Decoy Oligonucleotide Rescues IGF1R Expression from MicroRNA-223 Suppression

Introduction Insulin-like growth factor type 1 receptor (IGF1R) is overexpressed in various malignant tumors, which relates to their transformation and recurrence. Craniopharyngioma is a benign tumor with malignant results, often accompanied by a severe inflammatory reaction. However, the relationship between IGF1R expression and the inflammatory response of craniopharyngioma is unclear. Methods We enrolled 85 patients with adamantinomatous craniopharyngioma (ACP) in a study to explore the relationship between IGF1R expression and clinical features of this disease. Results Patients in the IGF1R high expression group had a significantly higher incidence of hypopituitarism, higher recurrence rate and lower progression-free survival. Beta-catenin can further regulate expression of the stem cell marker, CD44, by regulating IGF1R. Using immunofluorescence, we found that tumor stem cell–like cells did not express phosphorylated (p)-ERK, although p-ERK activation was evident in the surrounding cells. Picropodophyllin, a specific inhibitor of IGF1R, increased the expression of p-ERK protein, and decreased the transcription level of interleukin-6. Conclusions High expression of IGF1R might promote inflammation of ACP, which might be an unfavorable factor for pituitary function and prognosis. The high expression of IGF1R in tumor cell stem-like cells might inhibit the expression of p-ERK and promote the generation of inflammatory factors. Insulin-like growth factor type 1 receptor plays a stemness maintenance role in ACP and regulates the production of inflammatory factors through a p-ERK pathway, which suggests that targeting IGF1R and p-ERK might provide a new direction for alleviating tumor inflammation.

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Intra-Pancreatic Insulin Nourishes Cancer Cells: Do Insulin-Receptor Antagonists such as PGG and EGCG Play a Role?

The American Journal of Chinese Medicine ◽

10.1142/s0192415x20500482 ◽

2020 ◽

Vol 48 (04) ◽

pp. 1005-1019

Author(s):

Lijuan Hu ◽

Xijuan Chen ◽

Shuai Qiu ◽

Jing Yang ◽

Hongyi Liu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Insulin Receptor ◽

Cancer Cells ◽

Human Pancreatic Cancer ◽

Pancreatic Tumors ◽

Pancreatic Cancer Cells ◽

Pancreatic Insulin ◽

Igf1r Expression ◽

Expression And Activity

Harboring insulin-producing cells, the pancreas has more interstitial insulin than any other organ. In vitro, insulin activates both insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) to stimulate pancreatic cancer cells. Whether intra-pancreatic insulin nourishes pancreatic cancer cells in vivo remains uncertain. In the present studies, we transplanted human pancreatic cancer cells orthotopically in euglycemic athymic mice whose intra-pancreatic insulin was intact or was decreased following pretreatment with streptozotocin (STZ). In the next eight weeks, the tumor carriers were treated with one of the IR/IGF1R antagonists penta-O-galloyl-[Formula: see text]-D-glucose (PGG) and epigallocatechin gallate (EGCG) or treated with vehicle. When pancreatic tumors were examined, their fraction occupied with living cells was decreased following STZ pretreatment and/or IR/IGF1R antagonism. Using Western blot, we examined tumor grafts for IR/IGF1R expression and activity. We also determined proteins that were downstream to IR/IGF1R and responsible for signal transduction, glycolysis, angiogenesis, and apoptosis. We demonstrated that STZ-induced decrease in intra-pancreatic insulin reduced IR/IGF1R expression and activity, decreased the proteins that promoted cell survival, and increased the proteins that promoted apoptosis. These suggest that intra-pancreatic insulin supported local cancer cells. When tumor carriers were treated with PGG or EGCG, the results were similar to those seen following STZ pretreatment. Thus, the biggest changes in examined proteins were usually seen when STZ pretreatment and PGG/EGCG treatment concurred. This suggests that intra-pancreatic insulin normally combated pharmacologic effects of PGG and EGCG. In conclusion, intra-pancreatic insulin nourishes pancreatic cancer cells and helps the cells resist IR/IGF1R antagonism.

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Triggering of CD40 Antigen Inhibits Fludarabine-Induced Apoptosis in B Chronic Lymphocytic Leukemia Cells

Blood ◽

10.1182/blood.v92.3.990 ◽

1998 ◽

Vol 92 (3) ◽

pp. 990-995 ◽

Cited By ~ 101

Author(s):

Maria Fiammetta Romano ◽

Annalisa Lamberti ◽

Pierfrancesco Tassone ◽

Fiorella Alfinito ◽

Silvia Costantini ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Consensus Sequence ◽

Significant Proportion ◽

Lymphocytic Leukemia ◽

Antiapoptotic Effect ◽

Apoptotic Effect ◽

American Society ◽

Induced Apoptosis ◽

Decoy Oligonucleotide

Abstract We analyzed the effect of CD40 triggering on the fludarabine-induced apoptosis of B chronic lymphocytic leukemia (B-CLL) cells. Peripheral blood samples obtained from 15 patients were incubated with fludarabine in the absence or the presence of the anti-CD40 monoclonal antibody (MoAb) G28-5. In 12 patients a significant proportion of apoptotic cells, ranging from 22% to 38% (mean ± SE: 28.5 ± 1.6), were detected after 3 days of culture. In 9 of these samples, the addition of G28-5 reduced apoptosis by at least 30.1% and by 57.1% ± 7.8% on average (P = .0077). Because the CD40 antigen activates NF-κB/Rel transcription factors in B cells, and NF-κB/Rel complexes can inhibit cell apoptosis, we investigated whether the antiapoptotic effect of G28-5, in our system, could be related to modulation of NF-κB/Rel activity. As expected, B-CLL cells displayed significant levels of nuclear NF-κB/Rel activity; p50, RelA, and c-Rel components of the NF-κB/Rel protein family were identified in these complexes. After exposure to fludarabine, NF-κB/Rel complexes were decreased in the nuclei. The addition of G28-5 upregulated the NF-κB/Rel levels. To determine the involvement of NF-κB/Rel activity in the G28-5–mediated inhibition of apoptosis, we blocked the transcription factor with a decoy oligonucleotide, corresponding to the NF-κB/Rel consensus sequence. Cells incubated with the anti-CD40 MoAb in the presence of the decoy oligonucleotide but not a control oligonucleotide displayed a complete impairment of the G28-5 antiapoptotic effect, indicating that NF-κB/Rel activity was required for the inhibition of apoptosis. These results suggest that CD40 triggering in vivo could counteract the apoptotic effect of fludarabine on B-CLL cells and that its neutralization, or the use of NF-κB/Rel inhibitors, could improve the therapeutic effect of fludarabine. © 1998 by The American Society of Hematology.

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A Novel Mutation in Insulin-Like Growth Factor 1 Receptor (c.641-2A>G) Is Associated with Impaired Growth, Hypoglycemia, and Modified Immune Phenotypes

Hormone Research in Paediatrics ◽

10.1159/000510764 ◽

2020 ◽

Vol 93 (5) ◽

pp. 322-334

Author(s):

Melanie R. Shapiro ◽

Timothy P. Foster ◽

Daniel J. Perry ◽

Ron G. Rosenfeld ◽

Andrew Dauber ◽

...

Keyword(s):

Growth Factor ◽

Mononuclear Cells ◽

Phenotypic Expression ◽

The Body ◽

Mrna Splicing ◽

Insulin Like Growth Factor ◽

T Helper ◽

Adaptive Immune Cells ◽

Immune Phenotypes ◽

Igf1r Expression

Introduction: Insulin-like growth factor 1 receptor (IGF1R) mutations lead to systemic disturbances in growth and glucose homeostasis due to widespread IGF1R expression throughout the body. IGF1R is expressed by innate and adaptive immune cells, facilitating their development and exerting immunomodulatory roles in the periphery. Case Presentation: We report on a family presenting with a novel heterozygous IGF1R mutation with characterization of the mutation, IGF1R expression, and immune phenotyping. Twin probands presented clinically with short stature and hypoglycemia. Variable phenotypic expression was seen in 2 other family members carrying the IGF1R mutation. The probands were treated with exogenous growth hormone therapy and dietary cornstarch, improving linear growth and reducing hypoglycemic events. IGF1R c.641-2A>G caused abnormal mRNA splicing and premature protein termination. Flow cytometric immunophenotyping demonstrated lower IGF1R on peripheral blood mononuclear cells from IGF1R c.641-2A>G subjects. This alteration was associated with reduced levels of T-helper 17 cells and a higher percentage of T-helper 1 cells compared to controls, suggesting decreased IGF1R expression may affect CD4+ Th-cell lineage commitment. Discussion: Collectively, these data suggest a novel loss-of-function mutation (c.641-2A>G) leads to aberrant mRNA splicing and IGF1R expression resulting in hypoglycemia, growth restriction, and altered immune phenotypes.

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