Effective inhibition of irradiation on human gliomas growth in vitro and in vivo after epidermal growth factor receptor silencing with RNA interference

Neuroreport ◽  
2011 ◽  
Vol 22 (15) ◽  
pp. 773-777
Author(s):  
Guangbin Cui ◽  
Tao Zhang ◽  
Longxiao Wei ◽  
Pang Du ◽  
Feng Zhang ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Rna Interference ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Human Gliomas ◽  
Effective Inhibition ◽  
Epidermal Growth

scholarly journals Disruption of TP63-miR-27a* Feedback Loop by Mutant TP53 in Head and Neck Cancer

2019 ◽  
Vol 112 (3) ◽  
pp. 266-277 ◽  
Author(s):  
Nikhil S Chari ◽  
Cristina Ivan ◽  
Xiandong Le ◽  
Jinzhong Li ◽  
Ainiwaer Mijiti ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Oral Cavity ◽  
Head And Neck ◽  
Feedback Loop ◽  
Growth Factor Receptor ◽  
Epidermal Growth

Abstract Background Alterations in the epidermal growth factor receptor and PI3K pathways in head and neck squamous cell carcinomas (HNSCCs) are frequent events that promote tumor progression. Ectopic expression of the epidermal growth factor receptor–targeting microRNA (miR), miR-27a* (miR-27a-5p), inhibits tumor growth. We sought to identify mechanisms mediating repression of miR-27a* in HNSCC, which have not been previously identified. Methods We quantified miR-27a* in 47 oral cavity squamous cell carcinoma patient samples along with analysis of miR-27a* in 73 oropharyngeal and 66 human papillomavirus–positive (HPV+) samples from The Cancer Genome Atlas. In vivo and in vitro TP53 models engineered to express mutant TP53, along with promoter analysis using chromatin immunoprecipitation and luciferase assays, were used to identify the role of TP53 and TP63 in miR-27a* transcription. An HNSCC cell line engineered to conditionally express miR-27a* was used in vitro to determine effects of miR-27a* on target genes and tumor cells. Results miR-27a* expression was repressed in 47 oral cavity tumor samples vs matched normal tissue (mean log2 difference = −0.023, 95% confidence interval = −0.044 to −0.002; two-sided paired t test, P = .03), and low miR-27a* levels were associated with poor survival in HPV+ and oropharyngeal HNSCC samples. Binding of ΔNp63α to the promoter led to an upregulation of miR-27a*. In vitro and in vivo findings showed that mutant TP53 represses the miR-27a* promoter, downregulating miR-27a* levels. ΔNp63α and nucleoporin 62, a protein involved in ΔNP63α transport, were validated as novel targets of miR-27a*. Conclusion Our results characterize a negative feedback loop between TP63 and miR-27a*. Genetic alterations in TP53, a frequent event in HNSCC, disrupt this regulatory loop by repressing miR-27a* expression, promoting tumor survival.

scholarly journals An endosomally localized isoform of Eps15 interacts with Hrs to mediate degradation of epidermal growth factor receptor

2008 ◽  
Vol 180 (6) ◽  
pp. 1205-1218 ◽  
Author(s):  
Ingrid Roxrud ◽  
Camilla Raiborg ◽  
Nina Marie Pedersen ◽  
Espen Stang ◽  
Harald Stenmark
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Adaptor Protein ◽  
Coated Pits ◽  
Kinase Substrate ◽  
Epidermal Growth

Down-regulation of activated and ubiquitinated growth factor (GF) receptors by endocytosis and subsequent lysosomal degradation ensures attenuation of GF signaling. The ubiquitin-binding adaptor protein Eps15 (epidermal growth factor receptor [EGFR] pathway substrate 15) functions in endocytosis of such receptors. Here, we identify an Eps15 isoform, Eps15b, and demonstrate its expression in human cells and conservation across vertebrate species. Although both Eps15 and Eps15b interact with the endosomal sorting protein Hrs (hepatocyte growth factor–regulated tyrosine kinase substrate) in vitro, we find that Hrs specifically binds Eps15b in vivo (whereas adaptor protein 2 preferentially interacts with Eps15). Although Eps15 mainly localizes to clathrin-coated pits at the plasma membrane, Eps15b localizes to Hrs-positive microdomains on endosomes. Eps15b overexpression, similarly to Hrs overexpression, inhibits ligand-mediated degradation of EGFR, whereas Eps15 is without effect. Similarly, depletion of Eps15b but not Eps15 delays degradation and promotes recycling of EGFR. These results indicate that Eps15b is an endosomally localized isoform of Eps15 that is present in the Hrs complex via direct Hrs interaction and important for the sorting function of this complex.

Antibody-nanoparticle conjugate constructed with trastuzumab and nab-paclitaxel for the targeted therapy of positive human epidermal growth factor receptor 2 gastric cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15506-e15506
Author(s):  
Jian Xiong ◽  
Haijun Zhang
Keyword(s):  
Gastric Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Targeted Therapy ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tumor Volume ◽  
Growth Factor Receptor ◽  
Epidermal Growth

e15506 Background: Gastric cancer is the most lethal malignancies in the digestive system. This study was to investigate antibody-nanoparticle conjugate (ANC) constructed with Herceptin® and Abraxane® (Herceptin®/Abraxane®) as a novel strategy of targeted therapy for human epidermal growth factor receptor 2 (HER2) positive gastric cancer. Methods: Firstly, we fabricated the ANC with Herceptin and Abraxane by a “one-step” synthesis using EDC/NHS. In vitro study, the cell viability, apoptosis and cell cycle of the positive HER2 gastric cancer NCI-N87 cells were measured and compared in four groups of PBS, paclitaxel (Taxol), nano- paclitaxel (Abraxane) and ANC (Herceptin/ Abraxane). In addition, we constructed gastric cancer xenograft model in nude mice to evaluate the targeted antitumor effect in vivo. Furthermore, we chose the NIR797 to locate on the ANC and use the NIR imaging to demonstrate that the ANC could more precise target and delayed release of paclitaxel. Results: ANC of Herceptin/Abraxane was spherical in shape and in a suitable size (289.18 nm±102.6 nm). In vitro, the half-maximal inhibitory concentration (IC50), defined as the concentration of Taxol equivalent needed to kill 50% of cells, was found to be 0.24, 0.13 and 0.048 μg/ml for Taxol , Abraxane and ANC of Herceptin/Abraxane respectively for NCI-N87 cells with an excellent dose-effect relationship. Compared with Taxol and Abraxane, ANC of Herceptin/Abraxane could induce significant G2/M arrest. In vivo, at 4 weeks after treatment, mice treated by ANC of Herceptin/Abraxane had a mean tumor volume of 233±24 mm3, Abraxane of 559±97 mm3, Taxol of 871±94 mm3 and PBS as control of 1576±190 mm3. Obviously, the ANC could surpasses Abraxane and Taxol in reducing tumor volume with lesser side effects. Furthermore, NIRF imaging indicated a better targeting and sustained release of paclitaxel with ANC than that with Abraxane and Taxol. Conclusions: Antibody-nanoparticle conjugate of Herceptin/Abraxane could mediate targeted therapy and enhance antitumor activity, which could represent a novel targeted therapeutic agent for positive HER2 gastric cancer.

scholarly journals Epidermal growth factor receptor regulates pancreatic fibrosis

2009 ◽  
Vol 297 (3) ◽  
pp. G434-G441 ◽  
Author(s):  
Stacy A. Blaine ◽  
Kevin C. Ray ◽  
Kevin M. Branch ◽  
Pamela S. Robinson ◽  
Robert H. Whitehead ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Pancreatic Fibrosis ◽  
Pancreatic Stellate Cells ◽  
Heparin Binding ◽  
Epidermal Growth

The development of pancreatic fibrosis has been shown to be a major component in several diseases of the pancreas including pancreatic cancer, chronic pancreatitis, and type 2 diabetes mellitus, but its actual role in the progression of these disorders is still unknown. This fibrosis is characterized by stromal expansion and the excessive deposition of extracellular matrix (ECM) that replaces pancreatic tissue. This eventually leads to dysregulation of ECM turnover, production of cytokines, restriction of blood flow, and often exocrine and endocrine insufficiencies. Activated pancreatic stellate cells (PSCs) have been identified as key mediators in the progression of pancreatic fibrosis, serving as the predominant source of excess ECM proteins. Previously, we found that overexpression of the growth factor heparin-binding epidermal growth factor-like growth factor (HB-EGF) in pancreatic islets led to intraislet fibrosis. HB-EGF binds to and activates two receptors, epidermal growth factor receptor (EGFR) and ErbB4, as well as heparin moieties and CD9/DRAP27. To understand the mechanism underlying the induction of fibrogenesis by HB-EGF, we utilized a hypomorphic allele of Egfr, the Waved-2 allele, to demonstrate that EGFR signaling regulates fibrogenesis in vivo. Using an in vitro cell migration assay, we show that HB-EGF regulates both chemoattraction and stimulation of proliferation of PSCs via EGFR activation.

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