scholarly journals Role of IQGAP1 in Head and Neck Carcinogenesis

2018 ◽  
Author(s):  
Tao Wei ◽  
Suyong Choi ◽  
Darya Buehler ◽  
Alan C. Rapraeger ◽  
Richard A. Anderson ◽  
...  
Keyword(s):  
Growth Factor ◽  
Head And Neck ◽  
Human Cancer ◽  
Akt Signaling ◽  
Pi3k Signaling ◽  
Growth Factor Signaling ◽  
Iq Motif

ABSTRACTHead and neck squamous cell carcinoma (HNSCC) is a common cancer in humans. Phosphoinositide 3-kinase (PI3K)/AKT signaling, along with its downstream effector mTOR, is one of the most frequently altered pathways in HNSCC, and is downstream of growth factor signaling including that mediated by epidermal growth factor receptor (EGFR), which is also commonly upregulated in HNSCC. Recently, IQ motif-containing GTPase activation protein 1 (IQGAP1) has been reported to function as a scaffold for the enzymes involved in the PI3K/AKT signaling pathway. Iqgap1 gene expression is increased in human HNSCCs, raising the hypothesis that it acts as an oncogene in this cancer. Whether IQGAP1 is necessary for HNSCC development as well as what is its underlying mechanism are both unknown. Here we report on the role of IQGAP1 in HNSCC by performing a combination of in vitro studies using human cancer cell lines, and in vivo studies using a well-validated preclinical mouse model for HNSCC that is known to depend upon EGFR signaling. Cells knocked out for IQGAP1 lost AKT signaling. Disruption of IQGAP1-scaffolded PI3K/AKT signaling using a peptide that interferes with the ability of IQGAP1 to bind to PI3K reduced HNSCC cell survival. In vivo studies utilizing Iqgap1-null (Iqgap1-/-) mice demonstrated that IQGAP1 is necessary for efficient PI3K signaling upon EGF-stimulation. Treatment of Iqgap1-/- mice with the oral carcinogen, 4-nitroquinoline 1-oxide (4NQO), Iqgap1-/- led to significantly lower multiplicities of cancer foci as well as significantly lower numbers of high grade cancers than observed in similarly treated Iqgap1+/+ mice. IQGAP1 protein was increased in its expression in HNSCCs arising in the Iqgap1+/+ mice, consistent with that seen in human HNSCCs. We also observed a significant down-regulation of PI3K signaling in 4NQO-induced HNSCCs arising in the Iqgap1-/- mice, consistent with IQGAP1 contributing to carcinogenesis by promoting PI3K signaling. Our studies, therefore, support the hypothesis that IQGAP1 acts as an oncogene in head and neck carcinogenesis, and provide mechanistic insight into its role.

scholarly journals Hyperglycaemia up-regulates placental growth factor (PlGF) expression and secretion in endothelial cells via suppression of PI3 kinase-Akt signalling and activation of FOXO1

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Samir Sissaoui ◽  
Stuart Egginton ◽  
Ling Ting ◽  
Asif Ahmed ◽  
Peter W. Hewett
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Endothelial Dysfunction ◽  
Akt Activation ◽  
Forkhead Box ◽  
Pi3k Activity ◽  
Binding Sequence

AbstractPlacenta growth factor (PlGF) is a pro-inflammatory angiogenic mediator that promotes many pathologies including diabetic complications and atherosclerosis. Widespread endothelial dysfunction precedes the onset of these conditions. As very little is known of the mechanism(s) controlling PlGF expression in pathology we investigated the role of hyperglycaemia in the regulation of PlGF production in endothelial cells. Hyperglycaemia stimulated PlGF secretion in cultured primary endothelial cells, which was suppressed by IGF-1-mediated PI3K/Akt activation. Inhibition of PI3K activity resulted in significant PlGF mRNA up-regulation and protein secretion. Similarly, loss or inhibition of Akt activity significantly increased basal PlGF expression and prevented any further PlGF secretion in hyperglycaemia. Conversely, constitutive Akt activation blocked PlGF secretion irrespective of upstream PI3K activity demonstrating that Akt is a central regulator of PlGF expression. Knock-down of the Forkhead box O-1 (FOXO1) transcription factor, which is negatively regulated by Akt, suppressed both basal and hyperglycaemia-induced PlGF secretion, whilst FOXO1 gain-of-function up-regulated PlGF in vitro and in vivo. FOXO1 association to a FOXO binding sequence identified in the PlGF promoter also increased in hyperglycaemia. This study identifies the PI3K/Akt/FOXO1 signalling axis as a key regulator of PlGF expression and unifying pathway by which PlGF may contribute to common disorders characterised by endothelial dysfunction, providing a target for therapy.

scholarly journals Hypermethylation of DHRS3 as a Novel Tumor Suppressor Involved in Tumor Growth and Prognosis in Gastric Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Sha Sumei ◽  
Kong Xiangyun ◽  
Chen Fenrong ◽  
Sun Xueguang ◽  
Hu Sijun ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Suppressor ◽  
Tumor Growth ◽  
Human Cancer ◽  
Methylation Status ◽  
Ectopic Expression ◽  
Survival Times

Background/AimsThe role of DHRS3 in human cancer remains unclear. Our study explored the role of DHRS3 in gastric cancer (GC) and its clinicopathological significance and associated mechanisms.MaterialsBisulfite-assisted genomic sequencing PCR and a Mass-Array system were used to evaluate and quantify the methylation levels of the promoter. The expression levels and biological function of DHRS3 was examined by both in vitro and in vivo assays. A two-way hierarchical cluster analysis was used to classify the methylation profiles, and the correlation between the methylation status of the DHRS3 promoter and the clinicopathological characteristics of GC were then assessed.ResultsThe DHRS3 promoter was hypermethylated in GC samples, while the mRNA and protein levels of DHRS3 were significantly downregulated. Ectopic expression of DHRS3 in GC cells inhibited cell proliferation and migration in vitro, decreased tumor growth in vivo. DHRS3 methylation was correlated with histological type and poor differentiation of tumors. GC patients with high degrees of CpG 9.10 methylation had shorter survival times than those with lower methylation.ConclusionDHRS3 was hypermethylated and downregulated in GC patients. Reduced expression of DHRS3 is implicated in gastric carcinogenesis, which suggests DHRS3 is a tumor suppressor.

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.

Nitric oxide mediates mitogenic effect of VEGF on coronary venular endothelium

1996 ◽  
Vol 270 (1) ◽  
pp. H411-H415 ◽  
Author(s):  
L. Morbidelli ◽  
C. H. Chang ◽  
J. G. Douglas ◽  
H. J. Granger ◽  
F. Ledda ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Growth Factor ◽  
No Synthase ◽  
Mitogenic Effect ◽  
Microvascular Endothelium ◽  
Proliferative Effect

Vascular endothelial growth factor (VEGF) is a secreted protein that is a specific growth factor for endothelial cells. We have recently demonstrated that nitric oxide (NO) donors and vasoactive peptides promoting NO-mediated vasorelaxation induce angiogenesis in vivo as well as endothelial cell growth and motility in vitro; in contrast, inhibitors of NO synthase suppress angiogenesis. In this study we investigated the role of NO in mediating the mitogenic effect of VEGF on cultured microvascular endothelium isolated from coronary postcapillary venules. VEGF induced a dose-dependent increase in cell proliferation and DNA synthesis. The role of NO was determined by monitoring proliferation or guanosine 3',5'-cyclic monophosphate (cGMP) levels in the presence and absence of NO synthase blockers. The proliferative effect evoked by VEGF was reduced by pretreatment of the cells with NO synthase inhibitors. Exposure of the cells to VEGF induced a significant increment in cGMP levels. This effect was potentiated by superoxide dismutase addition and was abolished by NO synthase inhibitors. VEGF stimulates proliferation of postcapillary endothelial cells through the production of NO and cGMP accumulation.

scholarly journals AIB1 Is a Conduit for Kinase-Mediated Growth Factor Signaling to the Estrogen Receptor

2000 ◽  
Vol 20 (14) ◽  
pp. 5041-5047 ◽  
Author(s):  
Jaime Font de Mora ◽  
Myles Brown
Keyword(s):  
Estrogen Receptor ◽  
Growth Factors ◽  
Growth Factor ◽  
Mitogen Activated Protein Kinase ◽  
Growth Factor Signaling ◽  
Breast Cancers ◽  
Mapk Activation ◽  
Mitogen Activated Protein

ABSTRACT Growth factor modulation of estrogen receptor (ER) activity plays an important role in both normal estrogen physiology and the pathogenesis of breast cancer. Growth factors are known to stimulate the ligand-independent activity of ER through the activation of mitogen-activated protein kinase (MAPK) and the direct phosphorylation of ER. We found that the transcriptional activity of AIB1, a ligand-dependent ER coactivator and a gene amplified preferentially in ER-positive breast cancers, is enhanced by MAPK phosphorylation. We demonstrate that AIB1 is a phosphoprotein in vivo and can be phosphorylated in vitro by MAPK. Finally, we observed that MAPK activation of AIB1 stimulates the recruitment of p300 and associated histone acetyltransferase activity. These results suggest that the ability of growth factors to modulate estrogen action may be mediated through MAPK activation of the nuclear receptor coactivator AIB1.

scholarly journals Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma

Gut ◽  
2015 ◽  
Vol 66 (3) ◽  
pp. 530-540 ◽  
Author(s):  
Victoria Tovar ◽  
Helena Cornella ◽  
Agrin Moeini ◽  
Samuel Vidal ◽  
Yujin Hoshida ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factor ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Gene Signature ◽  
Signalling Pathways ◽  
Fgf Signalling

ObjectiveSorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterise the role of tumour-initiating cells (T-ICs) and signalling pathways involved in sorafenib resistance.DesignHCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: (1) role of T-ICs by in vitro sphere formation and in vivo tumourigenesis assays using NOD/SCID mice, (2) activation of alternative signalling pathways and (3) efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, quantitative real-time PCR (qRT-PCR)) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in two independent cohorts.ResultsSorafenib-acquired resistant tumours showed significant enrichment of T-ICs (164 cells needed to create a tumour) versus sorafenib-sensitive tumours (13 400 cells) and non-treated tumours (1292 cells), p<0.001. Tumours with sorafenib-acquired resistance were enriched with insulin-like growth factor (IGF) and fibroblast growth factor (FGF) signalling cascades (false discovery rate (FDR)<0.05). In vitro, cells derived from sorafenib-acquired resistant tumours and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumour growth and improved survival in sorafenib-resistant tumours. A sorafenib-resistance 175 gene signature was characterised by enrichment of progenitor cell features, aggressive tumorous traits and predicted poor survival in two cohorts (n=442 patients with HCC).ConclusionsAcquired resistance to sorafenib is driven by T-ICs with enrichment of progenitor markers and activation of IGF and FGF signalling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression.

scholarly journals The Neuroprotective Effects of Insulin-Like Growth Factor 1 via the Hippo/YAP Signaling Pathway is Mediated by the PI3K/AKT Pathway Following Cerebral Ischemia-Reperfusion Injury

2021 ◽  
Author(s):  
Pian Gong ◽  
Yichun Zou ◽  
Wei Zhang ◽  
Qi Tian ◽  
Shoumeng Han ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Growth Factor ◽  
Signaling Pathway ◽  
Neuronal Death ◽  
Infarct Volume ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Neuroprotective Effects

Abstract Insulin-like growth factor 1 (IGF-1) exhibits neuroprotective properties, such as vasodilatory and anti-inflammatory effects following ischemic stroke. However, the specific molecular mechanisms of action of IGF-1 following ischemic stroke remain elusive. We wanted to explore whether IGF-1 regulates Hippo/YAP signaling pathway, potentially via activation of the PI3K/AKT signaling pathway to exert its neuroprotective effects following ischemic stroke. In the in vitro study, we used oxygen–glucose deprivation to injure cultured PC12 and SH-5YSY cells, and cortical primary neurons. Cell viability was measured using CCK-8 assay. For the in vivo analyses, Sprague–Dawley rats were subjected to middle cerebral artery occlusion; neurological function was assessed using the neurological deficit score; infarct volume was measured using triphenyltetrazolium chloride staining, and neuronal death and apoptosis was evaluated by TUNEL staining, H&E staining and Nissl staining. Western blot was used to measure the levels of YAP/TAZ, PI3K and phosphorylated AKT (p-AKT) both in vitro and in vivo. We found that IGF-1 induced activation of YAP/TAZ, which resulted in improved cell viability in vitro, and decreased neurological deficits, neuronal death and apoptosis, and cerebral infarct volume in vivo. Notably, the neuroprotective effects of IGF-1 were reversed by an inhibitor of the PI3K/AKT signaling pathway, LY294002, which not only reduced expressions of PI3K and p-AKT, but also down-regulated expression of YAP/TAZ, leading to aggravation of neurological dysfunction. These findings indicate that neuroprotective effect of IGF-1 is partly realized by up-regulation of YAP/TAZ, which is mediated by activation of the PI3K/AKT signaling pathway following cerebral ischemic stroke.

scholarly journals Role of the Latent Transforming Growth Factor β-Binding Protein 1 in Fibrillin-Containing Microfibrils in Bone Cells In Vitro and In Vivo

2000 ◽  
Vol 15 (1) ◽  
pp. 68-81 ◽  
Author(s):  
Sarah L. Dallas ◽  
Douglas R. Keene ◽  
Scott P. Bruder ◽  
Juha Saharinen ◽  
Lynn Y. Sakai ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Bone Cells ◽  
Binding Protein ◽  
Transforming Growth Factor Β

Small Molecule SHIP Agonist AQX-MN100 Inhibits Multiple Myeloma (MM) Cell Growth In NOD/SCID Mice and Reduces Immune Suppressive Myeloid Derived Suppressor Cells (MDSC) and Regulatory T Cells (Tregs) In Mouse Model

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 792-792
Author(s):  
Alice Mui ◽  
Mike Kennah ◽  
Christopher Ong ◽  
Raymond Anderson ◽  
Heather Sutherland
Keyword(s):  
Tumor Volume ◽  
Suppressor Cells ◽  
Pi3k Pathway ◽  
Akt Signaling ◽  
Myeloid Derived Suppressor Cells ◽  
Hemopoietic Cells ◽  
Equity Ownership

Abstract Abstract 792 We recently described a novel anti-MM drug (AQX-MN100) which is a small molecule agonist of SHIP (Src homology-2 (SH2) containing inositol-5¢-phosphatase) a signaling molecule found only in hemopoietic cells.(Ong et al, Blood; 110:1942, 2007) The molecule was developed using a high-throughput SHIP enzyme assay to screen an invertebrate marine natural product library and isolate the Pelorol.(Yang et al Org Lett; 7:1073, 2005) SHIP normally functions to negatively regulate the PI3K pathway important to normal hemopoietic cells growth and function. Inappropriate activation of the phosphoinositide 3- kinase (PI3K) pathway has been shown to be involved in the pathogenesis of MM and tumour aggressiveness correlates with the degree of activation. The critical role the PI3K/Akt signaling pathway plays in regulating MM cell survival, has stimulated efforts in designing therapeutics that target this pathway. Pan PI3K inhibitors have limited utility in a clinical setting because of their inhibitory effects on all isoforms of the PI3K family as well as non-PI3K targets. SHIP is an exceptionally good target for MM and other hematopoietic disorders that display elevated PI3K/Akt signaling because its expression is restricted to hemopoietic cells. We have shown that an analogue of Pelorol, AQX-MN100 is able to inhibit PI3K signaling and prevent phosphorylation of Akt. AQX-MN100 induced MM cell line apoptosis mediated by caspase and was specific for SHIP expressing cells which are exclusively hematopoietic. AQX-MN100 also enhances the growth inhibition effects of current myeloma drugs Dexamethasone and Bortezomib on human MM tumour cell lines in vitro. (Kennah et al Expt Hematol; 37:1274, 2009) In this study we have extended these finding to further evaluate the role of this compound in the treatment of myeloma. NOD-SCID mice were injected in the lateral flanks with 2 million luciferase tagged MM1.S multiple myeloma cells in Matrigel. Tumors were allowed to establish for two weeks and then either AQX-MN100 or vehicle was administered in an oil deposit subcutaneously in the lower flank at a dose of 50 mg/kg every three days. Tumor volume was quantified by imaging on a Xenogen IVIS 200 after 6 and 11 days. These studies demonstrate a significant reduction of tumor volume at 6 days p<0.05 and a highly significant reduction at 11 days p<0.01 in the mice receiving AQX-MN100 as compared to vehicle. We have shown that AQX-MN100 can directly kill MM cells in in vitro and in vivo. However, based on the known functions of SHIP, we predict that SHIP agonists will additionally target critical steps in MM pathogenesis in vivo, including the ability of MM cells to interact with stromal elements and to subvert the immune system. In order to evaluate this later feature we evaluated the ability of SHIP agonists to reverse the tumor associated immune suppression in MM patients. Tumor and host cell/tumor microenvironment secreted factors promote the production and activation of cells associated with cancer progression: the immune suppressive myeloid derived suppressor cells (MDSC) and regulatory T cells (Tregs). These cells normally regulate immune responses by inhibiting the activation of immune effector cells. The involvement of SHIP in the regulation of these cells is predicted by the observation that MDSC and Treg numbers are elevated in SHIP deficient mice. In this study Balb/C mice, 6 mice/group in duplicate were given either AQX-MN100 3 mg/kg and 10 mg/kg or vehicle once daily orally. At the end of three weeks mesenteric lymph nodes were harvested and subjected to FACS analysis to determine the proportion of MDSC (CD11b+Gr1+) and Treg (CD4+CD25+FoxP3+) cells. Spleen cells were also analysed for B cells, NK cells and granulocytes. In both of the AQX-MN100 treated groups the numbers of MDSC and Tregs were significantly lower than controls while Total CD11b, Total CD3, and spleen B, NK and granulocytes were not different from vehicle treated controls. The known role of SHIP in regulating hemopoietic cell function and the role of SHIP agonists in MM cell killing as well as additional actions on other aspects of MM pathophysiology may make them a powerful treatment option for MM, either alone or in synergy with other known MM therapies. Further development of this agent for the treatment of MM is ongoing. Disclosures: Mui: Aquinox: Equity Ownership, Patents & Royalties. Ong:Aquinox: Equity Ownership, Patents & Royalties. Anderson:Aquinox: Equity Ownership, Patents & Royalties. Sutherland:Celgene: Honoraria; Orthobiotech: Honoraria.

Sign in / Sign up

Export Citation Format

Share Document