scholarly journals The IGF pathway is activated in insulinomas but downregulated in metastatic disease

2018 ◽  
Vol 25 (12) ◽  
pp. 1005-1018
Author(s):  
Mieke E R Henfling ◽  
Aurel A Perren ◽  
Anja M Schmitt ◽  
Christiane M Saddig ◽  
Achim A Starke ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Expression ◽  
Signaling Pathway ◽  
Metastatic Disease ◽  
Growth Factor Receptor ◽  
Disease Free Survival ◽  
Pancreatic Neuroendocrine Tumor ◽  
Mtor Signaling ◽  
Mrna Levels ◽  
Mrna And Protein Expression

Clinical and molecular studies have implicated epidermal growth factor receptor (EGFR), insulin-like growth factor (IGF) and target of rapamycin (mTOR) signaling pathways in the regulation of pancreatic neuroendocrine tumor (PanNET) growth. Interpretation and comparison of these studies is complex due to clinical and molecular tumor heterogeneity. We therefore focused in this study on insulinomas, which we examined for mRNA and protein expression of EGFR, IGF and mTOR signaling pathway components by quantitative real-time PCR (n = 48) and immunohistochemistry (n = 86). Findings were compared with normal pancreatic islets and correlated with histopathological data and clinical outcome. Insulinomas showed low EGFR and high IGF2 expression. IGFBP2, IGFBP3 and IGFBP6 mRNA levels were 2- to 4-folds higher than those in islets. High protein expression of IGF2, IGF1R and INSR (in 51–92% of the tumors) and low-to-moderate expression of mTORC1 pathway proteins p-S6k and p-4EBP1 (7–28% of the tumors) were observed. Correlations were found between (1) ERK1 mRNA expression and that of numerous IGF pathway genes, (2) p-ERK and IGF1R protein expression and (3) decrease of IGF pathway components and both metastatic disease and shorter 10-year disease-free survival. In conclusion, our observations suggest that high expression of IGF signaling pathway components is a hallmark of insulinomas, but does not necessarily lead to increased mTOR signaling. Reduced expression of IGF pathway components may be an adverse prognostic factor in insulinomas.

T-cadherin deficiency promotes endometriosis progression through the PI3K/AKT/mTOR signaling pathway

2020 ◽  
Author(s):  
yutao guan ◽  
Fu-bin Zhang ◽  
Yan-qing Huang ◽  
Ling-ling Zhou ◽  
Wei-feng Li ◽  
...  
Keyword(s):  
Cell Migration ◽  
Protein Expression ◽  
Signaling Pathway ◽  
Benign Disease ◽  
Mtor Signaling ◽  
Migration And Invasion ◽  
Mtor Signaling Pathway ◽  
Cell Migration And Invasion ◽  
Female Patients ◽  
Mrna And Protein Expression

Abstract Background: Endometriosis is a progressive and benign disease characterized by the presence of endometrial glands and stroma tissue outside of the uterine cavity. Though endometriosis is a benign disease, it has the characteristics of malignant tumour growth. Abnormal expression of T-cadherin is involved in the occurrence and progression of many tumours. We aimed to investigate whether T-cadherin promotes the migration and invasion of endometriosis cells through the PI3K/AKT/mTOR signaling pathway. Methods: Ectopic and eutopic endometrial samples from 62 female patients with endometriosis and endometrial samples from 51 female patients without endometriosis were collected. The immortalized endometrial stromal cell line hEM15A was cultured. Real-time RT-PCR, immunohistochemistry and Western blot were used to detect the expression of T-cadherin, phospho-PI3K/Akt/mTOR and matrix metalloproteinase 2 (MMP-2). Transfection technology was employed to upregulate T-cadherin expression. The migration and invasion abilities of hEM15A cells were measured by the transwell assay with uncoated or Matrigel-coated membranes. Results: The mRNA and protein expression of T-cadherin was significantly decresed in the ectopic tissues of the patients with endometriosis, while the mRNA and protein expression in the eutopic endometrial tissues of the same patients did not significantly differ from that in the patients without endometriosis. The migration and invasion ability and phospho-PI3K/Akt/mTOR and MMP-2 expression levels were decreased in hEM15A cells with high T-cadherin expression compared with the corresponding parameters in the normal control group. However, everolimus and BEZ235 inhibited cell migration and invasion in cells with low T-cadherin expression, and weakened overexpression of T‑cadherin significantly attenuated MMP-2 protein expression. Conclusion: Loss of T-cadherin promotes cell migration and invasion in endometriosis via the PI3K/AKT/mTOR signalling pathway.

scholarly journals Notch Signaling Pathway Is Involved in bFGF-Induced Corneal Lymphangiogenesis and Hemangiogenesis

2019 ◽  
Vol 2019 ◽  
pp. 1-13
Author(s):  
Fang Xie ◽  
Xue Zhang ◽  
Wenting Luo ◽  
Hongyan Ge ◽  
Dawei Sun ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Expression ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Notch Signaling Pathway ◽  
Expression Level ◽  
Control Group ◽  
Fluorescence Signal ◽  
Mrna And Protein Expression ◽  
Corneal Lymphangiogenesis

Background. Notch/Dll4 involvement in cornea neovascularization (CRNV) and lymphangiogenesis is unclear. This study aimed to explore the role of notch signaling in basic fibroblast growth factor- (bFGF-) induced corneal lymphangiogenesis and hemangiogenesis. Methods. Corneal stroma of C57BL/6 mice was implanted with bFGF- or phosphate-buffered saline- (PBS-) soaked pellets. Corneal lymphangiogenesis and neovascularization were evaluated by immunofluorescence. Vascular endothelial growth factor-A (VEGF-A), Delta-like ligand 4 (Dll4), and Notch1 mRNA and protein expression were examined on days 1, 3, 7, and 14 by real-time polymerase chain reaction and western blot. Corneal cells were treated with ranibizumab, dexamethasone, and γ-secretase inhibitor (GSI). Microspheres were used to evaluate corneal hemangiogenesis in vivo. Results. Corneal hemangiogenesis reached its peak on day 7 after bFGF implantation, and corneal lymphangiogenesis was significantly higher on day 7 and 14, compared with PBS. mRNA and protein expression of VEGF-A, Dll4, and Notch1 were higher in bFGF-induced animal models compared with controls. Corneal hemangiogenesis and lymphangiogenesis decreased after 7 days of ranibizumab or dexamethasone treatment. After adding GSI for 24 h in bFGF-induced cells, the expression of Notch1 and Dll4 were downregulated compared with that in the control group whereas the expression level of VEGF-A was upregulated. Fluorescent particle number was higher in the GSI group. Ranibizumab and dexamethasone decreased the fluorescence signal. Conclusion. The notch signaling pathway plays a role in regulating VEGF expression, affecting corneal lymphangiogenesis and hemangiogenesis in mice. The molecular imaging probe technique can visualize the changes in the VEGF-A expression level of corneal limbus hemangiogenesis.

scholarly journals Transactivation of Platelet-Derived Growth Factor Receptor α by the GTPase-Deficient Activated Mutant of Gα12

2006 ◽  
Vol 26 (1) ◽  
pp. 50-62 ◽  
Author(s):  
Rashmi N. Kumar ◽  
Ji Hee Ha ◽  
Rangasudhagar Radhakrishnan ◽  
Danny N. Dhanasekaran
Keyword(s):  
Growth Factor ◽  
Cell Growth ◽  
Signaling Pathway ◽  
Growth Factor Receptor ◽  
Platelet Derived Growth Factor ◽  
Dominant Negative Mutant ◽  
Dependent Manner ◽  
3T3 Cells ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

ABSTRACT The GTPase-deficient, activated mutant of Gα12 (Gα12Q229L, or Gα12QL) induces neoplastic growth and oncogenic transformation of NIH 3T3 cells. Using microarray analysis, we have previously identified a role for platelet-derived growth factor receptor α (PDGFRα) in Gα12-mediated cell growth (R. N. Kumar et al., Cell Biochem. Biophys. 41:63-73, 2004). In the present study, we report that Gα12QL stimulates the functional expression of PDGFRα and demonstrate that the expression of PDGFRα by Gα12QL is dependent on the small GTPase Rho. Our results indicate that it is cell type independent as the transient expression of Gα12QL or the activation of Gα12-coupled receptors stimulates the expression of PDGFRα in NIH 3T3 as well as in human astrocytoma 1321N1 cells. Furthermore, we demonstrate the presence of an autocrine loop involving PDGF-A and PDGFRα in Gα12QL-transformed cells. Analysis of the functional consequences of the Gα12-PDGFRα signaling axis indicates that Gα12 stimulates the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway through PDGFR. In addition, we show that Gα12QL stimulates the phosphorylation of forkhead transcription factor FKHRL1 via AKT in a PDGFRα- and PI3K-dependent manner. Since AKT promotes cell growth by blocking the transcription of antiproliferative genes through the inhibitory phosphorylation of forkhead transcription factors, our results describe for the first time a PDGFRα-dependent signaling pathway involving PI3K-AKT-FKHRL1, regulated by Gα12QL in promoting cell growth. Consistent with this view, we demonstrate that the expression of a dominant negative mutant of PDGFRα attenuated Gα12-mediated neoplastic transformation of NIH 3T3 cells.

scholarly journals Insulin-like Growth Factor Receptor 1 (IGF1R) Gene Copy Number Is Associated With Survival in Operable Non–Small-Cell Lung Cancer: A Comparison Between IGF1R Fluorescent In Situ Hybridization, Protein Expression, and mRNA Expression

2010 ◽  
Vol 28 (13) ◽  
pp. 2174-2180 ◽  
Author(s):  
Rafal Dziadziuszko ◽  
Daniel T. Merrick ◽  
Samir E. Witta ◽  
Adelita D. Mendoza ◽  
Barbara Szostakiewicz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Protein Expression ◽  
Squamous Cell ◽  
Copy Number ◽  
Gene Copy Number ◽  
Growth Factor Receptor ◽  
Gene Copy ◽  
Cell Versus

PurposeThe purpose of this study was to characterize insulin-like growth factor-1 receptor (IGF1R) protein expression, mRNA expression, and gene copy number in surgically resected non–small-cell lung cancers (NSCLC) in relation to epidermal growth factor receptor (EGFR) protein expression, patient characteristics, and prognosis.Patients and MethodsOne hundred eighty-nine patients with NSCLC who underwent curative pulmonary resection were studied (median follow-up, 5.3 years). IGF1R protein expression was evaluated by immunohistochemistry (IHC) with two anti-IGF1R antibodies (n = 179). EGFR protein expression was assessed with PharmDx kit. IGF1R gene expression was evaluated using quantitative reverse transcription polymerase chain reaction (qRT-PCR) from 114 corresponding fresh-frozen samples. IGF1R gene copy number was assessed by fluorescent in situ hybridization using customized probes (n = 181).ResultsIGF1R IHC score was higher in squamous cell carcinomas versus other histologies (P < .001) and associated with stage (P = .03) but not survival (P = .46). IGF1R and EGFR protein expression showed significant correlation (r = 0.30; P < .001). IGF1R gene expression by qRT-PCR was higher in squamous cell versus other histologies (P = .006) and did not associate with other clinical features nor survival (P = .73). Employing criteria previously established for EGFR copy number, patients with IGF1R amplification/high polysomy (n = 48; 27%) had 3-year survival of 58%, patients with low polysomy (n = 87; 48%) had 3-year survival of 47% and patients with trisomy/disomy (n = 46; 25%) had 3-year survival of 35%, respectively (P = .024). Prognostic value of high IGF1R gene copy number was confirmed in multivariate analysis.ConclusionIGF1R protein expression is higher in squamous cell versus other histologies and correlates with EGFR expression. IGF1R protein and gene expression does not associate with survival, whereas high IGF1R gene copy number harbors positive prognostic value.

scholarly journals Receptor-driven invasion profiles in diffuse intrinsic pontine glioma (DIPG)

2021 ◽  
Author(s):  
Anju Karki ◽  
Noah E Berlow ◽  
Jin-Ah Kim ◽  
Esther Hulleman ◽  
Qianqian Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Protein Expression ◽  
Cell Viability ◽  
Rna Sequencing ◽  
Cell Invasion ◽  
Growth Factor Receptor ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Sequencing Data ◽  
Pontine Glioma

Abstract Background Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric cancer with unmet clinical need. DIPG is invasive in nature, where tumor cells interweave into the fiber nerve tracts of the pons making the tumor unresectable. Accordingly, novel approaches in combating the disease is of utmost importance and receptor-driven cell invasion in the context of DIPG is under-researched area. Here we investigated the impact on cell invasion mediated by PLEXINB1, PLEXINB2, platelet growth factor receptor (PDGFR)α, PDGFRβ, epithelial growth factor receptor (EGFR), activin receptor 1 (ACVR1), chemokine receptor 4 (CXCR4) and NOTCH1. Methods We used previously published RNA-sequencing data to measure gene expression of selected receptors in DIPG tumor tissue versus matched normal tissue controls (n=18). We assessed protein expression of the corresponding genes using DIPG cell culture models. Then, we performed cell viability and cell invasion assays of DIPG cells stimulated with chemoattractants/ligands. Results RNA-sequencing data showed increased gene expression of receptor genes such as PLEXINB2, PDGFRα, EGFR, ACVR1, CXCR4 and NOTCH1 in DIPG tumors compared to the control tissues. Representative DIPG cell lines demonstrated correspondingly increased protein expression levels of these genes. Cell viability assays showed minimal effects of growth factors/chemokines on tumor cell growth in most instances. Recombinant SEMA4C, SEM4D, PDGF-AA, PDGF-BB, ACVA, CXCL12 and DLL4 ligand stimulation altered invasion in DIPG cells. Conclusions We show that no single growth factor-ligand pair universally induces DIPG cell invasion. However, our results reveal a potential to create a composite of cytokines or anti-cytokines to modulate DIPG cell invasion.

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