A peptide containing the receptor binding site of insulin-like growth factor binding protein-2 enhances bone mass in ovariectomized rats

Male Igfbp2-/-mice have a significant reduction in bone mass and administration of a peptide that contains the insulin-like growth factor binding protein-2(IGFBP-2) receptor-binding domain stimulates bone formation in these animals. Female Igfbp2-/-mice do not have this phenotype but following ovariectomy(OVX) lose more bone than OVX wild-type mice. This suggests that in the absence of estrogen, IGFBP-2 is required to maintain bone mass. Therefore these studies were undertaken to determine if this peptide could stimulate bone acquisition in OVX rats. OVX rats were divided into seven treatment groups: sham animals, OVX animals, OVX animals receiving a control scrambled peptide, or one of three doses of the active peptide termed PEG-HBD-1(0.7, 2,and 6 mg·kg^(-1)) and an OVX group receiving parathyroid hormone(PTH)(50 μg·kg-1 per day). The peptides were administered for8 weeks. DXA revealed a significant reduction in femoral and tibial areal bone mineral density(aBMD) after OVX, whereas treatment with the high-dose peptide increased aBMD by 6.2% ± 2.4%(P < 0.01) compared to control peptide; similar to the increase noted with PTH(5.6% ± 3.0%, P < 0.01). Similar increases were noted with two lower doses of the peptide(3.8% ± 1.5%, P < 0.05 for low dose; 3.1% ± 1.6%, P = 0.07 for middle dose). Micro CT showed that the OVX control peptide animals had reductions of 41% and64% in femoral trabecular BV/TV and trabecular number, respectively. All three doses of the peptide increased bone volume/total volume(BV/TV) significantly, while the low and middle doses increased trabecular number. Cortical BV/TV and thickness at the midshaft increased significantly with each dose of peptide(18.9% ± 9.8%, P < 0.01 and 14.2% ± 7.9%, P < 0.01 for low dose; 23.7% ±10.7%, P < 0.001 and 15.8% ± 6.1%, P < 0.001 for middle dose; 19.0% ± 6.9%, P < 0.01 and 16.2% ± 9.7%, P < 0.001 for high dose)and with PTH(25.8% ± 9.2%, P < 0.001 and 19.4% ± 8.8%, P < 0.001). Histomorphometry showed that the lowest dose of peptide stimulated BV/TV, trabecular thickness, mineral apposition rate(MAR), bone formation rate/bone surface(BFR/BS), number of osteoblasts/bone perimeter(N.ob/B.pm), and decreased osteoclast surface/bone perimeter(Oc.S/B.Pm). The highest dose stimulated each of these parameters except MAR and BFR/BS. Thus, the heparin-binding domain receptor region of IGFBP-2 accounts for its anabolic activity in bone. Importantly, this peptide enhances bone mass in estrogen-deficient animals.

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.

Interplay between micro RNA-17-5p, insulin-like growth factor-Ⅱ through binding protein-3 in hepatocellular carcinoma

AIM: To investigate the effect of microR NA on insulinlike growth factor binding protein-3(IGFBP-3) and hence on insulin-like growth factor-Ⅱ(IGF-Ⅱ) bioavailability in hepatocellular carcinoma(HCC).METHODS: Bioinformatic analysis was performed using microrna.org, DIANA lab and Segal lab softwares. Total RNA was extracted from 23 HCC and 10 healthy liver tissues using mir Vana mi RNA Isolation Kit. microR NA-17-5p(miR-17-5p) expression was mimicked and antagonized in Hu H-7 cell lines using Hi Per Fect Transfection Reagent, then total RNA was extracted using Biozol reagent then reverse transcribed into cD NA followed by quantification of mi R-17-5p and IGFBP-3 expression using Taq Man real-time quantitative PCR. Luciferase reporter assay was performed to validate the binding of miR-17-5p to the 3'UTR of IGFBP-3. Free IGF-Ⅱ protein was measured in transfected Hu H-7 cells using IGF-Ⅱ ELISA kit. RESULTS: Bioinformatic analysis revealed IGFBP-3 as a potential target for miR-17-5p. Screening of miR-17-5p and IGFBP-3 revealed a moderate negative correlation in HCC patients, where mi R-17-5p was extensively underexpressed in HCC tissues(P = 0.0012), while IGFBP-3 showed significant upregulation in the same set of patients(P = 0.0041) compared to healthy donors. Forcing mi R-17-5p expression in Hu H-7 cell lines showed a significant downregulation of IGFBP-3 mR NA expression(P = 0.0267) and a significant increase in free IGF-Ⅱ protein(P = 0.0339) compared to mock untransfected cells using unpaired t-test. Luciferase assay validated IGFBP-3 as a direct target of mi R-17-5p; luciferase activity was inhibited by 27.5% in cells co-transfected with miR-17-5p mimics and the construct harboring the wild-type binding region 2 of IGFBP-3 compared to cells transfected with this construct alone(P = 0.0474).CONCLUSION: These data suggest that regulating IGF-Ⅱ bioavailability and hence HCC progression can be achieved through targeting IGFBP-3 via manipulating the expression of miR NAs.

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.

Changes of insulin-like growth factor-Ⅱ and insulin-like growth factor binding protein-3 in cerebrospinal fluid of children with tuberculous meningitis

BACKGROUND： Recent studies have found that insulin-like growth factors （IGFs） and insulin-like growth factor binding protein-3 （IGFBP-3） have stronger neurotrophic and neuroprotective effects. But whether their levels in cerebrospinal fluid could be used as an auxiliary indicator in differentially diagnosing tuberculous meningitis and viral encephalitis is not yet clear. OBJECTIVE： To explore the changes of insulin-like growth factor-Ⅱ （IGF-Ⅱ ） and IGFBP-3 in cerebrospinal fluid （CSF） of children with tuberculous meningitis and the significance of the changes. DESIGN： A non-randomized concurrent controlled study. SETTING： Department of Pediatric Internal Medicine, the First Affiliated Hospital of Xinxiang Medical College. PARTICIPANTS： Thirty children with tuberculous meningitis （14 males and 16 females） were selected from the Department of Pediatric Internal Medicine, the First Affiliated Hospital of Xinxiang Medical College from January 2005 to December 2006. Tuberculous meningitis was diagnosed according to their clinical manifestations, the history of close contact with tuberculosis, typical cerebrospinal fluid changes of tuberculous meningitis, positive tuberculosis antibody and effective antituberculosis treatment. There were 30 children （13 males and 17 females） with viral encephalitis, and viral encephalitis was diagnosed according to epidemiological history, clinical manifestations, conventional and biochemical changes of cerebrospinal fluid, and negative bacteriology judgment. Meanwhile, 30 children （13 males and 17 females） without infectious and central nervous system disease were selected as the control group. Informed consent was obtained from the parents of all the enrolled children. METHODS： ①The lumbar puncture operation was implemented immediately to obtain cerebrospinal fluid （3 mL）. The contents of IGF-Ⅱ and IGFBP-3 were detected with immunoradiometric assay. The concentrations of glucose and protein in cerebrospinal fluid were determined with a dry-chemical method. The number of white blood cells was counted by Fushi Method. ②The Pearson correlation analysis was used to analyze the correlation of the contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid with the leucocyte counting and the concentrations of glucose and protein in cerebrospinal fluid. MAIN OUTCOME MEASURES： The contents of IGF- Ⅱ and IGFBP-3 in cerebrospinal fluid, and their correlation with the leucocyte counting and the concentrations of glucose and protein in cerebrospinal fluid. RESULTS： ①Contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid： The contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid in the tuberculous meningitis group were significantly higher than those in the encephalitis virus group and control group （P 〈 0.05）. There was no significant difference in the contents of IGF- Ⅱ and IGFBP-3 in cerebrospinal fluid between the viral encephalitis group and control group （P 〉 0.05）. ②Correlation： The IGF- Ⅱ and IGFBP-3 contents in cerebrospinal fluid were positively correlated with the protein concentration in cerebrospinal fluid （r =0.821, 0.855, P 〈 0.01）, but negatively with the glucose （r =0.742, - 0.605, P 〈 0.01）. CONCLUSION- ①IGFs and IGVBPs are involved in the pathophysiological process of tuberculous meningitis, as well as the glucose and protein metabolism in cerebrospinal fluid. ②The IGF-Ⅱ and IGFBP-3 contents in cerebrospinal fluid can be used as the auxiliary indicators to differentially diagnose tuberculous meningitis and viral enceohalitis.

Effects of Exogenous Growth Hormone on Growth Hormone-Insulin-Like Growth Factor Axis of Human Gastric Cancer Cell

Aim: To study effects of recombinant human growth hormone (rhGH) on growth hormone-insulin-like growth factor axis (GH-IGFs) of human gastric cancer cell in vivo in order to reveal part mechanism of growth effects of rhGH on gastric cancer. Methods: Nude mice were randomly divided into control group, cisplatin (DDP) group, rhGH group and DDP + rhGH group after human gastric cancer xenograft model of node mice was successfully founded and drugs were used for 6 days. We investigated volume of tumor, inhibitory rate of tumor and cell cycle by slide gauge and flow cytometry. In addition, We also respectively investigated insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) of blood serum of nude mice, IGF-ImRNA, insulin-like growth factor-I receptor (IGF-IR) mRNA and IGFBP-3 mRNA of xenograft of nude mice by enzyme linked immunosorbent assay (ELISA) and semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) on the first day of completing use of drugs later. Results: Tumor grew obviously slowly and tumor inhibitory rate obviously rose in DDP group and DDP + rhGH group compared with control group and rhGH group (p p p < 0.05). Expressions of IGF-I mRNA and IGF-IR mRNA were not obviously different in all groups. But expression of IGFBP-3 mRNA obviously increased in rhGH group, DDP group and DDP + rhGH group compared with control group;meanwhile, expression of IGFBP-3 mRNA also obviously increased in DDP + rhGH group compared with control group, DDP group and rhGH group. Conclusion: Our results indicated rhGH in short-time use did not improve proliferation of human gastric cancer cells and its mechanism was possible that rhGH in short-time use raised simultaneously IGF-I and IGFBP-3 of blood serum and increased IGFBP-3 mRNA, but degraded ratio of IGF-I and IGFBP-3 of blood serum in human gastric cancer cells.

IGFBP-3 promotes cachexia-associated lipid loss by suppressing insulin-like growth factor/insulin signaling

Background:Progressive lipid loss of adipose tissue is a major feature of cancer-associated cachexia.In addition to systemic immune/inflammatory effects in response to tumor progression,tumor-secreted cachectic ligands also play essential roles in tumor-induced lipid loss.However,the mechanisms of tumor-adipose tissue interaction in lipid homeostasis are not fully understood.Methods:The yki-gut tumors were induced in fruit flies.Lipid metabolic assays were performed to investigate the lipolysis level of different types of insulin-like growth factor binding protein-3(IGFBP-3)treated cells.Immunoblotting was used to display phenotypes of tumor cells and adipocytes.Quantitative polymerase chain reaction(qPCR)analysis was carried out to examine the gene expression levels such as Acc1,Acly,and Fasn et al.Results:In this study,it was revealed that tumor-derived IGFBP-3 was an important ligand directly causing lipid loss in matured adipocytes.IGFBP-3,which is highly expressed in cachectic tumor cells,antagonized insulin/IGF-like signaling(IIS)and impaired the balance between lipolysis and lipogenesis in 3T3-L1 adipocytes.Conditioned medium from cachectic tumor cells,such as Capan-1 and C26 cells,contained excessive IGFBP-3 that potently induced lipolysis in adipocytes.Notably,neutralization of IGFBP-3 by neutralizing antibody in the conditioned medium of cachectic tumor cells significantly alleviated the lipolytic effect and restored lipid storage in adipocytes.Furthermore,cachectic tumor cells were resistant to IGFBP-3 inhibition of IIS,ensuring their escape from IGFBP-3-associated growth suppression.Finally,cachectic tumor-derived ImpL2,the IGFBP-3 homolog,also impaired lipid homeostasis of host cells in an established cancer-cachexia model in Drosophila.Most importantly,IGFBP-3 was highly expressed in cancer tissues in pancreatic and colorectal cancer patients,especially higher in the sera of cachectic cancer patients than non-cachexia cancer patients.Conclusion:Our study demonstrates that tumor-derived IGFBP-3 plays a critical role in cachexia-associated lipid loss and could be a biomarker for diagnosis of cachexia in cancer patients.

IGFBP-2对U251细胞增殖和ERK1/2磷酸化及核转移的影响

目的探讨外源性胰岛素样生长因子结合蛋白2(IGFBP-2)对人胶质母细胞瘤细胞株U251细胞增殖的影响及可能通过的信号转导通路。方法MTT比色法检测IGFBP-2对U251细胞增殖的影响;Western blot检测IGFBP-2对细胞外信号调节蛋白激酶(ERK1/2)磷酸化的影响;免疫荧光染色观察IGFBP-2对磷酸化ERK1/2细胞内转位的影响。结果各浓度外源性IGFBP-2(125、250、500 ng/ml)均促进U251细胞增殖(P<0.01);在U251细胞中500 ng/ml IGFBP-2作用5 min磷酸化ERK1/2增加近1倍(P<0.05),作用30 min磷酸化ERK1/2增加2倍以上(P<0.05);500 ng/ml IGFBP-2作用30 min磷酸化ERK1/2发生核转移(P<0.01)。结论IGFBP-2可能通过ERK信号通路促进U251细胞增殖。

胶质瘤与恶性脑膜瘤患者肿瘤组织ABCG2、IGFBP-2表达及预后的关系分析

目的探讨胶质瘤与恶性脑膜瘤患者肿瘤组织三磷酸腺苷结合转运蛋白G超家族成员2(ABCG2)、胰岛素样生长因子结合蛋白-2(IGFBP-2)表达及预后的关系。方法选取资阳市第一人民医院确诊胶质瘤患者96例和恶性脑膜瘤患者38例,采用免疫组化法检测患者肿瘤组织中ABCG2、IGFBP-2阳性细胞的表达,计算其阳性细胞百分率并划分阳性等级,并对比两组ABCG2、IGFBP-2表达差异及与预后死亡和复发的关系。结果胶质瘤组肿瘤组织ABCG2、IGFBP-2总阳性率与恶性脑膜瘤组比较,差异有统计学意义(P<0.05)。胶质瘤组随访中复发率和病死率与恶性脑膜瘤组比较,差异无统计学意义(P>0.05)。生存分析曲线结果显示,ABCG2、IGFBP-2高表达组出现不良事件(死亡、神经功能中度缺损)时间提前于低表达组,差异有统计学意义(P<0.05)。结论随着胶质瘤、恶性脑膜瘤患者肿瘤组织ABCG2、IGFBP-2阳性细胞百分率等级的升高,其预后的复发率与病死率也逐级升高。

胶质细胞瘤病人血浆IGFBP-2浓度的动态监测及其临床意义

目的探讨脑胶质瘤病人血浆类胰岛素样生长因子结合蛋白2(IGFBP-2)浓度的动态监测在病情判定、疗效及放射性损伤中的临床意义。方法用酶联免疫法(ELISA)对33例健康体检者及30例WHOⅡ级胶质瘤、21例间变胶质细胞瘤、65例胶质母细胞瘤病人测定血浆IGFBP-2浓度,并对65例胶质母细胞瘤病人中的63例在手术(18例)、放疗(15例)、化疗(14例)、综合治疗(16例)前后测定血浆IGFBP-2浓度。结果①星形细胞瘤病人血浆IGFBP-2浓度高于少枝细胞瘤(t=2.729,P=0.011)。②血浆IGFBP-2浓度随着胶质瘤级别的升高而增加(F=27.215,P=0.000),胶质母细胞瘤复发后浓度显著性升高(P=0.000)。③胶质母细胞瘤病人血浆IGFBP-2浓度术后及放疗后均升高(t=3.745,P=0.002;t=2.571,P=0.022);化疗后降低(t=2.565,P=0.024);先手术、后放疗、再化疗四疗程综合治疗结束后,IGFBP-2浓度明显下降(t=4.094,P=0.001)。结论血浆IGFBP-2浓度的动态监测对判定胶质瘤病变性质、恶性程度、化疗疗效及手术、放疗损伤等,具有一定的临床意义。

脑胶质瘤患者血清IGFBP2、miR-29c水平变化及其临床意义

【目的】探讨脑胶质瘤患者血清类胰岛素样生长因子结合蛋白2(IGFBP2)、微小RNA29c(miR-29c)水平变化及其临床意义。【方法】选取2016年1月至2017年12月本院收治的80例脑胶质瘤患者(观察组),选取同期于本院健康体检80例志愿者作为对照组。检测两组血清IGFBP2、miR-29c水平,并分析不同肿瘤直径、病理学类型、WHO分级、肿瘤位置的患者血清IGFBP2、miR-29c水平。【结果】观察组患者血清IGFBP2水平显著高于对照组,血清miR-29c水平显著低于对照组,差异均具有统计学意义(P<0.05)。WHO分级Ⅲ级患者血清IGFBP2水平显著高于Ⅰ级、Ⅱ级患者,而血清miR-29c水平显著低于Ⅰ级、Ⅱ级,其差异均具有统计学意义(P<0.05);不同病理学类型、病灶直径、肿瘤部位的患者血清IGFBP2、miR-29c水平比较,差异无统计学意义(P>0.05)。【结论】脑胶质瘤患者血清IGFBP2水平升高、miR-29c表达水平降低,并且与肿瘤分级具有相关性。

血浆IGFBP-2在高级别脑胶质瘤手术加放化疗前后的变化

目的:探讨脑胶质瘤病人血浆类胰岛素样生长因子结合蛋白2(insulin-like growth factor binding protein2;IGFBP-2)浓度在病情判定、预测复发中的临床意义。方法:用酶联免疫法(ELISA)对健康体检者、不同级别胶质瘤及高级别胶质瘤病人综合治疗后复发前后血浆IGFBP-2浓度进行统计学比较,随访其中55例高级别胶质瘤病人2.5年,分析术前血浆IGFBP-2浓度与其无瘤生存期关系。结果:(1)血浆IGFBP-2浓度随着胶质瘤级别的升高而增加(F=17.745,P=0.000);(2)高级别胶质细胞瘤病人经过手术、放疗、化疗综合治疗后,未复发病人血浆IGFBP-2明显下降(t=2.164,P=0.041),而复发后明显升高(t=8.295,P=0.000);(3)血浆中IGF-BP-2浓度<600ng/ml的高级别脑胶质瘤病人的无瘤生存期明显长于浓度>600ng/ml的高级别脑胶质瘤病人(Z=2.272,P=0.023)。结论:血浆IGFBP-2浓度的动态监测对判定胶质瘤病人病变恶性程度、预测高级别胶质瘤的复发有一定的临床意义。

IGFBP2和Lip45对胶质瘤侵袭性的调节(英文)

经过对不同级别胶质瘤的基因表达谱研究发现,在高级别胶质瘤(胶质母细胞瘤和多形性胶质母细胞瘤)中胰岛素样生长因子结合蛋白2 (IGFBP2)呈过度表达,随之进行的微阵列分析表明80%的多形性胶质母细胞瘤过表达IGFBP2,这是目前为止发现的多形性胶质母细胞瘤最普遍的分子生物学改变。功能学研究表明:IGFBP2能促进胶质瘤的侵袭性。通过采用酵母双杂交技术,确定了编码IGFBP2结合位点的IIp45基因,IIp45蛋白的作用为抑制胶质瘤的侵袭性。总之,基因功能学研究表明IGFBP2和IIp45为一对作用相反的胶质瘤侵袭性调节蛋白。

胶质瘤患者血清IGFBP-2的临床意义

目的探讨胰岛素样生长因子结合蛋白-2(IGFBP-2)在胶质瘤患者血清中的表达及其临床意义。方法健康体检者(对照组)20例,胶质瘤患者74例,其中Ⅳ级26例,Ⅲ级14例,Ⅱ级27例,Ⅰ级7例。采用酶联免疫吸附法(ELISA)检测血清IGFBP-2的浓度。结果胶质瘤Ⅱ级、Ⅲ级、Ⅳ级组浓度均高于对照组(P<0.05),Ⅳ级组浓度高于Ⅰ级、Ⅱ级、Ⅲ级组(P<0.05);Ⅳ级胶质瘤中,随着肿瘤的增大,IGFBP-2浓度不断增加;复发性肿瘤组IGFBP-2浓度显著高于未复发组(P<0.05)。结论监测血清IGFBP-2浓度对判断胶质瘤病变性质、恶性程度及复发具有一定的临床意义。

胰岛素样生长因子结合蛋白2在胶质瘤中的表达及临床意义

目的探讨不同病理分级胶质瘤中胰岛素样生长因子结合蛋白2(IGFBP-2)的表达情况,以及与其他分子及临床预后的相关性。方法应用免疫组化法检测45例不同病理分级胶质瘤组织中IGFBP-2的表达,并分析其表达与病理分级、肿瘤组织P53和Ki-67、患者预后的关系。结果IGFBP-2在肿瘤组织中的表达随肿瘤病理分级升高而升高,与P53和Ki-67的表达显著相关,肿瘤IGFBP-2表达高的患者复发期和总生存期均明显缩短。结论肿瘤组织IGFBP-2的表达情况是辅助胶质瘤诊断和预测预后的有效指标。

胰岛素样生长因子结合蛋白2促进神经胶质瘤干细胞的增殖与迁移侵袭

背景:目前关于血清胰岛素样生长因子结合蛋白2(recombinant insulin like growth factor binding protein 2,IGFBP-2)对神经胶质瘤影响的分子机制仍不明确,并且内源性IGFBP-2无法解释血清中IGFBP-2的一系列作用,需进一步阐明外源性IGFBP-2的作用。目的:观察IGFBP-2干预后神经胶质瘤干细胞的增殖与迁移侵袭能力变化。方法:采用免疫磁珠技术从人胶质瘤细胞U251细胞中分离CD133^+胶质瘤干细胞,免疫荧光染色检测细胞CD133、Nestin的表达进行鉴定;将CD133^+胶质瘤干细胞分2组干预,以500μg/L IGFBP-2干预48 h作为实验组,未经IGFBP-2干预作为对照组。CCK-8法检测细胞增殖能力,Transwell小室实验检测细胞迁移、侵袭能力,采用Western blot检测PCNA、Ki-67、ERK及p-ERK蛋白表达。结果与结论:(1)实验组培养2-5 d的吸光度值明显高于对照组,差异有显著性意义(P<0.05);实验组细胞增殖相关蛋白PCNA、Ki-67表达高于对照组,差异有显著性意义(P<0.05);(2)实验组迁移细胞数明显多于对照组,差异有显著性意义(P<0.05);(3)实验组侵袭细胞数明显多于对照组,差异有显著性意义(P<0.05);(4)两组ERK蛋白表达无差异,但实验组p-ERK蛋白明显高于对照组,差异有显著性意义(P<0.05);(5)结果表明,IGFBP-2可促进神经胶质瘤干细胞的增殖、迁移与侵袭,并且ERK通路可能在其中发挥了一定的作用。

Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis

AIM: To characterize how insulin-like growth factor 2 (IGF2) mRNA binding protein p62/IMP2-2 promotes steatohepatitis in the absence of dietary cholesterol.

胰岛素样生长因子结合蛋白-2在U251细胞中对FAK磷酸化的促进作用

目的探讨外源性胰岛素样生长因子结合蛋白-2(insulin-like growth factor binding protein-2,IGFBP-2)在人胶质母细胞瘤细胞株U251细胞中,对黏着斑激酶(focal adhesion kinase,FAK)磷酸化的影响,从而提示IGFBP-2增强肿瘤细胞迁移、侵袭的机制。方法通过免疫荧光染色及蛋白印记试验检测IGFBP-2对FAK磷酸化的影响。结果在U251细胞中,500ng/mlIGFBP-2作用5分钟后,FAK磷酸化增强近一倍(P<0.05),作用30min后,FAK磷酸化增强近2倍(P<0.01)。结论IGFBP-2可能通过FAK信号通路促进胶质瘤细胞迁移和侵袭。

Possible roles of insulin, IGF-1 and IGFBPs in initiation and progression of colorectal cancer

AIM: To investigate the roles of serum insulin, insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding proteins (IGFBPs) in the initiation and progression of colorectal cancer.

Expression of albumin, IGF-1, IGFBP-3 in tumor tissues and adjacent non-tumor tissues of hepatocellular carcinoma patients with cirrhosis

AIM： To explore the expression of albumin （ALB）, insulinlike growth factor （IGF）-I, and insulin-like growth factor binding protein （IGFBP）-3 in tumor tissues and adjacent non-tumor tissues of hepatocellular carcinoma （HCC） patients with cirrhosis.METHODS： Twenty-four HCC patients with cirrhosis who underwent hepatectomy were studied. ALB mRNA, IGF-1 mRNA, and IGFBP-3 mRNA in liver tissues （including tumor tissues and adjacent non-tumor tissues） were detected by reverse transcriptase-polymerase chain reaction（RT-PCR）. Liver Ki67 immunohistochemistry staining was studied. At the same time, 12 patients with cholelithiasis or liver angioma who underwent operation were segregated as normal control.RESULTS： In HCC patients with cirrhosis, hepatic ALB mRNA, IGF-1 mRNA, and IGFBP-3 mRNA of tumor tissues or adjacent non-tumor tissues were lower than the normal liver tissues, while in tumor tissues, hepatic ALB mRNA and IGFBP-3 mRNA were lower, hepatic IGF-1 mRNA was higher than in adjacent non-tumor tissues. Liver Ki67 labeling index （Ki67 LI） in tumor tissues or adjacent nontumor tissues were higher than that in the normal liver tissues, while in tumor tissues it was higher than that in adjacent non-tumor tissues.CONCLUSION： Imbalance of IGF-1 and IGFBP-3 may play a role in hepatocarcinogenesis and tumor development of liver cirrhosis patients.