IGF-I Receptor Gene Research Articles

The miRNA let-7a1 inhibits the expression of insulin-like growth factor 1 receptor (IGF1R) in prostate cancer PC-3 cells

Reduced microRNA (miRNA) let-7a expression and the activation of insulin-like growth factor-1 receptor (IGF1R) signalling are both involved in prostate cancer and progression. In the present study, we demonstrated that the growth inhibitory effect of let-7a1 is directly related to targeting IGF1R gene expression in PC-3 cells. TargetScan predicted three potential target sites (T1, T2 and T3) of let-7a in the 3' untranslational region (3' UTR) of IGF1R mRNA. Real-time PCR, Western blot and luciferase reporter assays were used to detect the effects of let-7a1 overexpression or let-7a1 inhibitor on the IGF1R gene expression in PC-3 cells. The results indicated that let-7a1 could inhibit IGF1R expression by directly targeting the T1 and T2 sites in the 3' UTR of the IGF1R mRNA. We then used RT-PCR, luciferase reporter assays, 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyl-2H-tetrazolium bromide (MTT) assay, flow cytometry and Hoechst 33342 staining to examine whether let-7a1-mediated inhibition of IGF1R expression also affects the IGF1R-mediated signalling events, including Elk1 activity and c-fos gene expression, proliferation, apoptosis and cell cycle. We demonstrated that let-7a1-mediated IGF1R downregulation was accompanied by attenuation of Elk1 activity and c-fos expression, inhibition of cell proliferation, enhanced apoptosis and cell cycle arrest, and that loss function of let-7a1 via inhibition can upregulate IGF1R accompanied by an increase of Elk1 activity and c-fos expression, thereby enhancing cell proliferation. Altogether, these findings suggest that let-7a may be novel therapeutic candidate for prostate cancer.

Novel polymorphisms of the IGF1R gene and their association with average daily gain in Egyptian buffalo (Bubalus bubalis)

The objective of this study was to detect insulin-like growth factor 1 receptor (IGF1R) polymorphisms, their allele, and genotype frequencies and to determine associations between these polymorphisms and growth traits in Egyptian water buffalo. Three loci of the IGF1R coding region were amplified by RT-PCR and, subsequently, subjected to sequence analysis, followed by single-strand conformation polymorphism to identify different allelic patterns. A total of 11 novel polymorphisms were detected; 6 SNPs among Egyptian water buffaloes and 5 polymorphisms compared with Indian buffalo (Y12700). Three of those polymorphisms; GAG Indel polymorphism, C261G, and G263C SNPs, were nonsynonymous mutations. The GAG Indel polymorphism led to deletion of E (glutamic) amino acid (aa) in the IGF1R of Egyptian water buffaloes compared with Indian buffalo. However, C261G SNP, which replaced A (alanine) by G (glycine) aa, and G263C SNP, which changed A (alanine) to P (proline) aa, were detected among Egyptian water buffaloes. Three different single-strand conformation polymorphism patterns were observed in exon 21: CC/CC, GG/GG, and CG/GC with frequencies of 0.291, 0.253, and 0.556, respectively. The heterozygous animals (CG/GC) had a higher ADG than homozygous animals (CC/CC and GG/GG) from birth to 6 mo of age. We conclude that the heterozygous haplotype, C261G/G263C, in exon 21 of the IGF1R gene is associated with the ADG during the early stages of life (from birth to 6 mo of age) and could be used as a genetic marker for selection of growth traits in Egyptian buffalo.

Association of two SNPs in the coding region of the insulin-like growth factor 1 receptor (IGF1R) gene with growth-related traits in Angus cattle

The insulin-like growth factor 1 (IGF-1) is considered to be a factor that mainly regulates growth, differentiation, and the maintenance of various function in numerous tissues through binding to a family of transmembrane tyrosine kinase receptors, signaling primarily through the insulin-like growth factor 1 receptor (IGF-1R) encoded by the IGF1R gene. The objectives of the present study were to estimate the allele and genotype frequencies of the IGF1R/MspI (silent mutation within exon 12) and the IGF1R/TaqI (within the 3′ untranslated region, 3′UTR) gene polymorphisms in beef cattle and to determine associations between these polymorphisms and growth traits. In a preliminary study on 310 Angus calves, association analyses with three production traits (birth weight, BWT; weaning weight adjusted to 210 days, WWT210; and average daily gain, ADG) were conducted. The GG genotype of the IGF1R/e12/MspI polymorphism was significantly associated (P ≤ 0.05) with a higher WWT210 (+5.06 kg) compared to the AG genotype. Polymorphism within the 3′UTR had no significant effect on growth traits. The effect of combined genotypes was also examined. At WWT210, calves with the GG/AA and GG/AG combinations were heavier than calves with the AG/AA and AG/AG combined genotypes (P ≤ 0.05). To our knowledge, this is the first report of a polymorphism within the coding region of the Bos taurus IGF1R gene.

Expression of insulin-like growth factor 1 receptor in rat retina following optic nerve injury

To investigate the apoptosis in retinal ganglion cells (RGCs) and insulin-like growth factor 1 receptor (IGF-1R) in the retina following optic nerve crush. Healthy Wistar rats (N = 70) were divided into two groups: a normal control group and an optic nerve injury group. Immunohistochemistry and flow cytometry were performed to detect the expression of IGF-1R and to measure the apoptosis of RGCs, respectively. Immunohistochemistry revealed that at 1 hr after optic nerve injury, IGF-1R immunoreactivity began to increase and reached a maximal level at 24 hr (p < 0.05), where it remained elevated up to 14 days after injury. RGC apoptosis in the normal control group was 0.53%, while the apoptosis rate in the optic nerve injury group increased over time. The apoptosis rate in the optic nerve injury group was 1.4% at 1 hr, 4.4% at 6 hr, 5.2% at 12 hr and reached a maximal level (8.5%) at 24 hr. Subsequently, the rate declined to 1.9% 7 days after injury and 0.9% 2 weeks after injury. The IGF-1R immunereactivity in the retina increased after optic nerve injury. IGF-1R may regulate the apoptosis and regeneration of RGCs at different stages after optic nerve injury.

Association of single nucleotide polymorphism of insulin-like growth factor-1 receptor with genetic susceptibility in different gender children with idiopathic short stature

Objective To explore the association between single nucleotide polymorphisms(SNP) in insulin-like growth factor-1 receptor gene(IGF-1R gene) and susceptibility to idiopathic short stature(ISS). Methods Case-control method was employed, an experimental group included 788 children with clinically diagnosed ISS (523 male and 265 female)and a healthy control group included 572 healthy children (286 male and 286 female). SNPs were genotyped by using the SNaPshot Multiplex System. Results 1.In male subjects, different genotypes at rs1976667 locus were statistically associated with genetic susceptibility to ISS(P=0.047), showing the G dominant inheritance(P=0.020) and being related to the genetic target height.G allele gene at rs2684788 locus was statistically associated with genetic susceptibility to ISS(P=0.021), showing G dominant inheritance(P<0.001), and being related to the genetic target height and body mass index.2.In female subjects, different genotypes at rs1976667 locus were statistically asso-ciated with genetic susceptibility to ISS(P=0.012), showing the G dominant inheritance(P=0.003). Different genotypes at rs2684788 locus genotypes(P=0.005), G allele(P=0.006)and G recessive mode(P<0.001) were all statistically associated with genetic susceptibility to ISS. Conclusions The rs1976667 and rs2684788 locus of human IGF-1R gene were probably associated with genetic susceptibility to ISS of different gender.Different clinical phenotypes of ISS may be relevant to SNP polymorphism. Key words: Idiopathic short stature; Insulin-like growth factor-1 receptor; Single nucleotide polymorphisms; Genetic susceptibility

Intragenic deletions of the IGF1 receptor gene in five individuals with psychiatric phenotypes and developmental delay

Haploinsufficiency of the gene encoding the insulin-like growth factor 1 receptor (IGF1R), either caused by telomeric 15q26 deletions, or by heterozygous point mutations in IGF1R, segregate with short stature and various other phenotypes, including microcephaly and dysmorphic facial features. Psychomotor retardation and behavioral anomalies have been seen in some cases. Here we report small, intragenic deletions of IGF1R, identified by chromosome microarray analysis in two unrelated families affected primarily with neuropsychiatric phenotypes including developmental delay, intellectual disability and aggressive/autoaggressive behaviors. The deletions are in frame, and both wild-type and mutant mRNAs are expressed as measured by quantitative real-time PCR. While short stature is considered a phenotypic hallmark of IGF1R haploinsufficiency, the present report suggests that in frame exon deletions of IGF1R present predominantly with cognitive and neuropsychiatric phenotypes.

Association of insulin growth factor-1 receptor gene polymorphisms with genetic susceptibility to idiopathic short stature

The association between single nucleotide polymorphisms (SNPs) in the insulin-like growth factor-1 receptor (IGF-1R) gene and susceptibility to idiopathic short stature (ISS) was investigated. Seven hundred and twelve Chinese children clinically diagnosed with ISS and 575 normal individuals were recruited between 2008 and 2011, and their SNPs were genotyped. Preliminary screening revealed that the rs1976667 and rs2684788 loci were significantly associated with genetic susceptibility to ISS (P = 0.03636 and P = 0.01352, respectively). Stratification by sex revealed that in males, different genotypes at the rs1976667 locus were significantly associated with genetic susceptibility to ISS (P = 0.047), showing G dominant inheritance (P = 0.018). The G allele at the rs2684788 locus was significantly associated with genetic susceptibility to ISS (P = 0.016), showing G dominant inheritance (P < 0.001). In females, different genotypes at the rs1976667 locus were significantly associated with genetic susceptibility to ISS (P = 0.011), showing G dominant inheritance (P = 0.005). Different genotypes at the rs2684788 locus, the G allele, and the G recessive mode of inheritance were all significantly associated with genetic susceptibility to ISS (P < 0.005). The genotypes at the rs1976667 locus in the female ISS group were significantly correlated to IGF-1 standard deviation integral value (SDS) (P = 0.006). The rs1976667 and rs2684788 loci of the human IGF-1R gene are likely associated with different genetic susceptibilities to ISS in males and females. Different clinical phenotypes of ISS may be associated with SNPs of IGF-1R.

Overexpression of insulin-like growth factor-I receptor as a pertinent biomarker for hepatocytes malignant transformation

To investigate the dynamic features of insulin-like growth factor-I receptor (IGF-IR) expression in rat hepatocarcinogenesis, and the relationship between IGF-IR and hepatocytes malignant transformation at mRNA or protein level. Hepatoma models were made by inducing with 2-fluorenylacetamide (2-FAA) on male Sprague-Dawley rats. Morphological changes of hepatocytes were observed by pathological Hematoxylin and eosin staining, the dynamic expressions of liver and serum IGF-IR were quantitatively analyzed by an enzyme-linked immunosorbent assay. The distribution of hepatic IGF-IR was located by immunohistochemistry. The fragments of IGF-IR gene were amplified by reverse transcription-polymerase chain reaction, and confirmed by sequencing. Rat hepatocytes after induced by 2-FAA were changed dynamically from granule-like degeneration, precancerous to hepatoma formation with the progressing increasing of hepatic mRNA or IGF-IR expression. The incidences of liver IGF-IR, IGF-IR mRNA, specific IGF-IR concentration (ng/mg wet liver), and serum IGF-IR level (ng/mL) were 0.0%, 0.0%, 0.63 ± 0.17, and 1.33 ± 0.47 in the control; 50.0%, 61.1%, 0.65 ± 0.2, and 1.51 ± 0.46 in the degeneration; 88.9%, 100%, 0.66 ± 0.14, and 1.92 ± 0.29 in the precancerosis; and 100%, 100%, 0.96 ± 0.09, and 2.43 ± 0.57 in the cancerous group, respectively. IGF-IR expression in the cancerous group was significantly higher (P < 0.01) than that in any of other groups at mRNA or protein level. The closely positive IGF-IR relationship was found between livers and sera (r = 0.91, t = 14.222, P < 0.01), respectively. IGF-IR expression may participate in rat hepatocarcinogenesis and its abnormality should be an early marker for hepatocytes malignant transformation.

Insulin-like growth factor-1 receptor protein expression and gene copy number alterations in non–small cell lung carcinomas

Insulin-like growth factor-1 receptor (IGF-1R) is a tyrosine kinase receptor implicated in the pathogenesis of several malignancies and is potentially an attractive target for anticancer treatment. In this study, we included 379 patients who underwent surgical resection (179 diagnosed as having adenocarcinoma [ADC]; 150, squamous cell carcinoma [SCC]; 41, sarcomatoid carcinoma and 9, large cell carcinoma). IGF-1R expression and gene copy number were assessed by immunohistochemistry and bright-field in situ hybridization (BISH), respectively. IGF-1R expression in non-small cell lung carcinoma was observed in 41.4% of samples and was more prevalent in SCC (69.3%) than in ADC (25.1%), large cell carcinoma (33.3%), and sarcomatoid carcinoma (12.2%) (P < .001). Among ADCs, most mucinous ADCs (75%) showed strong membranous staining with the IGF-1R antibody. Compared with protein expression, IGF-1R gene alteration was rare (8.4%). A statistically significant correlation between IGF-1R expression and positive IGF-1R BISH was observed (γ = 0.762, P < .001). IGF-1R-positive tumors were more common in smokers (P = .004), and these tumors were larger (P = .006) than the IGF-1R-negative tumors. IGF-1R BISH positivity was not correlated with any clinicopathologic factor. IGF-1R expression and IGF-1R BISH positivity were not correlated with overall survival. IGF-1R is highly expressed in SCC and mucinous ADC, although copy number alterations in the IGF-1R gene were rare. These findings may have important implications for future anti-IGF-1R therapeutic approaches.

192 RESVERATROL, A NATURAL FOOD COMPOUND, SUPPRESSED THE CELL GROWTH OF BG-1 OVARIAN CANCER CELLS INDUCED BY 17β-ESTRADIOL OR BISPHENOL A THROUGH DOWNREGULATING ESTROGEN RECEPTOR α AND INSULIN-LIKE GROWTH FACTOR-1 RECEPTOR

Resveratrol (trans-3,4,5-trihydroxystilbene; RES) was adopted in this study as a novel phytoestrogen displaying antioxidant, antiinflammatory, and anticancer effects. In this study, we evaluated the inhibitory effect of RES on the cell growth induced by 17β-oestradiol (E2), a typical oestrogen, and bisphenol A (BPA), an endocrine-disrupting chemical (EDC) in BG-1 ovarian cancer cells expressing oestrogen receptors (ER) through down-regulating oestrogen receptor α (ERa) and insulin-like growth factor-1 receptor (IGF-1R). The EDC and oestrogen appear to promote the development of the oestrogen-dependent cancers. Thus, we need to develop therapeutic methods for EDC-dependent cancers. In in vitro experiments, we examined the cell viability and mRNA expression of ERa ± IGF-1R genes following the treatments with E2 or BPA in the presence or absence of RES or ICI 182 780, an ER antagonist, by MTT assay and RT-PCR, respectively. We also examined the protein level of ERa, phosphorylated insulin receptor substrate-1 (IRS-1), phosphorylated Akt1/2/3, p21, and cyclin D1 by Western blot analysis. Treatment with E2 or BPA remarkably increased the growth of BG-1 ovarian cancer cells, and their enhanced cell growth appeared to be mediated by ERa. In addition, the treatment of BG-1 ovarian cancer cells with E2 or BPA resulted in an increase in ERa and IGF-1R gene expressions. However, co-treatment of RES reversed E2- or BPA-induced ovarian cancer cell growth and mRNA expressions of ERa and IGF-1R. The protein levels of phosphorylated IRS-1 and Akt were upregulated by E2 or BPA, whereas these levels were downregulated by co-treatment of RES in the presence of E2 or BPA. Taken together, these results indicate that RES may effectively inhibit ovarian cancer cell growth via downregulating cross-talk between ERa and IGF-1R. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Education, Science and Technology (MEST) of Korea government (no. 2011-0015385).

Protein expression and gene copy number changes of receptor tyrosine kinase in thymomas and thymic carcinomas

Insulin-like growth factor-1 receptor (IGF-1R), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor-type 2 (HER2), and c-Met are members of the receptor tyrosine kinases (RTKs). The associations between the RTK status [protein expression and gene copy number (GCN)] and patient characteristics and between the RTK status and prognosis remain undetermined. The study included 140 patients who underwent surgery for thymic tumors. Protein expression was evaluated by immunohistochemistry (IHC) and GCN was evaluated by bright-field in situ hybridization (BISH). The correlations between the RTK status and clinicopathological findings were examined. IGF-1R protein was frequently detected in thymic carcinoma (83.8%) and EGFR in thymic tumors (91.4%). Thirty-six and 39 tumors were BISH high for IGF-1R and EGFR, respectively: 28 and 25 exhibited high polysomy; 8 and 14 exhibited gene amplification. No tumor was positive for HER2 or c-Met by IHC and BISH. Multivariate analysis revealed that IGF-1R gene amplification (P = 0.027), thymic carcinoma histology, and higher tumor stage were significantly correlated with an adverse prognosis. Thymic epithelial tumors frequently express IGF-1R and/or EGFR proteins. IGF-1R gene amplification is suggested to define an unfavorable subset for thymic epithelial tumors.

Homozygous mutation of the IGF1 receptor gene in a patient with severe pre- and postnatal growth failure and congenital malformations

Heterozygous mutations in the IGF1 receptor (IGF1R) gene lead to partial resistance to IGF1 and contribute to intrauterine growth retardation (IUGR) with postnatal growth failure. To date, homozygous mutations of this receptor have not been described. A 13.5-year-old girl born from healthy first-cousin parents presented with severe IUGR and persistent short stature. Mild intellectual impairment, dysmorphic features, acanthosis nigricans, and cardiac malformations were also present. Auxological and endocrinological profiles were measured. All coding regions of the IGF1R gene including intron boundaries were amplified and directly sequenced. Functional characterization was performed by immunoblotting using patient's fibroblasts. IGF1 level was elevated at 950NG/ML (+7 S.D.). Fasting glucose level was normal associated with high insulin levels at baseline and during an oral glucose tolerance test. Fasting triglyceride levels were elevated. sequencing of the IGF1R gene led to the identification of a homozygous variation in exon 2: c.119G>T (p.Arg10Leu). As a consequence, IGF1-dependent receptor autophosphorylation and downstream signaling were reduced in patient's fibroblasts. Both parents were heterozygous for the mutation. The homozygous mutation of the IGF1R is associated with severe IUGR, dysmorphic features, and insulin resistance, while both parents were asymptomatic heterozygous carriers of the same mutation.

IGF receptor gene variants in normal adolescents: effect on stature

IGF1 is essential for human growth and mediates its effects through the type 1 IGF receptor (IGF1R). Our objective was to determine the frequency of certain previously reported IGF1R gene variants in the normal population and their effect on stature. A cross-sectional study was conducted in a population of 2500 children enrolled in public school grades 5 through 12 for whom DNA and anthropometric data were available. Subjects were genotyped at five previously reported loci that affect receptor abundance or function. The frequency of the following IGF1R variants Arg108Gln, Lys115Asn, Arg59stop, Arg481Gln, and Arg605His was measured by a PCR-based assay. Circulating concentrations of IGF1 or IGF binding protein-3 (IGFBP3) were measured by ELISA in those affected and matched controls. A scan of 1300 subjects detected none with Arg108Gln, Lys115Asn, or Arg59stop mutations. In contrast, nucleotide changes leading to heterozygosity at codon 605 were identified in nine of 2500 subjects and six of 1800 subjects at codon 481. These individuals were, on average, 4 cm shorter than the others. There were no differences in circulating concentrations of IGF1 or IGFBP3 between those with the gene variants and controls matched for sex, ethnicity, age, and BMI. Rare IGF1R variants exerting a moderate effect on stature are present in the general population, supporting the importance of IGF1R function in growth control and indicating that variation in height within healthy individuals may be explained, in some cases, by larger effects of a small subset of gene variants.

An association between lifespan and variation in insulin-like growth factor I receptor in sheep1

Longevity in livestock is a valuable trait. When productive animals live longer, fewer replacement animals need to be raised. However, selection for longevity is not commonly the focus of breeding programs as direct selection for long-lived breeding stock is virtually impossible until late in the reproductive life of the animal. Additionally the underlying genetic factors or genes associated with longevity are either not known, or not well understood. In humans, there is evidence that IGF 1 receptor (IGF1R) is involved in longevity. Polymorphism in the IGF1R gene has been associated with longevity in a number of species. Recently, 3 alleles of ovine IGF1R were identified, but no analysis of the effect of IGF1R variation on sheep longevity has been reported. In this study, associations between ovine IGF1R variation, longevity and fertility were investigated. Polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) was used to type IGF1R variation in 1,716 New Zealand sheep belonging to 6 breeds and 36 flocks. Ovine IGF1R C was associated with age when adjusting for flock (present 5.5 ± 0.2 yr, absent 5.0 ± 0.1 yr, P = 0.02). A general linear mixed effects model suggested an association (P = 0.06) between age and genotype, when correcting for flock. Pairwise comparison (least significant difference) of specific genotypes revealed the difference to be between AA (5.0 ± 0.1 yr) and AC (5.6 ± 0.2 yr, P = 0.02). A weak negative Pearson correlation between fertility and longevity traits was observed (r = -0.25, P < 0.01). The finding of an association between variation in IGF1R and lifespan in sheep may be useful in prolonging the lifespan of sheep.

Novel missense mutation in the IGF‐I receptor L2 domain results in intrauterine and postnatal growth retardation

IGFs play key roles in intrauterine and postnatal growth through the IGF-I receptor (IGF-IR). We identified a family bearing a new heterozygous missense mutation at the L2 domain of IGF-IR (R431L). We analysed the nucleotide sequences of the IGF1R gene of the family. We prepared R(-) cells (fibroblasts with targeted disruption of the IGF-IR gene) expressing wild-type or R431L IGF-IR and performed functional analyses by evaluating IGF-I binding, IGF-I-stimulated DNA synthesis, tyrosine phosphorylation of IGF-IR and its substrates, and internalization by measuring [(125) I]IGF-I internalization. We also performed confocal microscopy analysis. We identified a family bearing a new heterozygous missense mutation at the L2 domain of IGF-IR (R431L) through an 8-year-old girl and her mother, both born with intrauterine growth retardation. In experiments conducted using cells homozygously transfected with the IGF-IR R431L mutation; (i) IGF-I binding was not affected; (ii) DNA synthesis induced by IGF-I was decreased; (iii) IGF-IR internalization stimulated by IGF-I was decreased and (iv) IGF-I-stimulated tyrosine phosphorylation was reduced IGF-IR by low concentrations of IGF-I and on insulin receptor substrate (IRS)-1 and IRS-2. A missense mutation (R431L) leads to the inhibition of cell proliferation, attenuation of IGF signalling and decrease in internalization of IGF-IR. The results of this study suggest a novel link between a mutation at the IGF-IR L2 domain and intrauterine and postnatal growth retardation.

Association between polymorphisms of insulin-like growth factor receptor gene and susceptibility to non-small-cell lung cancer in Fujian Chinese

To assess the association between polymorphisms of insulin-like growth factor receptor (IGF-1R and IGF-2R) and genetic susceptibility and non-small-cell lung cancer (NSCLC). A case-control study of 260 patients with NSCLC and 258 cancer-free subjects from Fujian was carried out. Genotypes of polymorphisms of IGF-1R +1013 and IGF-2R +1619 were determined by DNA sequencing and polymerase chain reaction-restrictive fragment length polymorphism. (1) Significant differences in allele frequency and genotypes distribution of IGF-1R +1013 (G/A) were found between the two groups (P<0.05). On multivariate analysis after controlling age and gender, compared with GG genotype of the IGF-1R +1013 (G/A), the risk of lung cancer for individuals with GA genotype was increased by 0.80 times (95%CI: 1.24-2.59, P = 0.002), those with AA genotype was increased by 2.56 times (95%CI: 1.78-7.26, P = 0.000), and those with the polymorphic A variant (GA or AA) was increased by 0.98 times (95%CI: 1.39-2.83, P = 0.000). No significant differences in genotypic or allelic frequencies of IGF-2R +1619 (G/A) were found between the two groups (P> 0.05). (2) After stratification of the clinical status, the IGF-1R +1013 A allele increased the risk of lung squamous cell carcinoma (OR = 3.20, 95%CI: 1.75-5.84, P = 0.000), lung adenocarcinoma (OR = 1.55, 95%CI: 1.00-2.41, P = 0.049) and other types of lung cancer (OR = 1.96, 95% CI: 1.10-3.49, P = 0.023), but no association was found between the two SNPs and other clinical features. (3) IGF-1R +1013 (G/A) and IGF-2R +1619(G/A) polymorphisms showed a synergic effect (P = 0.003). The common IGF-1R gene polymorphism G1013A may influence the risk of lung cancer. The polymorphisms of IGF-1R +1013 (G/A) and IGF-2R +1619 (G/A) have synergistic influence on the risk of lung cancer.

BRCA1 is Expressed in Uterine Serous Carcinoma (USC) and Controls Insulin-Like Growth Factor I Receptor (IGF-IR) Gene Expression in USC Cell Lines

The insulin-like growth factor I receptor (IGF-IR) and BRCA1 affect cell growth and apoptosis. Little information is available about BRCA1 activity on the IGF signaling pathway. This study evaluated the effect of BRCA1 on IGF-IR expression. BRCA1 and IGF-IR immunohistochemistry on archival tissues (35 uterine serous carcinomas [USCs] and 17 metastases) were performed. USPC1 and USPC2 cell lines were transiently cotransfected with an IGF-IR promoter construct driving a luciferase reporter gene and a BRCA1 expression plasmid. Endogenous IGF-IR levels were evaluated by Western immunoblotting. We found high BRCA1 and IGF-IR protein expression in primary and metastatic USC tumors. All samples were immunostained for BRCA1-71% strongly stained; and 33/35 (94%) were stained positive for IGF-IR-2 (6%) strongly stained. No difference in BRCA1 and IGF-IR staining intensity was noted between BRCA1/2 mutation carriers and noncarriers. Metastatic tumors stained more intensely for BRCA1 than did the primary tumor site (P = 0.041) and with borderline significance for IGF-IR (P = 0.069). BRCA1 and IGF-IR staining did not correlate to survival. BRCA1 expression led to 35% and 54% reduction in IGF-IR promoter activity in the USPC1 and USCP2 cell lines, respectively. Western immunoblotting showed a decline in phosphorylated IGF-IR and phosphorylated AKT in both transiently and stably transfected cells. BRCA1 and IGF-IR are highly expressed in USC tumors. BRCA1 suppresses IGF-IR gene expression and activity. These findings suggest a possible biological link between the BRCA1 and the IGF-I signaling pathways in USC. The clinical implications of this association need to be explored.

Study of the correlation about IGF-I receptor and β-amyloid in Alzheimer's disease

To detect the expression of IGF-I receptor in the hippocampus neuron of rat treated by Aβ(1-42), and thus from the receptor level explore the disorder of central nervous insulin signaling and the possible molecular mechanism of Alzheimer disease. Cultured primary hippocampus neurons were treated with different concentrations of Aβ(1-42), apoptosis rate was detected by flow cytometry, real-time quantitative PCR and Western blot were used to detect IGF-I receptor expression. Primary cultured cells mature in 7(th) days; after detected by flow cytometry, early apoptosis rate in Aβ(1-42) 0, 30, 60, 100 µmol/L groups showed a concentration-dependent increase. PCR results showed that, in 30 (1.72 ± 0.33) and 60 µmol/L (1.86 ± 0.36) treatment groups levels of the IGF-I receptor gene were significantly higher than the control group (regarded as 1) (P < 0.01), 100 µmol/L group (0.70 ± 0.15) was significantly lower than the control group (P < 0.05). Results of Western blot showed 30 and 60 µmol/L protein level of the treatment groups are 1.08 ± 0.04, 1.74 ± 0.08 (P < 0.01) and 100 µmol/L group was 0.79 ± 0.11(P < 0.05), which had same trend with PCR. Aβ(1-42) induced altered expression of IGF-I receptors in rat hippocampus cells, maybe one of the molecule mechanisms of Alzheimer disease.

Abstract 2610: Association of polymorphisms and haplotypes in the insulin-like growth factor 1 receptor (IGF1R) gene with breast cancer in Korean women

Abstract Abstract The insulin-like growth factor (IGF) signaling axis plays an important role in cancer biology. The insulin-like growth factor 1 receptor (IGF1R) is a tyrosine kinase growth factor receptor that plays important roles in numerous cellular functions and signal transduction pathways. IGF1R may also play a role in the initiation and progression of breast cancer. However, studies of common variation in the IGF1R gene, involved in steroid hormone and IGF-1 metabolism, have yet to provide convincing evidence that such variants predict breast cancer risk. We genotyped 384 tagging single nucleotide polymorphisms (SNPs) in 1026 cases of breast cancer and 392 age-matched control in a population of Korean women. Of the 384 SNPs, fifty one SNPs in the IGF1R gene were examined for association with breast cancer in the study. All the SNPs investigated were in Hardy-Weinberg equilibrium. These SNPs tested were significantly associated with breast cancer risk, after correction for multiple comparisons stratified by adjusting for age at diagnosis, BMI, age at menarche, and age at first parturition. Among 51 IGF1R SNPs, three intron located SNPs (rs8032477, rs11635251, and rs12916884) with homozygous genotype (variant genotype) had increased risk of breast cancer (OR(CI 95%): 0.66(0.44-0.99), 0.54(0.37-0.80), and 0.59(0.37-0.94)). Seven of the 51 IGF1R SNPs were in LD and in one haplotype block, and were likely to be associated with breast cancer risk. Overall, this comprehensive case-control study found statistically significant associations between breast cancer risk and polymorphisms in IGF1R gene. Taking the status of the IGF1R polymorphism into consideration, our results may help in improving the ability to develop effective treatment modalities for those conditions in which IGF1R is involved. To the best of our knowledge, this study is the first to demonstrate the association between IGF1R polymorphisms with the risk of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2610. doi:1538-7445.AM2012-2610

Global Methylation Analysis Identifies PITX2 as an Upstream Regulator of the Androgen Receptor and IGF-I Receptor Genes in Prostate Cancer

The insulin-like growth factor-I (IGF-IR) and androgen (AR) receptors are important players in prostate cancer. Functional interactions between the IGF-I and androgen signaling pathways have crucial roles in the progression of prostate cancer from early to advanced stages. DNA methylation is a major epigenetic alteration affecting gene expression. Hypermethylation of tumor suppressor promoters is a frequent event in human cancer, leading to inactivation and repression of specific genes. The aim of the present study was to identify the entire set of methylated genes ("methylome") in a cellular model that replicates prostate cancer progression. The methylation profiles of the P69 (early stage, benign) and M12 (advanced stage, metastatic) prostate cancer cell lines were established by treating cells with the demethylating agent 5-aza-2'-deoxycytidine (5-Aza) followed by DNA microarray analysis. Comparative genome-wide methylation analyses of 5-Aza-treated versus untreated cells identified 297 genes overexpressed in P69 and 191 genes overexpressed in M12 cells. 102 genes were upregulated in both benign and metastatic cell lines. In addition, our analyses identified the PITX2 gene as a master regulator upstream of the AR and IGF-IR genes. The PITX2 promoter was semi-methylated in P69 cells but fully methylated (i. e., silenced) in M12 cells. Epigenetic regulation of PITX2 during the course of the disease may lead to orchestrated control of the AR and IGF signaling pathways. In summary, our results provide new insights into the epigenetic changes associated with progression of prostate cancer from an organ confined, androgen-sensitive disorder to an aggressive, androgen-insensitive disease.