性。【结论】益气化瘀汤联合羟苯磺酸钙治疗DN气虚血瘀证患者疗效确切,可有效下调血清VEGF、IGF-1水平,明显改善患者肾功能,显著减轻患者临床症状,且具有较高的安全性。

3D打印技术用于经鼻蝶窦入路垂体腺瘤切除术应用效果及对血清MMP-9和IGF-1水平的影响

目的:探究3D打印技术在经鼻蝶窦入路垂体腺瘤(PA)切除术的应用效果及对血清基质金属蛋白酶-9(MMP-9)和胰岛素样生长因子-1(IGF-1)水平的影响。方法:选取2020年5月至2022年5月秦皇岛市第一医院收治的84例PA患者,按照随机数表法将其分为观察组和对照组,每组42例。对照组行经鼻蝶窦入路垂体腺瘤切除术,观察组行经鼻蝶窦入路垂体腺瘤切除术联合应用3D打印技术,比较两组肿瘤切除效果、围术期指标、视力改善情况、MMP-9和IGF-1水平,以及鼻腔功能的鼻气道阻力(NAR)、T&T嗅觉测试评分及并发症。结果:观察组肿瘤切除效果优于对照组,差异有统计学意义(U=2.286,P<0.05);观察组手术时间、术中出血量及住院时间均少于对照组,差异有统计学意义(t=4.780、11.438、11.842,P<0.05);术后3 d、7 d时观察组血清MMP-9和IGF-1水平低于对照组,差异有统计学意义(F=7.526、4.985,P<0.05);术后1个月、3个月时观察组NAR及T&T嗅觉测试评分低于对照组,差异有统计学意义(F=6.359、8.436,P<0.05);两组视力视野改善情况及并发症发生率比较,差异无统计学意义(P>0.05)。结论:3D打印技术用于经鼻蝶窦入路垂体腺瘤切除术可提高肿瘤切除效果,优化手术操作,减少创伤,有利于减轻疼痛,改善嗅觉功能与视力视野,并能降低血清MMP-9、IGF-1水平,且安全性较高。

营养干预对生长迟缓患儿血清IGF-1水平的影响探讨

目的 对本院收治的营养干预对生长迟缓患儿血清IGF-1水平的影响进行分析,为生长迟缓患儿营养干预措施的制定与优化提供依据。方法 以本院2021年4月-2022年4月期间就诊的40例0~3岁生长迟缓患儿作为观察组,同时选取40例0~3岁的正常儿童作为对照组。对观察组患儿进行营养干预,测定干预前后观察组患儿血清IGF-1水平相关生长指标,以对照组为参考,比较2组各项指标。结果 营养干预前,观察组血清IGF-1水平显著低于对照组(P<0.05)营养干预后,观察组血清IGF-1水平显著高于本组营养干预前差异有统计学意义(P<0.05),且与同时段的对照组相当差异无统计学意义(P>0.05)。此外,观察组营养干预后的生长指标(HtSDS、生长速率)均显著优于营养干预前差异有统计学意义(P<0.05)。结论 血清IGF-1水平是判断儿童生长迟缓情况的重要指标,通过早期个性化的营养干预可提升生长迟缓患儿血清IGF-1水平,促进其生长发育。

Insulin-like growth factor 2 mRNA-binding protein 1 promotes cell proliferation via activation of AKT and is directly targeted by microRNA-494 in pancreatic cancer

BACKGROUND Studies have shown that insulin-like growth factor 2 mRNA-binding protein 1(IGF2BP1)plays critical roles in the genesis and development of human cancers.AIM To investigate the clinical significance and role of IGF2BP1 in pancreatic cancer.METHODS Expression levels of IGF2BP1 and microRNA-494(miR-494)were mined based on Gene Expression Omnibus datasets and validated in both clinical samples and cell lines by quantitative real-time polymerase chain reaction and Western blot.The relationship between IGF2BP1 expression and clinicopathological factors of pancreatic cancer patients was analyzed.The effect and mechanism of IGF2BP1 on pancreatic cancer cell proliferation were investigated in vitro and in vivo.Analyses were performed to explore underlying mechanisms of IGF2BP1 upregulation in pancreatic cancer and assays were carried out to verify the posttranscriptional regulation of IGF2BP1 by miR-494.RESULTS We found that IGF2BP1 was upregulated and associated with a poor prognosis in pancreatic cancer patients.We showed that downregulation of IGF2BP1 inhibited pancreatic cancer cell growth in vitro and in vivo via the AKT signaling pathway.Mechanistically,we showed that the frequent upregulation of IGF2BP1 was attributed to the downregulation of miR-494 expression in pancreatic cancer.Furthermore,we discovered that reexpression of miR-494 could partially abrogate the oncogenic role of IGF2BP1.CONCLUSION Our results revealed that upregulated IGF2BP1 promotes the proliferation of pancreatic cancer cells via the AKT signaling pathway and confirmed that the activation of IGF2BP1 is partly due to the silencing of miR-494.

Insulin-like growth factor binding protein related protein 1 knockdown attenuates hepatic ?brosis via the regulation of MMPs/TIMPs in mice

Background: Previous research suggested that insulin-like growth factor binding protein related protein 1(IGFBPrP1), as a novel mediator, contributes to hepatic fibrogenesis. Matrix metalloproteinases(MMP) and tissue inhibitors of metalloproteinases(TIMP) play an essential role in hepatic fibrogenesis by regulating homeostasis and remodeling of the extracellular matrix(ECM). However, the interaction between IGFBPrP1 and MMP/TIMP is not clear. The present study was to knockdown IGFBPrP1 to investigate the correlation between IGFBPrP1 and MMP/TIMP in hepatic fibrosis. Methods: Hepatic fibrosis was induced by thioacetamide(TAA) in mice. Knockdown of IGFBPrP1 expression by ultrasound-targeted microbubble destruction-mediated CMB-shRNA-IGFBPrP1 delivery, or inhibition of the Hedgehog(Hh) pathway by cyclopamine treatment, was performed in TAA-induced liver fibrosis mice. Hepatic fibrosis was determined by hematoxylin and eosin and Sirius red staining. Hepatic expression of IGFBPrP1, α-smooth muscle actin( α-SMA), transforming growth factor β 1(TGF β1), collagen I, MMPs/TIMPs, Sonic Hedgehog(Shh), and glioblastoma family transcription factors(Gli1) were investigated by immunohistochemical staining and Western blotting analysis. Results: We found that hepatic expression of IGFBPrP1, TGF β1, α-SMA, and collagen I were increased longitudinally in mice with TAA-induced hepatic fibrosis, concomitant with MMP2/TIMP2 and MMP9/TIMP1 imbalance and Hh pathway activation. Knockdown of IGFBPrP1 expression, or inhibition of the Hh pathway, reduced the hepatic expression of IGFBPrP1, TGF β1, α-SMA, and collagen I and re-established MMP2/TIMP2 and MMP9/TIMP1 balance. Conclusions: Our findings suggest that IGFBPrP1 knockdown attenuates liver fibrosis by re-establishing MMP2/TIMP2 and MMP9/TIMP1 balance, concomitant with the inhibition of hepatic stellate cell activation, down-regulation of TGF β1 expression, and degradation of the ECM. Furthermore, the Hh pathway mediates IGFBPrP1 knockdown-induced attenuation of hepatic fibrosis through the regulation of MMPs/TIMPs balance.

Interaction between insulin-like growth factor binding protein-related protein 1 and transforming growth factor beta 1 in primary hepatic stellate cells

BACKGROUND: We previously showed that insulin-like growth factor binding protein-related protein 1 (IGFBPrP1) is a novel mediator in liver fibrosis. Transforming growth factor beta 1 (TGF beta 1) is known as the strongest effector of liver fibrosis. Therefore, we aimed to investigate the detailed interaction between IGFBPrP1 and TGF beta 1 in primary hepatic stellate cells (HSCs). METHODS: We overexpressed TGF beta 1 or IGFBPrP1 and inhibited TGF beta 1 expression in primary HSCs for 6, 12, 24, 48, 72, and 96 hours to investigate their interaction and observe the accompanying expressions of a-smooth muscle actin (alpha-SMA), collagen I, fibronectin, and phosphorylated-mothers against decapentaplegic homolog 2/3 (p-Smad2/3). RESULTS: We found that the adenovirus vector encoding the TGF beta 1 gene (AdTGF beta 1) induced IGFBPrP1 expression while that of alpha-SMA, collagen I, fibronectin, and TGF beta 1 increased gradually. Concomitantly, AdIGFBPrP1 upregulated TGF beta 1, alpha-SMA, collagen I, fibronectin, and p-Smad2/3 in a time-dependent manner while IGFBPrP1 expression was decreased at 96 hours. Inhibition of TGF beta 1 expression reduced the IGFBPrP1-stimulated expression of alpha-SMA, collagen I, fibronectin, and p-Smad2/3. CONCLUSIONS: These findings for the first time suggest the existence of a possible mutually regulation between IGFBPrP1 and TGF beta 1, which likely accelerates liver fibrosis progression. Furthermore, IGFBPrP1 likely participates in liver fibrosis in a TGF beta 1-depedent manner, and may act as an upstream regulatory factor of TGF beta 1 in the Smad pathway.

Human insulin-like growth factor 1-transfected umbilical cord blood neural stem cell transplantation improves hypoxic-ischemic brain injury

Human insulin-like growth factor 1-transfected umbilical cord blood neural stem cells were transplanted into a hypoxic-ischemic neonatal rat model via the tail vein. BrdU-positive cells at day 7 post-transplantation, as well as nestin- and neuron specific enolase-positive cells at day 14 were increased compared with those of the single neural stem cell transplantation group. In addition, the proportion of neuronal differentiation was enhanced. The genetically modified cell-transplanted rats exhibited enhanced performance in correctly crossing a Y-maze and climbing an angled slope compared with those of the single neural stem cell transplantation group. These results showed that human insulin-like growth factor 1-transfected neural stem cell transplantation promotes the recovery of the leaming, memory and motor functions in hypoxic-ischemic rats.

Effect of sericin on diabetic hippocampal growth hormone/insulin-like growth factor 1 axis

Previous studies have shown that sericin extracted from silk cocoon significantly reduces blood glucose levels and protects the nervous system against diabetes mellitus. In this study, a rat type 2 diabetes mellitus model was established by intraperitoneal injection of 25 mg/kg streptozotocin for 3 successive days, following which the rats were treated with sericin for 35 days. After treatment, the blood glucose levels of the diabetic rats decreased significantly, the growth hormone level in serum and its expression in the hippocampus decreased significantly, while the insulin-like growth factor-1 level in serum and insulin-like growth factor-1 and growth hormone receptor expression in the hippocampus increased significantly. The experimental findings indicate that sericin improves disorders of the growth hormone/insulin-like growth factor 1 axis to alleviate hippocampal damage in diabetic rats.

Role of insulin/insulin-like growth factor 1 signaling pathway in longevity

The insulin/insulin-like growth factor 1 (IGF-1) signaling pathway is evolutionary conserved in diverse speciesincluding C.elegans, saccharomyces cerevisiae, Drosophila melanogaster, rodents and humans, which is involved in many interrelated functions that are necessary for metabolism, growth and reproduction. Interestingly, more and more research has revealed that insulin/IGF-1 signaling pathway plays a pivotal role in the regulation of longevity. Generally, disruption of the power of this pathway will extend longevity in species ranging from C.elegansto humans. The role of insulin/IGF-1 in longevit yis probably related to stress resistance. Although the underlying mechanisms of longevity are not fully understood, the Insulin/IGF-1 signaling pathway has attracted substantial attention and it will be a novel target to prevent or postpone age-related diseases and extend life span. In this review, we mainly focus on the similar constitution and role of insulin/IGF-1 signaling pathway in C.elegans, saccharomyces cerevisiae, rodents and humans.

Integrating insulin-like growth factor 1 and sex hormones into neuroprotection:Implications for diabetes

Brain integrity and cognitive aptitude are often impaired in patients with diabetes mellitus, presumably a result of the metabolic complications inherent to the disease. However, an increasing body of evidence has demonstrated the central role of insulin-like growth factor 1(IGF1) and its relation to sex hormones in many neuroprotective processes. Both male and female patients with diabetes display abnormal IGF1 and sexhormone levels but the comparison of these fluctuations is seldom a topic of interest. It is interesting to note that both IGF1 and sex hormones have the ability to regulate phosphoinositide 3-kinase-Akt and mitogen-activated protein kinases-extracellular signal-related kinasesignaling cascades in animal and cell culture models of neuroprotection. Additionally, there is considerable evidence demonstrating the neuroprotective coupling of IGF1 and estrogen. Androgens have also been implicated in many neuroprotective processes that operate on similar signaling cascades as the estrogen-IGF1 relation. Yet, androgens have not been directly linked to the brain IGF1 system and neuroprotection. Despite the sex-specific variations in brain integrity and hormone levels observed in diabetic patients, the IGF1-sex hormone relation in neuroprotection has yet to be fully substantiated in experimental models of diabetes. Taken together, there is a clear need for the comprehensive analysis of sex differences on brain integrity of diabetic patients and the relationship between IGF1 and sex hormones that may influence brain-health outcomes. As such, this review will briefly outline the basic relation of diabetes and IGF1 and its role in neuroprotection. We will also consider the findings on sex hormones and diabetes as a basis for separately analyzing males and females to identify possible hormone-induced brain abnormalities. Finally, we will introduce the neuroprotective interplay of IGF1 and estrogen and how androgen-derived neuroprotection operates through similar signaling cascades. Future research on both neuroprotection and diabetes should include androgens into the interplay of IGF1 and sex hormones.

A predictive score for retinopathy of prematurity by using clinical risk factors and serum insulin-like growth factor-1 levels

AIM：To detect the impact of insulin-like growth factor-1（IGF-1）and other risk factors for the early prediction of retinopathy of prematurity（ROP）and to establish a scoring system for ROP prediction by using clinical criteria and serum IGF-1 levels.METHODS：The study was conducted with 127 preterm infants.IGF-1 levels in the 1st day of life,1st,2nd,3rd and4th week of life was analyzed.The score was established after logistic regression analysis,considering the impact of each variable on the occurrences of any stage ROP.A validation cohort containing 107 preterm infants was included in the study and the predictive ability of ROP score was calculated.RESULTS：Birth weights（BW）,gestational weeks（GW）and the prevalence of breast milk consumption were lower,respiratory distress syndrome（RDS）,bronchopulmonarydysplasia（BPD）and necrotizing enterocolitis（NEC）were more frequent,the duration of mechanical ventilation and oxygen supplementation was longer in patients with ROP（P〈0.05）.Initial serum IGF-1 levels tended to be lower in newborns who developed ROP.Logistic regression analysis revealed that low BW（〈1250 g）,presence of intraventricular hemorrhage（IVH）and formula feeding increased the risk of ROP.Afterwards,the scoring system was validated on 107 infants.The negative predictive values of a score less than 4 were 84.3%,74.7%and 79.8%while positive predictive values were 76.3%,65.5%and71.6%respectively.CONCLUSION：In addition to BW〈1250 g and IVH,formula consumption was detected as a risk factor for the development of ROP.Breastfeeding is important for prevention of ROP in preterm infants.

Significance of highly phosphorylated insulin-like growth factor binding protein-1 and cervical length for prediction of preterm delivery in twin pregnancies

BACKGROUND A twin pregnancy can carry greater risks than singleton pregnancies.About 60 in 100 twin pregnancies result in spontaneous birth before 37 wk,which is associated with several complications in the premature babies.Clinical detection of biomarkers may help to predict the possibility of premature birth so that corresponding interventions can be given to the pregnant women in a timely manner,in order to reduce the risk of preterm birth and improve the outcomes of the newborn infants.AIM To explore the clinical value of transvaginal ultrasound measurement of cervical length combined with insulin-like growth factor binding protein-1(IGFBP-1)hyperphosphorylation in cervical secretions as predictors of preterm delivery in twin pregnancies.METHODS A total of 254 pregnant women with twin pregnancies,who were admitted to Hainan General Hospital and underwent maternity examination,were selected as the study subjects from January 2015 to December 2018.All participants received transvaginal ultrasound measurement of cervical length and phosphorylated IGFBP-1(phIGFBP-1)test between 24 and 34 wk gestation.The pregnancy outcomes were analyzed.RESULTS Of the women with a positive phIGFBP-1 test result,preterm birth rate was higher in those with a cervical length≤25 mm than those with a cervical length>25 mm(all P<0.05).Similarly,in women with a negative phIGFBP-1 test result,preterm birth rate was higher in those with a cervical length≤25 mm than those with a cervical length>25 mm(all P<0.05).The sensitivity,specificity,and positive and negative predictive values of the phIGFBP-1 test combined with the cervical length test were 95.71%,91.21%,95.12%and 92.22%,respectively,for the prediction of preterm birth.CONCLUSION Cervical length combined with phIGFBP-1 tests is of value for the prediction of outcomes of preterm delivery in twin pregnancies.

Expression of insulin-like growth factor-1 in breast cancer tissues

Objective: We investigated the expression of insulin-like growth factor-1 (IGF-1) so as to explore its relationship with carcinogenesis and development of breast cancer. Methods: IGF-1 mRNA levels in tissues of breast cancer, adjacent breast cancer in 70 cases breast cancer patients were analyzed by RT-PCR with the normal breast tissues of paired breast as the control. Results: The level of IGF-1 mRNA expression in breast cancer tissues was significantly higher than that in the paired adjacent to breast cancer tissues, normal mammary gland tissues. The ration of IGF-1/β-actin were 0.679 ± 0.075, 0.463 ± 0.085, 0.305 ± 0.031, respectively. There was significant difference between different groups (P < 0.005). Expression of IGF-1 was associated with lymph node metastasis, pathological staging and estrogen receptor status of breast cancer and no significant relationship with tumor pathological grouping (P > 0.005). Conclusion: The high-level expression of IGF-1 in breast cancer tissues is correlated with carcinogenesis, development and metastasis of breast cancer.

Preparatory training attenuates drastic response of the insulin-like growth factor binding protein 1 at the point of maximal oxygen consumption in handball players

Background:Intensive exercise changes physiological need for glucose and several biochemical pathways responsible for its metabolism response.Among them are those which involve insulin,insulin-like growth factor(IGF-1),and IGF-binding proteins(IGFBPs).Different types and degrees of exercise,as well as an athlete's fitness,may induce a range of responses regarding concentrations and time needed for the alteration.The idea of the work was to find out whether and how insulin/IGF axis responds to additional physical activity in the already trained subjects and if so,is the adaptation potentially beneficial from the aspect of metabolic control.Methods:The effect of 4-week intensive training on campus(preparatory training) on the levels of insulin,IGF-1,and IGFBPs during maximal progressive exercise test(MPET) on a treadmill was compared to the results obtained during MPET conducted after a regular training season of a female elite handball team(n = 17,age:17 ± 1 years,height:171 ± 8 cm,weight:65 ± 8 kg,body mass index:22 ± 1 kg/m^2 at the beginning of the study;there were no significant changes at the end).Serum samples were obtained from players immediately before the test(basal),at the end of the test after reaching the point of maximal oxygen consumption(VO_(2max)),and after recovery.Results:The concentration of insulin decreased at VO_(2max),but remained higher in players after preparatory training(12.2 ± 2.5 m U/L vs.8.9 ± 4.4 m U/L,p = 0.049).The level of IGFBP-1 decreased in players at VO_(2max) in either case of training,but it remained much higher in tests performed after the preparatory regime than before(p = 0.029).Concentrations of IGF-1,IGFBP-2,-3,and-4 did not change significantly.Conclusion:The inverse relation between insulin and IGFBP-1 was lost during MPET,as these 2 molecules changed in the same direction.The results obtained suggest less severe stress-induced depression of insulin and IGFBP-1 after preparatory training.But another metabolic mechanism cannot be excluded,and that is potentially impaired insulin sensitivity resulting in higher level of IGFBP-1.

RNA interference affects tumorigenicity and expression of insulin-like growth factor-1,insulin-like growth factor-1 receptor,and basic fibroblast growth factor-2 in rat C6 glioma cells

BACKGROUND： Human gliomas are more likely to express basic fibroblast growth factor-2 （FGF-2） insulin-like growth factor-1（IGF-1）, and IGF-1 receptor （IGF-1R） than normal brain tissue. These factors activate signal transduction systems of Ras/MAPK and PI3K/Akl, which promote glioma growth. OBJECTIVE： To utilize RNA interference （RNAi） technique to down-regulate FGF-2, IGF-1, and IGF-1R gene expression, and to investigate the effects of these genes on rat C6 glioma cells, as well as the feasibility of RNAi for treating glioma. DESIGN, TIME AND SETTING： This neurooncological, randomized, controlled, in vivo and in vitro experiment, which used RNAi methodology, was performed at the Laboratory of Molecular Biology, Institute of Biochemistry, Chinese Academy of Sciences between August 2005 and February 2008. MATERIALS： Rat C6 cell lines were purchased from Shanghai Institute of Cellular Biology Affiliated to Chinese Academy of Sciences. Small interfering RNA （siRNA） was synthesized by Shanghai GenePharma. Anti-IGF-1, anti-IGF-1R, anti-FGF-2, anti-mouse and anti-rabbit IgG G1-HRP antibodies were provided by Santa Cruz Biotechnology, USA. Four to six week-old BALB/c nude mice were purchased from the Laboratory Animal Center, Chinese Academy of Sciences. METHODS： C6 glioma cells were transfected with siRNA, which was chemically synthesized in vitro to correspond to endogenous FGF-2, IGF-1, and IGF-1R genes. The inhibition ratio of targeting mRNA expression was detected by semiquantitative RT-PCR, and protein expression was determined by Western blot analysis. C6 glioma cell proliferation was observed using a growth curve C6 glioma cell apoptosis rate and cell cycle were detected by flow cytometry. C6 glioma cell growth regression was observed by transwell migration assay. In addition, nude mouse subcutaneous tumor models were used in this study. For studying the anti-tumor effects of IGF-1 and IGF-1R siRNA, two blank control groups, with six mice each, were set up： A （2.5 μg siRNA was injected one week after C6 cells were inoculated, Le., when tumor volume reached 8 mm × 8 mm） and B （siRNA was injected at the same time with C6 cells were inoculated. To study the effects of FGF-2 siRNA, the groups consisted of a blank control group, negative control group, 2.6 μg siRNA group, 4 μg siRNA group, and 5.3 μg siRNA group, with six mice each. MAIN OUTCOME MEASURES： mRNA and protein inhibition ratio of FGF-2, IGF-1, and IGF-1 R; C6 glioma cell proliferation, apoptosis, and cycle growth arrest; C6 glioma cell growth regression and subcutaneous tumorigenicity rates. RESULTS： All siRNA constructs proved to be effective. After 48 hours, transfection of 200 nmol/L siRNA resulted in a FGF-2 or IGF-1R gene inhibition ratio 〉 80% and an IGF-1 gene inhibition ratio of approximately 70%. Protein expression levels for FGF-2, IGF-1, and IGF-1R decreased in a dose-dependent manner following siRNA transfection, with an inhibition rate 〉 85%, 60%, and 50%, respectively. C6 glioma cell proliferation and apoptosis rates increased in proportion to siRNA. The apoptosis rate of C6 glioma cells induced by FGF-2, IGF-1, and IGF-1R siRNA was 39.96%, 15.07% and 22.47%, respectively （P 〈 0.01）. Transfection of 200 nmol/L IGF or IGF-1R siRNA for 48 hours suppressed C6 glioma cell migration. At 30 days after intratumoral injection of 2.6, 4, and 5.3 tJg FGF-2 siRNA, tumor growth regression rate of FGF-2 siRNA was 56%, 67%, and 86%, respectively. The tumor growth regression rate was 71.88% and 45.71%, respectively, when IGF-1 or IGF-1R siRNA was intratumorally injected 1 week after C6 glioma cell transplantation. When IGF-1 or IGF-1 R siRNA was intratumorally injected during C6 glioma cell transplantation, the tumor growth regression rate was 78.13% and 74.29%, respectively. CONCLUSION： siRNA transfection downregulated gene expression of FGF-2, IGF-1, and IGF-1R In addition, siRNA treatment markedly suppressed glioma cell proliferation, growth, and migration, and concomitantly reduced subcutaneous tumorigenicity.

Paravertebral fascial massage promotes brain development of neonatal rats via the insulin-like growth factor 1 pathway

Massage in traditional Chinese medicine can promote body and brain development of premature and normal newborn infants. In the present study, neonatal rats （1 day old） underwent paravertebral fascial massage （15 consecutive days）, followed by subcutaneous injection of insulin-like growth factor 1 receptor antagonist, JB1 （9 consecutive days）. Paravertebral fascial massage significantly increased insulin-like growth factor 1 expression and cell proliferation in the subventricular zone of the lateral ventricle and dentate gyrus of the hippocampus. However, JB1 inhibited this increase. Results suggest that paravertebral fascial massage can promote brain development of neonatal rats via the insulin-like growth factor I pathway.

The effect of insulin-like growth factor 1 on the fusion of cranial suture

Objective To evaluate the effect of insulin-like growth factor 1 for the bone induction and the regulation for the fusion of the sagittal cranial sutures. Methods The cells, derived from cranial sutures in the newborn SD rats and the sagittal suture from the mice, were cultured with a serum-free medium and treated with and without insulin-like growth factor 1. The osteoblast phetotypes (osteocalcin, alkaline, osteoponcin and type-1 collagen) were measured with the RT -PCR and ELISA, and the explanted sagittal sutures were then evaluated under light microscopy. Results The cells, treated with the insulin-like growth factor 1, significantly produced more osteocalcin, alkaline, osteoponcin and type-1 collagen than those without insulin-like growth factor 1. The fusion of the sagittal suture explants will delay till to 30 days when it was not treated with IGF1. However, in the group with IGF1 the fusion was observed to start in 8 days, and a small amount of the sagittal suture fusion was found at the 20th