scholarly journals Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor—MIG6 Axis

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1515
Author(s):  
Keiichiro Okuda ◽  
Atsushi Umemura ◽  
Shiori Umemura ◽  
Seita Kataoka ◽  
Hiroyoshi Taketani ◽  
...  
Keyword(s):  
Mouse Model ◽  
Glucocorticoid Receptor ◽  
Nuclear Translocation ◽  
Growth Factor Receptor ◽  
Public Health Problem ◽  
Egfr Signaling ◽  
Alcoholic Steatohepatitis ◽  
Genetic Mouse Model ◽  
Treatment And Prevention ◽  
Egfr Expression

Non-alcoholic steatohepatitis (NASH) has become a serious public health problem associated with metabolic syndrome. The mechanisms by which NASH induces hepatocellular carcinoma (HCC) remain unknown. There are no approved drugs for treating NASH or preventing NASH-induced HCC. We used a genetic mouse model in which HCC was induced via high-fat diet feeding. This mouse model strongly resembles human NASH-induced HCC. The natural product honokiol (HNK) was tested for its preventative effects against NASH progression to HCC. Then, to clarify the mechanisms underlying HCC development, human HCC cells were treated with HNK. Human clinical specimens were also analyzed to explore this study’s clinical relevance. We found that epidermal growth factor receptor (EGFR) signaling was hyperactivated in the livers of mice with NASH and human HCC specimens. Inhibition of EGFR signaling by HNK drastically attenuated HCC development in the mouse model. Mechanistically, HNK accelerated the nuclear translocation of glucocorticoid receptor (GR) and promoted mitogen-inducible gene 6 (MIG6)/ERBB receptor feedback inhibitor 1 (ERRFI1) expression, leading to EGFR degradation and thereby resulting in robust tumor suppression. In human samples, EGFR-positive HCC tissues and their corresponding non-tumor tissues exhibited decreased ERRFI1 mRNA expression. Additionally, GR-positive non-tumor liver tissues displayed lower EGFR expression. Livers from patients with advanced NASH exhibited decreased ERRFI1 expression. EGFR degradation or inactivation represents a novel approach for NASH–HCC treatment and prevention, and the GR–MIG6 axis is a newly defined target that can be activated by HNK and related compounds.

scholarly journals A non-hierarchical organization of tumorigenic NG2 cells in glioblastoma promoted by EGFR

2018 ◽  
Vol 21 (6) ◽  
pp. 719-729 ◽  
Author(s):  
Talal F Al-Mayhani ◽  
Richard M Heywood ◽  
Vamsidhara Vemireddy ◽  
Justin D Lathia ◽  
Sara G M Piccirillo ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Hierarchical Organization ◽  
Egfr Signaling ◽  
Resistant Disease ◽  
Egfr Expression ◽  
Ng2 Cells ◽  
Human Gbm ◽  
Rna Knockdown ◽  
Cellular Hierarchy ◽  
Relationship Of

Abstract Background Expression of neuron-glial antigen 2 (NG2) identifies an aggressive malignant phenotype in glioblastoma (GBM). Mouse models have implicated NG2 in the genesis, evolution, and maintenance of glial cancers and have highlighted potential interactions between NG2 and epidermal growth factor receptor (EGFR). However, it is unknown whether the lineage relationship of NG2+ and NG2− cells follows a hierarchical or stochastic mode of growth. Furthermore, the interaction between NG2 and EGFR signaling in human GBM is also unclear. Methods Single GBM NG2+ and NG2− cells were studied longitudinally to assess lineage relationships. Short hairpin RNA knockdown of NG2 was used to assess the mechanistic role of NG2 in human GBM cells. NG2+ and NG2− cells and NG2 knockdown (NG2-KD) and wild type (NG2-WT) cells were analyzed for differential effects on EGFR signaling. Results Expression of NG2 endows an aggressive phenotype both at single cell and population levels. Progeny derived from single GBM NG2− or GBM NG2+ cells consistently establish phenotypic equilibrium, indicating the absence of a cellular hierarchy. NG2 knockdown reduces proliferation, and mice grafted with NG2-KD survive longer than controls. Finally, NG2 promotes EGFR signaling and is associated with EGFR expression. Conclusions These data support a dynamic evolution in which a bidirectional relationship exists between GBM NG2+ and GBM NG2− cells. Such findings have implications for understanding phenotypic heterogeneity, the emergence of resistant disease, and developing novel therapeutics.

scholarly journals Therapy-induced transdifferentiation promotes glioma growth independent of EGFR signaling

2020 ◽  
Author(s):  
Hwanhee Oh ◽  
Inah Hwang ◽  
Lingxiang Wu ◽  
Dongqing Cao ◽  
Jun Yao ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Malignant Gliomas ◽  
Growth Factor Receptor ◽  
Glioma Cells ◽  
Underlying Mechanism ◽  
Therapy Resistance ◽  
Small Population ◽  
Dominant Negative ◽  
Egfr Signaling ◽  
Glioma Growth

AbstractEpidermal growth factor receptor (EGFR) is frequently amplified, mutated and overexpressed in malignant gliomas. Yet the EGFR-targeted therapies have thus far produced only marginal clinical response, and the underlying mechanism remains poorly understood. Through analyses of an inducible oncogenic EGFR-driven glioma mouse model system, our current study reveals a small population of glioma cells that can evade therapy-initiated apoptosis and potentiate relapse development by adopting a mesenchymal-like phenotypic state that no longer depends on oncogenic EGFR signaling. Transcriptome analyses of proximal and distal treatment responses further identify TGFβ/YAP/Slug signaling cascade activation as major regulatory mechanism that promotes therapy-induced glioma mesenchymal lineage transdifferentiation. Following anti-EGFR treatment, the TGFβ secreted from the stressed glioma cells acts to promote YAP nuclear translocation and activation, which subsequently stimulates upregulation of the pro-mesenchymal transcriptional factor Slug and then glioma lineage transdifferentiation towards a stable therapy-refractory state. Blockade of this adaptive response through enforced dominant negative YAP expression significantly delayed anti-EGFR relapse and significantly prolonged animal survival. Together, our findings shed new insight into EGFR-targeted therapy resistance and suggest that combinatorial therapies of targeting both EGFR and mechanisms underlying glioma lineage transdifferentiation could ultimately lead to deeper and more durable responses.SignificanceThis study demonstrates that molecular reprogramming and lineage transdifferentiation underlie anti-EGFR therapy resistance and is clinically relevant to the development of new combinatorial targeting strategies against malignant gliomas carrying aberrant EGFR signaling.

scholarly journals Establishment of dorsal-ventral polarity of theDrosophilaegg requirescapicuaaction in ovarian follicle cells

Development ◽  
2001 ◽  
Vol 128 (22) ◽  
pp. 4553-4562 ◽  
Author(s):  
Deborah J. Goff ◽  
Laura A. Nilson ◽  
Donald Morisato
Keyword(s):  
Target Genes ◽  
Nuclear Translocation ◽  
Ovarian Follicle ◽  
Growth Factor Receptor ◽  
Follicle Cell ◽  
Dorsal Side ◽  
Follicle Cells ◽  
Follicular Epithelium ◽  
Egfr Signaling ◽  
Cell Nuclei

The dorsal-ventral pattern of the Drosophila egg is established during oogenesis. Epidermal growth factor receptor (Egfr) signaling within the follicular epithelium is spatially regulated by the dorsally restricted distribution of its presumptive ligand, Gurken. As a consequence, pipe is transcribed in a broad ventral domain to initiate the Toll signaling pathway in the embryo, resulting in a gradient of Dorsal nuclear translocation. We show that expression of pipe RNA requires the action of fettucine (fet) in ovarian follicle cells. Loss of maternal fet activity produces a dorsalized eggshell and embryo. Although similar mutant phenotypes are observed with regulators of Egfr signaling, genetic analysis suggests that fet acts downstream of this event. The fet mutant phenotype is rescued by a transgene of capicua (cic), which encodes an HMG-box transcription factor. We show that Cic protein is initially expressed uniformly in ovarian follicle cell nuclei, and is subsequently downregulated on the dorsal side. Earlier studies described a requirement for cic in repressing zygotic target genes of both the torso and Toll pathways in the embryo. Our experiments reveal that cic controls dorsal-ventral patterning by regulating pipe expression in ovarian follicle cells, before its previously described role in interpreting the Dorsal gradient.

scholarly journals Epidermal growth factor receptor expression and signaling are essential in glutamine's cytoprotective mechanism in heat-stressed intestinal epithelial-6 cells

2013 ◽  
Vol 304 (5) ◽  
pp. G543-G552 ◽  
Author(s):  
Stefanie Niederlechner ◽  
Christine Baird ◽  
Benjamin Petrie ◽  
Erhard Wischmeyer ◽  
Paul E. Wischmeyer
Keyword(s):  
Small Interfering Rna ◽  
Growth Factor Receptor ◽  
Intestinal Epithelial ◽  
Egfr Signaling ◽  
Cellular Protection ◽  
Akt Phosphorylation ◽  
Egfr Expression ◽  
Epidermal Growth ◽  
Interfering Rna

Epidermal growth factor receptor (EGFR) expression and signaling can induce cellular protection after intestinal inflammation. l-Glutamine (GLN) is known to prevent apoptosis after intestinal injury by activating MAPK and phosphatidylinositol 3-kinase (PI3-K)/Akt pathways. However, the role of EGFR expression and signaling in GLN-mediated cellular protection in intestinal epithelial-6 (IEC-6) cells after heat stress (HS) is unknown. To address the role of EGFR in GLN-mediated protection, IEC-6 cells were treated with GLN in the presence or absence of EGFR small interfering RNA, the EGFR tyrosine kinase inhibitor AG1478, the ERK1/2 inhibitor PD98059, the p38MAPK inhibitor SB203580, or the PI3-K/Akt inhibitor LY294002 under basal and HS conditions. GLN-mediated cell survival was measured using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. Phosphorylated and/or total levels of EGFR, cleaved caspase-3, poly(ADP-ribose) polymerase-1, ERK1/2, p38MAPK, and Akt were assessed by Western blotting. We showed that HS induced a decrease in total, cytoplasmic, and nuclear EGFR levels in IEC-6 cells, which was prevented by GLN supplementation, leading to attenuated apoptosis via EGFR small interfering RNA. Furthermore, the protective effect of GLN was lessened by AG1478, PD98059, and LY294002 but was not affected by SB203580. AG1478 attenuated GLN-mediated increases in ERK1/2 and decreases in p38MAPK phosphorylation. However, AG1478 had no effect on GLN-mediated augmentations in Akt phosphorylation. In summary, EGFR expression was important in the protective mechanism of GLN, as well as GLN-mediated activation of EGFR tyrosine kinase activity. GLN-mediated EGFR signaling activated ERK1/2 and decreased p38MAPK signaling. However, GLN-mediated Akt phosphorylation after HS seems to be independent of EGFR signaling.

scholarly journals HCMV-induced signaling through gB–EGFR engagement is required for viral trafficking and nuclear translocation in primary human monocytes

2020 ◽  
Vol 117 (32) ◽  
pp. 19507-19516
Author(s):  
Heather L. Fulkerson ◽  
Liudmila S. Chesnokova ◽  
Jung Heon Kim ◽  
Jamil Mahmud ◽  
Laura E. Frazier ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Nuclear Translocation ◽  
Growth Factor Receptor ◽  
Major Axis ◽  
Productive Infection ◽  
Blood Monocytes ◽  
Egfr Signaling ◽  
Viral Binding ◽  
Subsequent Degradation ◽  
Egfr Kinase

Previous analysis of postentry events revealed that human cytomegalovirus (HCMV) displays a unique, extended nuclear translocation pattern in monocytes. We determined that c-Src signaling through pentamer engagement of integrins is required upon HCMV entry to avoid sorting of the virus into late endosomes and subsequent degradation. To follow up on this previous study, we designed experiments to investigate how HCMV-induced signaling through the other major axis—the epidermal growth factor receptor (EGFR) kinase—regulates viral postentry events. Here we show that HCMV induces chronic and functional EGFR signaling that is distinct to the virus as compared to the natural EGFR ligand: EGF. This chronic EGFR kinase activity in infected monocytes is required for the proper subcellular localization of the viral particle during trafficking events, as well as for promoting translocation of viral DNA into the host nucleus. Our data indicate that HCMV glycoprotein B (gB) binds to EGFR at the monocyte surface, the virus and EGFR are internalized together, and gB remains bound to EGFR throughout viral postentry events until de-envelopment to promote the chronic EGFR kinase activity required for viral trafficking and nuclear translocation. These data highlight how initial EGFR signaling via viral binding is necessary for entry, but not sufficient to promote each viral trafficking event. HCMV appears to manipulate the EGFR kinase postentry, via gB–EGFR interaction, to be active at the critical points throughout the trafficking process that leads to nuclear translocation and productive infection of peripheral blood monocytes.

scholarly journals NFAT5 promotes oral squamous cell carcinoma progression in a hyperosmotic environment

2020 ◽  
Vol 101 (1) ◽  
pp. 38-50 ◽  
Author(s):  
Shohei Yoshimoto ◽  
Hiromitsu Morita ◽  
Miho Matsuda ◽  
Yoshinori Katakura ◽  
Masato Hirata ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cancer Cells ◽  
Squamous Cell ◽  
Nuclear Translocation ◽  
Growth Factor Receptor ◽  
Protein Glycosylation ◽  
Cancer Development ◽  
Egfr Signaling

AbstractEpidermal growth factor receptor (EGFR) is highly expressed in several types of cancer cells including oral squamous cell carcinoma (OSCC). EGF/EGFR signaling is recognized as an important molecular target in cancer therapy. However, cancer cells often become tolerant to EGF/EGFR signaling-targeted therapies. In the tumor microenvironment, the tumor incites inflammation and the inflammation-derived cytokines make a considerable impact on cancer development. In addition, hyperosmolarity is also induced, but the role of osmotic stress in cancer development has not been fully understood. This study demonstrates molecular insights into hyperosmolarity effect on OSCC development and shows that NFAT5 transcription factor plays an important functional role in enhancing the oral cancer cell proliferation by inducing the EGFR translocation from the endoplasmic reticulum to the plasma membrane through increase the expression of DPAGT1, an essential enzyme for catalyzing the first committed step of N-linked protein glycosylation. These results suggest that hyperosmolarity-induced intra-nuclear translocation of NFAT5 essential for DPAGT1 activation and EGFR subcellular translocation responsible for OSCC tumor progression.

scholarly journals Mig6 decreases hepatic EGFR activation and survival during saturated fatty acid-induced endoplasmic reticulum stress

2020 ◽  
Author(s):  
Andrew J. Lutkewitte ◽  
Yi-Chun Chen ◽  
Jeffrey L. Hansen ◽  
Patrick T. Fueger
Keyword(s):  
Endoplasmic Reticulum ◽  
Fatty Acid ◽  
Er Stress ◽  
Growth Factor Receptor ◽  
Rat Hepatocytes ◽  
Egfr Signaling ◽  
Egfr Expression ◽  
Egfr Activation ◽  
Feedback Inhibitor ◽  
Novel Target

ABSTRACTHyperlipidemia associated with obesity and type 2 diabetes (T2D) promotes excess hepatic lipid storage (steatosis) and endoplasmic reticulum (ER) stress, thereby reducing hepatic cell proliferation and survival. An important receptor tyrosine kinase controlling liver proliferation and survival is the epidermal growth factor receptor (EGFR). EGFR expression and activation are decreased during steatosis in humans and several animal models of obesity. Therefore, restoring EGFR activation in obesity-induced ER stress and diabetes could restore the liver’s capacity for survival and regeneration. As an inducible feedback inhibitor of EGFR activity, mitogen-inducible gene 6 (Mig6) is a novel target for enhancing EGFR signaling during diet-induced obesity (DIO) and T2D. Thus, we hypothesized hepatic ER stress induces Mig6 expression and decreases EGFR activation during DIO and diabetes. We identified that Mig6 expression was increased during obesity-induced insulin resistance in C57Bl/6J mice fed a high fat diet. We also discovered that both pharmacological- and fatty acid-driven ER stress increased Mig6 expression and decreased EGF-mediated EGFR activation in primary rat hepatocytes and cell lines. Furthermore, siRNA-mediated Mig6 knockdown restored EGFR signaling and reduced caspase 3/7 activation during ER stress. Therefore, we conclude Mig6 is increased during ER stress in DIO, thereby reducing EGFR activation and enhancing cell death. The implications are the induction of Mig6 during DIO and diabetes may decrease hepatocyte survival, thus hindering cellular repair and regenerative mechanisms.

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