IGF-I Receptor Gene Research Articles

Expression of insulin-like growth factor 2 receptor in corneal keratocytes during differentiation and in response to wound healing.

Insulin-like growth factor 2 receptor (IGF2R) associates with ligands that influence wound healing outcomes. However, the expression pattern of IGF2R and its role in the cornea is unknown. Human keratocytes were isolated from donor corneas. Fibroblasts (fibroblast growth factor 2 [FGF2]-treated) or myofibroblasts (TGF-β1-treated) were analyzed for IGF2R and α-smooth muscle actin (α-SMA) expression by Western blotting and immunolocalization. Mouse corneas were wounded in vivo and porcine corneas ex vivo. The IGF2R and α-SMA protein expression were visualized and quantified by immunohistochemistry. The IGF2R gene expression in human corneal fibroblasts was knocked-down with targeted lentiviral shRNA. The IGF2R is expressed in epithelial and stromal cells of normal human, mouse, and porcine corneas. The IGF2R increases (11.2 ± 0.4-fold) in the epithelial and (11.7 ± 0.9-fold) stromal layers of in vivo wounded mouse corneas. Double-staining with α-SMA- and IGF2R-specific antibodies reveals that IGF2R protein expression is increased in stromal myofibroblasts in the wounded cornea relative to keratocytes in the normal cornea (11.2 ± 0.8-fold). Human primary stromal keratocytes incubated with FGF2 or TGF-β1 in vitro demonstrate increased expression (2.0 ± 0.4-fold) of IGF2R in myofibroblasts relative to fibroblasts. Conversion of IGF2R shRNA-lentiviral particle transduced corneal fibroblasts to myofibroblasts reveals a dependence on IGF2R expression, as only 40% ± 10% of cells transduced converted to myofibroblasts compared to 86% ± 3% in control cells. The IGF2R protein expression is increased during corneal wound healing and IGF2R regulates human corneal fibroblast to myofibroblast differentiation.

Silencing insulin-like growth factor-1 receptor expression inhibits gastric cancer cell proliferation and invasion.

The oncoprotein insulin-like growth factor-1 receptor (IGF-1R) has previously been shown to promote tumorigenesis. Overexpression of IGF-1R is considered to be a critical prerequisite for malignant transformation in numerous human cancers. Therefore, targeting IGF-1R for cancer therapy has gained a lot of interest. In the present study, an RNA interference (RNAi)-mediated IGF-1R gene silencing approach was conducted in BGC823 gastric cancer cells. The tumorigenic and malignant properties of the cells were assessed, in response to reduced IGF-1R expression. Notably, IGF-1R depletion not only inhibited gastric cancer cell growth, resulted in G1 cell cycle arrest and consequently led to apoptosis, but also suppressed cancer cell motility and invasion. The findings of the present study are the first, to the best of our knowledge, to suggest that RNAi-based IGF-1R silencing may be a potential and promising therapeutic strategy for gastric cancer treatment.

PO-0069 Terminal Deletion Of Chromosome 15q Resulting In Haploinsufficiency Of The Igf-1 Receptor And Marked Elevation Of Igf-1

<h3>Introduction</h3> Ten to fifteen percent of small for gestational age (SGA) infants demonstrate failure of catch-up growth. Haploinsufficiency of the insulin-like growth factor-1 receptor (IGF1R) gene due to monosomy 15q is an extremely rare cause with 16 cases reported in the literature. We describe the phenotype of such a patient including biochemical findings, auxology and management. <h3>Case</h3> A three-year-old female with global developmental delay and autistic spectrum disorder was evaluated for short stature. Height was 82 cm (-3.7 SDS) and weight was 12.5 kg (-1.3 SDS). She was born at term weighing 2.88 kg and was microcephalic and dysmorphic. Array CGH revealed an unbalanced translocation resulting in trisomy of the terminal portion of chromosome 10p and monosomy 15q26.3- &gt;qter which contains the region coding for IGF1R. IGF-1(243 µg/L) and IGFBP-3 (3501 ng/ml) levels were markedly elevated; +4.7 SDS and +3.3 SDS respectively. The marked elevation in IGF-1 levels was considered a relative contraindication to GH therapy. <h3>Discussion</h3> Haploinsufficency of IGF1R gene is associated with elevated levels of IGF-1 as a result of target organ resistance. Exogenous growth hormone, while further elevating IGF-1, in many cases facilitates catch-up growth albeit to a lesser extent than other ex-SGA infants. In this case IGF-1 levels were exceptionally high, precluding growth hormone therapy. <h3>Conclusion</h3> Deletions involving the IGF1R gene are a rare but treatable cause of short stature. This case is unusual however, as marked elevation of IGF-1 at baseline precluded GH therapy.

Genetic association study between INSULIN pathway related genes and high myopia in a Han Chinese population.

To investigate the association between insulin (INS) pathway related genes, including INS, insulin receptor (INSR), insulin receptor substrate 1 (IRS1), insulin-like growth factor 2 (IGF2), IGF2 receptor (IGF2R) and IGF binding protein 1 (IGFBP1), and high myopia (HM) in a Han Chinese population, we have genotyped 24 single nucleotide polymorphisms (SNPs) of these genes in this cohort by Sequenom MassARRAY method. The genotyping data was analyzed by χ(2) test and the linkage disequilibrium block structure was examined by Haploview software. SNPs in the INS-IGF2 region (rs2070762 and rs1003483), and the INSR gene (rs3745551 and rs2229429) showed significant association with HM (allelic P = 0.0085, 0.0494, 0.0171 and 0.0238, respectively). Under the model of risk genotype combination of INSR and IRS1, carrying the variant allele (A) of the IRS1 Gly972Arg SNP (rs1801278) further increased the risk among the rs2229429T allele carriers (odds ratio 6.865, 95 % confidence interval 1.533-30.745). None of the SNPs in the IGF2R and IGFBP1 genes were found to be significantly associated with HM. Genetic variants in the insulin signaling pathway genes may increase the susceptibility of high myopia in Han Chinese.

Angelica Sinensis polysaccharides stimulated UDP-sugar synthase genes through promoting gene expression of IGF-1 and IGF1R in chondrocytes: promoting anti-osteoarthritic activity.

BackgroundOsteoarthritis (OA) is a chronic joints disease characterized by progressive degeneration of articular cartilage due to the loss of cartilage matrix. Previously, we found, for the first time, that an acidic glycan from Angelica Sinensis Polysaccharides (APSs), namely the APS-3c, could protect rat cartilage from OA due to promoting glycosaminoglycan (GAG) synthesis in chondrocytes. In the present work, we tried to further the understanding of ASP-3c’s anti-OA activity.Methodology/Principal FindingsHuman primary chondrocytes were treated with APS-3c or/and recombinant human interleukin 1β (IL-1β). It turned out that APS-3c promoted synthesis of UDP-xylose and GAG, as well as the gene expression of UDP-sugar synthases (USSs), insulin like growth factor 1 (IGF1) and IGF1 receptor (IGF1R), and attenuated the degenerative phenotypes, suppressed biosynthesis of UDP-sugars and GAG, and inhibited the gene expression of USSs, IGF1 and IGF1R induced by IL-1β. Then, we induced a rat OA model with papain, and found that APS-3c also stimulated GAG synthesis and gene expression of USSs, IGF1 and IGF1R in vivo. Additionally, recombinant human IGF1 and IGF1R inhibitor NP-AEW541 were applied to figure out the correlation between stimulated gene expression of USSs, IGF1 and IGF1R induced by APS-3c. It tuned out that the promoted GAG synthesis and USSs gene expression induced by APS-3c was mediated by the stimulated IGF1 and IGF1R gene expression, but not through directly activation of IGF1R signaling pathway.Conclusions/SignificancesWe demonstrated for the first time that APS-3c presented anti-OA activity through stimulating IGF-1 and IGF1R gene expression, but not directly activating the IGF1R signaling pathway, which consequently promoted UDP-sugars and GAG synthesis due to up-regulating gene expression of USSs. Our findings presented a better understanding of APS-3c’s anti-OA activity and suggested that APS-3c could potentially be a novel therapeutic agent for OA.

Apoptosis of Purkinje and granular cells of the cerebellum following chronic ethanol intake.

Ethanol alters motricity, learning, cognition, and cellular metabolism in the cerebellum. We evaluated the effect of ethanol on apoptosis in Golgi, Purkinje, and granule cells of the cerebellum in adult rats. There were two groups of 20 rats: a control group that did not consume ethanol and an experimental group of UChA rats that consumed ethanol at 10% (<2 g ethanol/kg body weight/day). At 120 days old, rats were anesthetized and decapitated, and their cerebella were collected and fixed. Cerebellar sections were subjected to immunohistochemistry for terminal deoxynucleotide transferase dUTP nick end labeling (TUNEL), caspase-3, X-linked inhibitor of apoptosis protein (XIAP), and insulin-like growth factor 1-receptor (IGF-1R); real-time PCR (RT-PCR) to determine caspase-3, XIAP, and IGF-1R gene expression; and transmission electron microscopy (TEM). We identified fragmentation of DNA and an increase in caspase-3 protein and XIAP in Purkinje cells, whereas granule cells exhibited increased caspase-3 and XIAP. IGF-1R expression was unchanged. There was no significant difference in gene expression of caspase-3, XIAP, and IGF-1R. There were an increase in lipid droplets, a reduction in the cellular cytoplasm in electron-dense nuclei, and changes in the myelin sheath in the cerebellar cortex. In conclusion, our data demonstrated that ethanol induced apoptosis in the Purkinje and granule cells of the cerebellum of adult UChA rats.

Alterations of insulin-like growth factor-1 receptor gene copy number and protein expression are common in non-small cell lung cancer

AimsInsulin-like growth factor-1 receptor (IGF1R) is a tyrosine kinase membrane receptor involved in tumourigenesis that may be a potential therapeutic target. We aimed to investigate the incidence and prognostic significance...

Relevance of insulin-like growth factor 1 receptor gene expression as a prognostic factor in non-small-cell lung cancer.

Signalling through the insulin-like growth factor 1 receptor (IGF-1R) is implicated in carcinogenesis, metastasis, and resistance to cytotoxic cancer therapies. The purpose of this study was to investigate the prognostic role of IGF-1R expression in surgically resected non-small-cell lung cancer (NSCLC), and responses to IGF-1R tyrosine kinase inhibitor NVP-ADW742 in a panel of lung cancer cell lines. Insulin-like growth factor 1 receptor (IGF-1R) expression was evaluated by quantitative RT-PCR in 115 NSCLC samples and in a panel of 6 NSCLC cell lines. Cytotoxicity experiments with IGF-1R inhibitor and conventional systemic drugs such as paclitaxel in cell lines were realised. Insulin-like growth factor 1 receptor (IGF-1R) was differentially expressed across histologic subtypes, with the lowest levels observed in squamous cell tumours. Median survival was longer in patients with squamous tumour histology expressing low IGF-1R levels. In multivariable analysis, ageing and high tumour stage were significant predictors of worse overall survival. The hazard of death was lower in patients with squamous histology and low IGF-1R gene expression. There was no correlation between IGF-1R expression and response to tyrosine kinase inhibitor in cell lines tested. However, combination drug treatment resulted in synergistically enhanced antiproliferative effects on several cell lines. These findings suggest that IGF-1R is a potential target for therapy in NSCLC patients. Combination therapies will have an important role in treatment.

Impact of insulin-like growth factor 2, insulin-like growth factor receptor 2, insulin receptor substrate 2 genes polymorphisms on susceptibility and clinicopathological features of hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is one of the major causes of cancer-related death worldwide. Insulin-like growth factor-2 (IGF-2) is an important autocrine and paracrine growth factor which may induce cell proliferation and inhibit cell apoptosis leading to the transformation of normal cells into malignant cells. This study aimed to evaluate the possible roles of IGF-2, insulin-like growth factor-2 receptor (IGF-2R), and insulin receptor substrate (IRS)-2 genes polymorphisms in susceptibility and clinicopathological features of HCC in Egyptian population. Materials and methodsFour hundred and twenty-six HCC patients and 334 controls were enrolled in the study. Polymorphisms of IGF-2+3580, IGF-2+3123, IGF-2R 1619, and IRS-2 1057 gene were detected using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Serum IGF-2 were determined using ELISA. ResultsSerum IGF-2 levels were significantly lower in HCC patients than in healthy controls. IGF-2+3580 AA genotype, IGF-2+3123 GG genotype or G allele, IRS-2 1057 DD genotype and D allele were significantly associated with HCC risk. The combination of IGF-2+3580 AA homozygosity and IGF-2R 1619 GG homozygosity presented a significant protective effect against HCC (OR=0.16,95% CI=0. 08–0.34, P=0. 005). Serum IGF-2 concentrations were significantly increased in HCC patients with the IGF-2+3580 AA genotype. We also observed that increased alpha-fetoprotein (AFP), Child–Pugh grade, tumor size, and number of malignant lesions were accompanied by a significant increase of serum IGF-2 mean values of in HCC patients. ConclusionIGF-2, IGF-2R, and IRS-2 genes polymorphisms and their combinations are associated with risk of HCC.

Insulin-like growth factor-1 (IGF-1) enhances developmental competence of cat embryos cultured singly by modulating the expression of its receptor (IGF-1R) and reducing developmental block

ObjectiveThe aim of this study is to determine the effects of insulin-like growth factor-1 (IGF-1) and the mRNA expression of IGF-1 receptor (IGF-1R) during the in vitro development of cat embryos cultured in groups versus singly. MethodsCumulus-oocyte complexes (COCs) were matured and fertilized in vitro with frozen-thawed semen. Cleaved embryos (48h post-fertilization) were randomly assigned to one of the following treatments: 1) group embryo culture without IGF-1 (10 embryos per 50μl droplet), 2) single-embryo culture without IGF-1, and 3) to 6) single-embryo culture (50μl droplet per embryo) supplemented with different concentrations of IGF-1 (5, 25, 50 and 100ng/ml, respectively). During in vitro culture, the embryos were analyzed for development to the morula, blastocyst and hatching blastocyst stage. Relative mRNA expression of IGF-1R was also examined by qPCR at the morula and blastocyst stages. In addition, the mRNA expression of IGF-1R in morula-stage embryos treated with IGF-1 was determined. The influence of IGF-1 to preimplantation embryo development was then explored by co-incubation with 0.5μM IGF-1R inhibitor (Picropodophyllin; PPP). ResultsGroup embryo culture led to a significantly higher blastocyst development rate compared with single-embryo culture (P<0.05). The poor development of singly cultured embryos coincided with the significantly lower IGF-1R expression in morulae than in group-cultured morulae. IGF-1 (25 or 50ng/ml) supplementation significantly improved the blastocyst formation rate of single embryos to a level similar to group culture by promoting the morula-to-blastocyst transition. IGF-1 supplementation (25 or 50ng/ml) of singly cultured embryos upregulated the expression of IGF-1R mRNA in morula-stage embryos to the same level as that observed in group-cultured embryos (without IGF-1). The beneficial effects of IGF-1 on singly cultured embryo were (P<0.05) suppressed by PPP even in the group culture embryo without growth factor supplementation. ConclusionIGF-1 supplementation improves the developmental competence of feline embryos cultured individually and also increases IGF-1R gene expression to levels similar to group-cultured embryos.

Effects of a novel SNP of IGF2R gene on growth traits and expression rate of IGF2R and IGF2 genes in gluteus medius muscle of Egyptian buffalo

Insulin-like growth factor 2 receptor (IGF2R) is responsible for degradation of the muscle development initiator, IGF2, and thus it can be used as a marker for selection strategies in the farm animals. The aim of this study was to search for polymorphisms in three coding loci of IGF2R, and to analyze their effect on the growth traits and on the expression levels of IGF2R and IGF2 genes in the gluteus medius muscle of Egyptian buffaloes. A novel A266C SNP was detected in the coding sequences of the third IGF2R locus (at nucleotide number 51 of exon 23) among Egyptian water buffaloes. This SNP was non-synonymous mutation and led to replacement of Y (tyrosine) amino acid (aa) by D (aspartic acid) aa. Three different single-strand conformation polymorphism patterns were observed in the third IGF2R locus: AA, AC, and CC with frequencies of 0.555, 0.195, and 0.250, respectively. Statistical analysis showed that the homozygous AA genotype significantly associated with the average daily gain than AC and CC genotypes from birth to 9 mo of age. Expression analysis showed that the A266C SNP was correlated with IGF2, but not with IGF2R, mRNA levels in the gluteus medius muscle of Egyptian buffaloes. The highest IGF2 mRNA level was estimated in the muscle of animals with the AA homozygous genotype as compared to the AC heterozygotes and CC homozygotes. We conclude that A266C SNP at nucleotide number 51 of exon 23 of the IGF2R gene is associated with the ADG during the early stages of life (from birth to 9 mo of age) and this effect is accompanied by, and may be caused by, increased expression levels of the IGF2 gene.

Associations of polymorphisms in GHRL, GHSR, and IGF1R genes with feed efficiency in chickens

The ghrelin (GHRL), ghrelin receptor (GHSR), and insulin-like growth factor 1 receptor (IGF1R) genes have crucial effects on body weight (BW), body weight gain (BWG), feed intake (FI), and feed conversion ratio (FCR) in many species. However, few studies on associations of GHRL, GHSR, and IGF1R with BWG, FI, and FCR have been reported in chickens. In this study, 16 SNPs in GHRL, GHSR, and IGF1R genes were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The objective of this study was to examine the associations of GHRL, GHSR, and IGF1R genes polymorphisms with BW at 49 days (BW49) and 70 days (BW70) of age, BWG, FI, and FCR in the interval in two yellow meat-type populations with a total of 724 birds. The results showed that rs15675067 of GHRL was significantly associated with BW70, BWG, and FCR (P < 0.05). For GHSR, rs16675844 had significant effects on FI and FCR (P < 0.01), and that rs14678932 showed significant association with BWG and FI (P < 0.05). Rs14011780 of IGF1R was strongly associated with BW49, BW70, and FCR (P < 0.05). Furthermore, haplotypes based on three SNPs of rs14986828, rs15675067, and rs15675065 in GHRL were significantly associated with BW70 and FCR (P < 0.05). Meanwhile, a three-SNP haplotype comprising rs14011783, rs14011780, and rs14011776 in IGF1R showed significant effects on BW49, BW70, and FCR (P < 0.05). Therefore, it was concluded that the identified SNPs and analyzed haplotypes in this study might be useful for broiler breeding programs.

Insulin-like growth factor 1 pathway mutations and protein expression in resected non-small cell lung cancer.

The purpose of this study was to characterize the prevalence of insulin-like growth factor 1 receptor (IGF1R) mutations, single nucleotide polymorphisms (SNP), and protein overexpression in surgically resected non-small cell lung cancers in relation to patient characteristics and prognosis. This retrospective study was conducted on 304 patients with non-small cell lung cancers who underwent curative pulmonary resection (median follow-up for surviving patients, 3.6 years). IGF1R gene alterations (n = 304) and protein expression (n = 181) were evaluated by polymerase chain reaction-based assays and immunohistochemistry, respectively. Membranous and cytoplasmic staining were analyzed separately. In an exploratory analysis, 1 silent mutation in exon 16 and 3 mutations in introns of the IGF1R gene comprising the tyrosine kinase domain were detected. Moreover, evaluating selected IGF1R SNPs, patients with adenocarcinomas and homozygous for the rs8038415 T-allele had a significantly better survival (P = .025) but no different disease-free survival. Regarding expression, membranous but not cytoplasmic IGF1R staining was higher in squamous cell carcinomas versus other histologies (P < .0001) and showed a trend to longer survival (P = .08). No association between SNP variations and protein expression was found. Membranous IGF1R protein expression is higher in squamous cell versus other histologies but does not correlate with prognosis. SNPs and mutations can be detected and may harbor prognostic value. These alterations may be of interest when evaluating the IGF1R as potential therapeutic target and should receive further research.

Metformin Inhibits Androgen-Induced IGF-IR Up-Regulation in Prostate Cancer Cells by Disrupting Membrane-Initiated Androgen Signaling

We have previously demonstrated that, in prostate cancer cells, androgens up-regulate IGF-I receptor (IGF-IR) by inducing cAMP-response element-binding protein (CREB) activation and CREB-dependent IGF-IR gene transcription through androgen receptor (AR)-dependent membrane-initiated effects. This IGF-IR up-regulation is not blocked by classical antiandrogens and sensitizes cells to IGF-I-induced biological effects. Metformin exerts complex antitumoral functions in various models and may inhibit CREB activation in hepatocytes. We, therefore, evaluated whether metformin may affect androgen-dependent IGF-IR up-regulation. In the AR(+) LNCaP prostate cancer cells, we found that metformin inhibits androgen-induced CRE activity and IGF-IR gene transcription. CRE activity requires the formation of a CREB-CREB binding protein-CREB regulated transcription coactivator 2 (CRTC2) complex, which follows Ser133-CREB phosphorylation. Metformin inhibited Ser133-CREB phosphorylation and induced nuclear exclusion of CREB cofactor CRTC2, thus dissociating the CREB-CREB binding protein-CRTC2 complex and blocking its transcriptional activity. Similarly to metformin action, CRTC2 silencing inhibited IGF-IR promoter activity. Moreover, metformin blocked membrane-initiated signals of AR to the mammalian target of rapamycin/p70S6Kinase pathway by inhibiting AR phosphorylation and its association with c-Src. AMPK signals were also involved to some extent. By inhibiting androgen-dependent IGF-IR up-regulation, metformin reduced IGF-I-mediated proliferation of LNCaP cells. These results indicate that, in prostate cancer cells, metformin inhibits IGF-I-mediated biological effects by disrupting membrane-initiated AR action responsible for IGF-IR up-regulation and suggest that metformin could represent a useful adjunct to the classical antiandrogen therapy.

Association of Polymorphisms and Haplotypes in the Insulin-Like Growth Factor 1 Receptor (IGF1R) Gene with the Risk of Breast Cancer in Korean Women

The insulin-like growth factor (IGF) signaling pathway plays an important role in cancer biology. The IGF 1 receptor (IGF1R) overexpression has been associated with a number of hematological neoplasias and solid tumors including breast cancer. However, molecular mechanism involving IGF1R in carcinogenic developments is clearly not known. We investigated the genetic variations across the IGF1R polymorphism and the risk of breast cancer risk in Korean women. A total of 1418 individuals comprising 1026 breast cancer cases and 392 age-matched controls of Korean were included for the analysis. Genomic DNA was extracted from whole blood and single nucleotide polymorphisms (SNPs) were analyzed on the GoldenGate Assay system by Illumina’s Custom Genetic Analysis service. SNPs were selected for linkage disequilibrium (LD) analysis by Haploview. We genotyped total 51 SNPs in the IGF1R gene and examined for association with breast cancer. All the SNPs investigated were in Hardy-Weinberg equilibrium. These SNPs tested were significantly associated with breast cancer risk, after correction for multiple comparisons by adjusting for age at diagnosis, BMI, age at menarche, and age at first parturition. Among 51 IGF1R SNPs, five intron located SNPs (rs8032477, rs7175052, rs12439557, rs11635251 and rs12916884) with homozygous genotype (variant genotype) were associated with decreased risk of breast cancer. Fisher’s combined p-value for the five SNPs was 0.00032. Three intron located SNPs with heterozygous genotypes also had decreased risk of breast cancer. 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 case-control study demonstrates statistically significant associations between breast cancer risk and polymorphisms in IGF1R gene.

Tissue factor/factor VIIa induces cell survival and gene transcription by transactivation of the insulin-like growth factor 1 receptor

The insulin-like growth factor 1 receptor (IGF-1R) is known to promote survival and has also been implicated in the pathogenesis of several disease states, including cardiovascular disorders and cancer. Recently, we showed that binding of coagulation factor VIIa (FVIIa) to its receptor tissue factor (TF) protects cancer cells from TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis. Here we present evidence that this biological function of TF/FVIIa is dependent on the IGF-1R. IGF-1R inhibitors AG1024 and PPP as well as siRNA-mediated downregulation of IGF-1R, abolished the TF/FVIIa-mediated protection against TRAIL-induced apoptosis. Moreover, FVIIa rapidly induced a time- and concentration-dependent tyrosine phosphorylation of the IGF-1R in MDA-MB-231 breast cancer cells and in primary human monocytes, an event that was accompanied by IGF-1R chromatin binding and gene transcription. We hereby present novel evidence of a cross-talk between the coagulation and IGF-1R signalling systems, and propose that the IGF-1R is a key player in mediating TF/FVIIa-induced cell survival.

MicroRNA let-7a and let-7f as novel regulatory factors of the sika deer (Cervus nippon) IGF-1R gene

MicroRNAs and their roles in rapid antler growth and regeneration have attracted much attention. In the present study, we examined the effects of microRNAs let-7a and let-7f on antler cell proliferation. We used a luciferase reporter screen to demonstrate that insulin-like growth factor 1 receptor (IGF-1R) can be regulated by let-7a and let-7f. MTT assay confirmed that chondrocyte proliferation was inhibited by let-7a and let-7f mimics. In contrast, transfection of let-7a and let-7f inhibitors increased chondrocyte proliferation, indicating that inhibitors can competitively bind to endogenous miRNA, reducing the inhibitory effect of miRNA. Moreover, western blotting analysis further identified that let-7a and let-7f mimics suppressed IGF-1R expression, and that let-7a and let-7f inhibitors increased the expression level of IGF-1R. Taken together, our study demonstrates the important roles of let-7a and let-7f in antler proliferation and its potential application in antler development. let-7a and let-7f may represent novel regulatory factors of IGF-1R expression in deer antler.

Resposta reprodutiva de vacas de corte associada a marcadores moleculares relacionados à fertilidade

O objetivo deste estudo foi buscar associação entre a taxa de prenhez após inseminação e natalidade com marcadores moleculares ligados aos genes do receptor para IGF-1, LHβ, Leptina e receptores do FSH e LH. Utilizaram-se 249 vacas adultas Aberdeen Angus, das quais 199 foram submetidas a protocolos distintos para a IATF, seguida pelo repasse com touros, e 50 vacas formaram o grupo controle representado pelo acasalamento com touros. Foram avaliados o escore de condição corporal (ECC) e o escore de condição ovariana (ECO) ao início da estação reprodutiva. O ECC influenciou a taxa de natalidade, respectivamente de 55,6%, 75,8% e 82,4% (P&lt;0,05) para os animais com ECC menor que 2,5, entre 2,5 a 2,9, e maior ou igual a 3,0, por ocasião da estação reprodutiva. Os marcadores relacionados ao gene do receptor para o IGF-1 (AFZ-1 e HEL5) mostraram associação com a taxa de natalidade. Vacas homozigóticas para o marcador AFZ-1 apresentaram 84,4% de natalidade em comparação às heterozigóticas, com 71,5% (P&lt;0,05). A presença do alelo*161 para o marcador HEL5 foi negativa sobre a natalidade, respectivamente de 33,3% e 76,5% para vacas com e sem esse alelo (P&lt;0,05). Esses resultados demonstram uma importante associação entre os marcadores envolvidos com o receptor para o IGF-1 e desempenho reprodutivo de vacas Angus.

P031 Expression of IGF-1 receptor gene in clear cell renal cell cancer

P031 Expression of IGF-1 receptor gene in clear cell renal cell cancer

Effects in cattle of genetic variation within the IGF1R gene on the superovulation performance and pregnancy rates after embryo transfer

The insulin-like growth factor 1 receptor (IGF1R) is a membrane glycoprotein mediating most biological actions of IGF1 and IGF2, and has an important effect on ovulation, pre-implantation embryo development and pregnancy rate. The objectives of this study were to detect IGF1R gene polymorphisms of cattle and analyze the relationship with superovulation performance and pregnancy rates after embryo transfer (ET), as well as the hormone concentrations at the day of ET. One reported SNP of IGF1R G404T and a novel SNP of IGF1R G399A were analyzed in 170 Chinese Holstein donor cows and 118 Luxi recipients cattle. Statistical analysis revealed that the G404T mutation was associated (p=0.019) with increased ovulation rate and females with this mutation had enhanced performance in producing transferable embryos. For the polymorphic locus G399A, recipients with g.399 GG and g.399 GA genotypes had greater pregnancy rates after ET than that of g.399 AA genotype. Furthermore, the same tendency was observed that the genotype groups with greater pregnancy rates had greater progesterone and lesser estrogen concentrations, but these did not reach statistical significance. Results of the present study showed, for the first time, that the polymorphism in IGF1R is associated with superovulation traits, and indicated that the IGFIR gene can be used as a potential marker for donor selection.