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Molecular and epidemiologic characterization of Wilms tumor from Baghdad, Iraq.
Phelps HM, Al-Jadiry MF, Corbitt NM, Pierce JM, Li B, Wei Q, Flores RR, Correa H, Uccini S, Frangoul H, Alsaadawi AR, Al-Badri SAF, Al-Darraji AF, Al-Saeed RM, Al-Hadad SA, Lovvorn Iii HN
(2018) World J Pediatr 14: 585-593
MeSH Terms: Adaptor Proteins, Signal Transducing, Child, Preschool, DNA Topoisomerases, Type II, Female, Homeodomain Proteins, Humans, Immunohistochemistry, Infant, Insulin-Like Growth Factor II, Iraq, Kidney Neoplasms, Male, Multiplex Polymerase Chain Reaction, Mutation, N-Myc Proto-Oncogene Protein, Nerve Tissue Proteins, Neural Cell Adhesion Molecules, Nuclear Proteins, Poly-ADP-Ribose Binding Proteins, Receptors, Retinoic Acid, Sequence Analysis, DNA, Transcription Factors, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, WT1 Proteins, Wilms Tumor, beta Catenin
Show Abstract · Added January 28, 2019
BACKGROUND - Wilms tumor (WT) is the most common childhood kidney cancer worldwide, yet its incidence and clinical behavior vary according to race and access to adequate healthcare resources. To guide and streamline therapy in the war-torn and resource-constrained city of Baghdad, Iraq, we conducted a first-ever molecular analysis of 20 WT specimens to characterize the biological features of this lethal disease within this challenged population.
METHODS - Next-generation sequencing of ten target genes associated with WT development and treatment resistance (WT1, CTNNB1, WTX, IGF2, CITED1, SIX2, p53, N-MYC, CRABP2, and TOP2A) was completed. Immunohistochemistry was performed for 6 marker proteins of WT (WT1, CTNNB1, NCAM, CITED1, SIX2, and p53). Patient outcomes were compiled.
RESULTS - Mutations were detected in previously described WT "hot spots" (e.g., WT1 and CTNNB1) as well as novel loci that may be unique to the Iraqi population. Immunohistochemistry showed expression domains most typical of blastemal-predominant WT. Remarkably, despite the challenges facing families and care providers, only one child, with combined WT1 and CTNNB1 mutations, was confirmed dead from disease. Median clinical follow-up was 40.5 months (range 6-78 months).
CONCLUSIONS - These data suggest that WT biology within a population of Iraqi children manifests features both similar to and unique from disease variants in other regions of the world. These observations will help to risk stratify WT patients living in this difficult environment to more or less intensive therapies and to focus treatment on cell-specific targets.
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27 MeSH Terms
YB-1 is elevated in medulloblastoma and drives proliferation in Sonic hedgehog-dependent cerebellar granule neuron progenitor cells and medulloblastoma cells.
Dey A, Robitaille M, Remke M, Maier C, Malhotra A, Gregorieff A, Wrana JL, Taylor MD, Angers S, Kenney AM
(2016) Oncogene 35: 4256-68
MeSH Terms: Animals, Cell Line, Tumor, Cell Proliferation, Cerebellar Neoplasms, Cerebellum, Gene Expression Regulation, Neoplastic, Hedgehog Proteins, Insulin-Like Growth Factor II, Medulloblastoma, Mice, Neural Stem Cells, Signal Transduction, Y-Box-Binding Protein 1
Show Abstract · Added April 25, 2016
Postnatal proliferation of cerebellar granule neuron precursors (CGNPs), proposed cells of origin for the SHH-associated subgroup of medulloblastoma, is driven by Sonic hedgehog (Shh) and insulin-like growth factor (IGF) in the developing cerebellum. Shh induces the oncogene Yes-associated protein (YAP), which drives IGF2 expression in CGNPs and mouse Shh-associated medulloblastomas. To determine how IGF2 expression is regulated downstream of YAP, we carried out an unbiased screen for transcriptional regulators bound to IGF2 promoters. We report that Y-box binding protein-1 (YB-1), an onco-protein regulating transcription and translation, binds to IGF2 promoter P3. We observed that YB-1 is upregulated across human medulloblastoma subclasses as well as in other varieties of pediatric brain tumors. Utilizing the cerebellar progenitor model for the Shh subgroup of medulloblastoma in mice, we show for the first time that YB-1 is induced by Shh in CGNPs. Its expression is YAP-dependent and it is required for IGF2 expression in CGNPs. Finally, both gain-of function and loss-of-function experiments reveal that YB-1 activity is required for sustaining CGNP and medulloblastoma cell (MBC) proliferation. Collectively, our findings describe a novel role for YB-1 in driving proliferation in the developing cerebellum and MBCs and they identify the SHH:YAP:YB1:IGF2 axis as a powerful target for therapeutic intervention in medulloblastomas.
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13 MeSH Terms
Insulin-mediated signaling promotes proliferation and survival of glioblastoma through Akt activation.
Gong Y, Ma Y, Sinyuk M, Loganathan S, Thompson RC, Sarkaria JN, Chen W, Lathia JD, Mobley BC, Clark SW, Wang J
(2016) Neuro Oncol 18: 48-57
MeSH Terms: Animals, Antigens, CD, Brain Neoplasms, Cell Proliferation, Cell Survival, Female, Glioblastoma, Humans, Insulin, Insulin-Like Growth Factor I, Insulin-Like Growth Factor II, Mice, Nude, Proto-Oncogene Proteins c-akt, Receptor, Insulin, Receptors, Somatomedin, Signal Transduction, Tumor Cells, Cultured
Show Abstract · Added July 23, 2015
BACKGROUND - Metabolic complications such as obesity, hyperglycemia, and type 2 diabetes are associated with poor outcomes in patients with glioblastoma. To control peritumoral edema, use of chronic high-dose steroids in glioblastoma patients is common, which can result in de novo diabetic symptoms. These metabolic complications may affect tumors via profound mechanisms, including activation of insulin receptor (InsR) and the related insulin-like growth factor 1 receptor (IGF1R) in malignant cells.
METHODS - In the present study, we assessed expression of InsR in glioblastoma surgical specimens and glioblastoma response to insulin at physiologically relevant concentrations. We further determined whether genetic or pharmacological targeting of InsR affected oncogenic functions of glioblastoma in vitro and in vivo.
RESULTS - We showed that InsR was commonly expressed in glioblastoma surgical specimens and xenograft tumor lines, with mitogenic isoform-A predominating. Insulin at physiologically relevant concentrations promoted glioblastoma cell growth and survival, potentially via Akt activation. Depletion of InsR impaired cellular functions and repressed orthotopic tumor growth. The absence of InsR compromised downstream Akt activity, but yet stimulated IGF1R expression. Targeting both InsR and IGF1R with dual kinase inhibitors resulted in effective blockade of downstream signaling, loss of cell viability, and repression of xenograft tumor growth.
CONCLUSIONS - Taken together, our work suggests that glioblastoma is sensitive to the mitogenic functions of insulin, thus significant insulin exposure imposes risks to glioblastoma patients. Additionally, dual inhibition of InsR and IGF1R exhibits promise for treating glioblastoma.
© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
1 Communities
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17 MeSH Terms
Value of circulating insulin-like growth factor-associated proteins for the detection of stage I non-small cell lung cancer.
Kubasiak JC, Seder CW, Pithadia R, Basu S, Fhied C, Phillips WW, Daly S, Shersher DD, Yoder MA, Chmielewski G, Edell ES, Maldonado F, Liptay MJ, Borgia JA
(2015) J Thorac Cardiovasc Surg 149: 727-34.e1-3; discussion 734
MeSH Terms: Adult, Aged, Aged, 80 and over, Algorithms, Area Under Curve, Biomarkers, Tumor, Carcinoma, Non-Small-Cell Lung, Cytokines, Female, Humans, Illinois, Insulin-Like Growth Factor Binding Proteins, Insulin-Like Growth Factor I, Insulin-Like Growth Factor II, Lung Neoplasms, Male, Middle Aged, Minnesota, Multivariate Analysis, Neoplasm Staging, Predictive Value of Tests, ROC Curve, Reproducibility of Results, Retrospective Studies, Tomography, X-Ray Computed, Young Adult
Show Abstract · Added July 28, 2015
OBJECTIVE - Circulating biomarkers related to insulin-like growth factor (IGF) signaling are associated with disease progression in multiple carcinomas, but their potential diagnostic value for lung cancer screening has been inadequately examined. We evaluated 9 circulating IGF-related factors for their ability to assign clinical significance to indeterminate pulmonary nodules identified via computed tomography-based radiologic studies.
METHODS - Patients (n = 224 stage I non-small cell lung cancer; n = 123 benign) were enrolled by Rush University and the Mayo Clinic and had pretreatment serum evaluated for levels of IGF-1, IGF-2, and insulin-like growth factor binding proteins (IGFBPs) 1-7. The Mann-Whitney rank-sum test and receiver-operator characteristics curves were used to assess differences in biomarker concentrations relevant to malignant versus benign pathology. These targets were used to help refine our companion blood test for assigning clinical significance to computed tomography-detected solitary nodules (discovery cohort, n = 94) and were validated against an independent cohort from the Mayo Clinic (n = 81).
RESULTS - Patients with benign pulmonary nodules were found to have serum concentrations of IGFBP-3, IGFBP-5, IGF-1, and IGF-2 that were higher (P = .001, P < .001, P = .002, and P = .011, respectively) than those with non-small cell lung cancer, with distinct associations with histologic subtypes observed. Refinement of our multianalyte classification algorithm using IGF-related factors provided a new panel consisting of interleukin-6, interleukin-1 receptor antagonist, interleukin-10, stromal cell-derived factor-1(α + β), IGFBP-4, IGFBP-5, and IGF-2 with improved assay performance-achieving a (validated) negative predictive value of 100%.
CONCLUSIONS - Our findings suggest a divergent role for IGF signaling in the biology of benign and malignant pulmonary nodules. Upon further validation, these observations may help identify cases of false positives resulting from computed tomography-based screening studies.
Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
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26 MeSH Terms
Organ-specific defects in insulin-like growth factor and insulin receptor signaling in late gestational asymmetric intrauterine growth restriction in Cited1 mutant mice.
Novitskaya T, Baserga M, de Caestecker MP
(2011) Endocrinology 152: 2503-16
MeSH Terms: Animals, Brain, Disease Models, Animal, Female, Fetal Growth Retardation, Gestational Age, Humans, Insulin-Like Growth Factor I, Insulin-Like Growth Factor II, Kidney, Liver, Mice, Mice, Knockout, Nuclear Proteins, Organ Size, Organ Specificity, Pregnancy, Pregnancy Complications, Receptor, IGF Type 1, Receptor, Insulin, Signal Transduction, Trans-Activators
Show Abstract · Added November 21, 2013
Late gestational placental insufficiency resulting in asymmetric intrauterine organ growth restriction (IUGR) is associated with an increased incidence of diabetes, cardiovascular and renal disease in adults. The molecular mechanisms mediating these defects are poorly understood. To explore this, we investigated the mechanisms leading to IUGR in Cited1 knockout mice, a genetic model of late gestational placental insufficiency. We show that loss of placental Cited1 leads to asymmetric IUGR with decreased liver, lung, and kidney sizes and preservation of fetal brain weight. IGF and insulin signaling regulate embryonic organ growth. IGF-I and IGF-II protein and mRNA expression are reduced in livers, lungs, and kidneys of embryonic d 18.5 embryos with IUGR. Decreased IGF-I is associated with reduced activating phosphorylation of the type 1 IGF receptor (pIGF-IR) in the kidney, whereas reduced IGF-II is associated with decreased phosphorylation of the insulin receptor (pIR) in the lung. In contrast, decreased pIR is associated with reduced IGF-I but not IGF-II in the liver. However, pancreatic β-cell mass and serum insulin levels are also decreased in mice with IUGR, suggesting that hepatic IR signaling may be regulated by alterations in fetal insulin production. These findings contrast with observations in IUGR fetal brains in which there is no change in IGF-IR/IR phosphorylation, and IGF-I and IGF-II expression is actually increased. In conclusion, IUGR disrupts normal fetal IGF and insulin production and is associated with organ-specific defects in IGF-IR and IR signaling that may regulate asymmetric IUGR in late gestational placental insufficiency.
2 Communities
1 Members
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22 MeSH Terms
Mutated beta-catenin evades a microRNA-dependent regulatory loop.
Veronese A, Visone R, Consiglio J, Acunzo M, Lupini L, Kim T, Ferracin M, Lovat F, Miotto E, Balatti V, D'Abundo L, Gramantieri L, Bolondi L, Pekarsky Y, Perrotti D, Negrini M, Croce CM
(2011) Proc Natl Acad Sci U S A 108: 4840-5
MeSH Terms: Apoptosis Regulatory Proteins, Cell Line, Tumor, Genetic Loci, HEK293 Cells, Humans, Insulin-Like Growth Factor II, Introns, MicroRNAs, Mutation, Proto-Oncogene Proteins, Transcription Factors, beta Catenin
Show Abstract · Added December 22, 2013
hsa-mir-483 is located within intron 2 of the IGF2 gene. We have previously shown oncogenic features of miR-483-3p through cooperation with IGF2 or by independently targeting the proapoptotic gene BBC3/PUMA. Here we demonstrate that expression of miR-483 can be induced independently of IGF2 by the oncoprotein β-catenin through an interaction with the basic helix-loop-helix protein upstream stimulatory transcription factor 1. We also show that β-catenin itself is a target of miR-483-3p, triggering a negative regulatory loop that becomes ineffective in cells harboring an activating mutation of β-catenin. These results provide insights into the complex regulation of the IGF2/miR-483 locus, revealing players in the β-catenin pathway.
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12 MeSH Terms
IGF-II promoter specific methylation and expression in epithelial ovarian cancer and their associations with disease characteristics.
Qian B, Katsaros D, Lu L, Canuto EM, Benedetto C, Beeghly-Fadiel A, Yu H
(2011) Oncol Rep 25: 203-13
MeSH Terms: Adult, Aged, Aged, 80 and over, DNA Methylation, Disease-Free Survival, Female, Gene Expression Regulation, Neoplastic, Humans, Insulin-Like Growth Factor II, Middle Aged, Neoplasm Staging, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Promoter Regions, Genetic, Reverse Transcriptase Polymerase Chain Reaction
Show Abstract · Added February 22, 2016
High expression of insulin-like growth factor-II (IGF-II) in epithelial ovarian cancer is associated with aggressive disease and poor prognosis. IGF-II transcription is initiated from multiple promoters. Promoter-specific expression is regulated by DNA methylation, which is often dysregulated in cancer. Here, the effects of promoter-specific methylation on IGF-II expression are investigated in ovarian cancer. Fresh tumor samples were collected from 211 patients for analyses of IGF-II promoter methylation using methylation-specific PCR, and of promoter-specific expression of IGF-II mRNA with qRT-PCR, as well as tissue levels of IGF-II peptide with an ELISA. Cox regression analysis was performed to assess IGF-II methylation and expression in association with progression-free and overall survival. DNA methylation was high in IGF-II promoters 2 (P2, 64.2%) and 3 (P3, 52.1%) and low in promoter 4 (P4, 9.8%). High methylation was associated with low mRNA expression in a promoter-specific manner. P3 methylation and expression appeared to be critical in ovarian cancer compared to other promoters. While methylation in an individual promoter was not associated with the disease, a methylation pattern involving P2 and P3 was significantly different among patients with distinct tumor grade, debulking results, residual tumor size and treatment response. The methylation pattern was also associated with disease progression. The study suggests that DNA methylation regulates IGF-II promoter-specific expression in ovarian cancer and the regulation may play a role in disease progression. Assessing methylation patterns in IGF-II promoters may have clinical implications.
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15 MeSH Terms
Loss of imprinting and marked gene elevation are 2 forms of aberrant IGF2 expression in colorectal cancer.
Cheng YW, Idrees K, Shattock R, Khan SA, Zeng Z, Brennan CW, Paty P, Barany F
(2010) Int J Cancer 127: 568-77
MeSH Terms: Colorectal Neoplasms, DNA Methylation, Genomic Imprinting, Humans, Insulin-Like Growth Factor II, Polymorphism, Genetic, Promoter Regions, Genetic
Show Abstract · Added March 28, 2014
Loss of imprinting (LOI) of insulin-like growth factor 2 (IGF2) is a common event in many cancers and typically activates the maternally silenced allele. The resulting biallelic IGF2 expression correlates strongly with the hypomethylation of a differentially methylated region (DMR) near its promoter. It has also been shown that IGF2 undergoes overexpression in human malignancies; nevertheless, this phenomenon and its link to aberrant DMR methylation have not been reported in colorectal cancer (CRC). The aim of this study was to determine the relationship between IGF2 LOI, overexpression and DMR hypomethylation in CRC. By analyzing IGF2 and H19 methylation in 97 primary CRC and 64 matched normal colorectal tissues, we have shown a significant correlation between IGF2 LOI and DMR hypomethylation of IGF2 and H19. Additionally, when analyzing Affymetrix expression data of 167 primary CRC tumors and 32 normal tissues, 15% of tumors showed marked IGF2 elevation. We further investigated if substantially elevated IGF2 levels were linked to IGF2 or H19 hypomethylation, but found no significant correlation. However, we demonstrated that noticeable IGF2 overexpression, rather than LOI, negatively correlated with CRC microsatellite instability. These observations indicate that IGF2 expression, particularly when transcribed at significantly high levels, is a result of mechanisms unrelated to LOI. Our results suggest that IGF2 participates in CRC tumorigenesis through 2 different forms of aberrant gene expression.
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7 MeSH Terms
Racial differences in the association between body mass index and serum IGF1, IGF2, and IGFBP3.
Fowke JH, Matthews CE, Yu H, Cai Q, Cohen S, Buchowski MS, Zheng W, Blot WJ
(2010) Endocr Relat Cancer 17: 51-60
MeSH Terms: Adult, African Americans, Age of Onset, Aged, Body Mass Index, Breast Neoplasms, Cross-Sectional Studies, European Continental Ancestry Group, Female, Follow-Up Studies, Genetic Predisposition to Disease, Humans, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor Binding Proteins, Insulin-Like Growth Factor I, Insulin-Like Growth Factor II, Middle Aged, Postmenopause, Premenopause, Prospective Studies, Southeastern United States, Young Adult
Show Abstract · Added December 10, 2013
African-American (AA) race/ethnicity, lower body mass index (BMI), and higher IGF1 levels are associated with premenopausal breast cancer risk. This cross-sectional analysis investigated whether BMI or BMI at age 21 years contributes to racial differences in IGF1, IGF2, IGF-binding protein 3 (IGFBP3), or free IGF1. Participants included 816 white and 821 AA women between ages 40 and 79 years across a wide BMI range (18.5-40 kg/m(2)). Compared with white women, AA women had higher mean IGF1 (146.3 vs 134.4 ng/ml) and free IGF1 (0.145 vs 0.127) levels, and lower IGF2 (1633.0 vs 1769.3 ng/ml) and IGFBP3 (3663.3 vs 3842.5 ng/ml) levels (all P<0.01; adjusted for age, height, BMI, BMI at age 21 years, and menopausal status). Regardless of race, IGF1 and free IGF1 levels rose sharply as BMI increased to 22-24 kg/m(2), and then declined thereafter, while IGF2 and IGFBP3 levels tended to rise with BMI. In contrast, BMI at age 21 years was inversely associated with all IGF levels, but only among white women (P-interaction=0.01). With the decline in IGF1 with BMI at age 21 years among whites, racial differences in IGF1 significantly increased among women who were obese in early adulthood. In summary, BMI was associated with IGF1 levels regardless of race/ethnicity, while obesity during childhood or young adulthood may have a greater impact on IGF1 levels among white women. The effects of obesity throughout life on the IGF axis and racial differences in breast cancer risk require study.
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5 Members
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22 MeSH Terms
Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins.
Guix M, Faber AC, Wang SE, Olivares MG, Song Y, Qu S, Rinehart C, Seidel B, Yee D, Arteaga CL, Engelman JA
(2008) J Clin Invest 118: 2609-19
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Carcinoma, Squamous Cell, Cell Line, Tumor, Cell Survival, Drug Resistance, Neoplasm, ErbB Receptors, Female, Gefitinib, Gene Expression, Humans, Insulin Receptor Substrate Proteins, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor Binding Protein 4, Insulin-Like Growth Factor Binding Proteins, Insulin-Like Growth Factor I, Insulin-Like Growth Factor II, Mice, Mice, Nude, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Quinazolines, Receptor, ErbB-3, Receptor, IGF Type 1, Xenograft Model Antitumor Assays
Show Abstract · Added March 5, 2014
Although some cancers are initially sensitive to EGFR tyrosine kinase inhibitors (TKIs), resistance invariably develops. We investigated mechanisms of acquired resistance to the EGFR TKI gefitinib by generating gefitinib-resistant (GR) A431 squamous cancer cells. In GR cells, gefitinib reduced phosphorylation of EGFR, ErbB-3, and Erk but not Akt. These cells also showed hyperphosphorylation of the IGFI receptor (IGFIR) and constitutive association of IRS-1 with PI3K. Inhibition of IGFIR signaling disrupted the association of IRS-1 with PI3K and restored the ability of gefitinib to downregulate PI3K/Akt signaling and to inhibit GR cell growth. Gene expression analyses revealed that GR cells exhibited markedly reduced IGF-binding protein 3 (IGFBP-3) and IGFBP-4 RNA. Addition of recombinant IGFBP-3 restored the ability of gefitinib to downregulate PI3K/Akt signaling and to inhibit cell growth. Finally, gefitinib treatment of mice with A431 xenografts in combination with an IGFIR-specific monoclonal antibody prevented tumor recurrence, whereas each drug given alone was unable to do so. These data suggest that loss of expression of IGFBPs in tumor cells treated with EGFR TKIs derepresses IGFIR signaling, which in turn mediates resistance to EGFR antagonists. Moreover, combined therapeutic inhibition of EGFR and IGFIR may abrogate this acquired mechanism of drug resistance and is thus worthy of prospective clinical investigation.
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27 MeSH Terms