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Project description:Epidermal growth factor receptor (EGFR) is mostly known for its proliferative role in liver. Our earlier investigations indicated a paradoxical cell-death promoting facet of EGFR in acetaminophen (APAP)-induced liver injury (AILI) model. The current study investigates this unexpected role of EGFR in promoting AILI using a hepatocyte-specific EGFR deletion mouse model. Hepatocyte-specific EGFR-deficient mice were generated by administering AAV8-TBG-CRE in EGFRfl/fl mice and were subsequently treated with a severely toxic dose (500 mg/kg) of APAP. Liver injury, regeneration and associated signaling pathways were assessed at different time intervals. EGFR deletion significantly attenuated the progression of liver injury (beyond 12hr post-APAP) without altering early liver injury (up to 6 hr) following APAP overdose. Consistently, the key injury initiating events such as APAP-protein adducts formation and early JNK activation remained intact in EGFR-deficient mice. However, EGFR deletion restricted prolonged JNK activation and its mitochondrial translocation, resulting in reduced propagation of mitochondrial damage and release of cell death drivers. Further, the replenishment of antioxidant glutathione (GSH), which is known to limit the progression of liver injury, was strikingly faster in EGFR-deficient mice. RNA-seq analysis and consequent validation revealed marked upregulation of autophagy and its transcriptional regulator TFEB, a key response to remove damaged mitochondria, in EGFR-deficient mice. Paradoxically, EGFR deletion also promoted compensatory liver proliferative response secondary to decreased progression of liver injury. Overall, hepatocyte-specific EGFR deletion halted the progression of AILI. Our study established an unexpected death promoting function of EGFR in AILI progression, which has wide implications in liver biology.
2025-11-13 | GSE309117 | GEO
Project description:Epidermal growth factor receptor (EGFR) is mostly known for its proliferative role in liver. Our earlier investigations indicated a paradoxical cell-death promoting facet of EGFR in acetaminophen (APAP)-induced liver injury (AILI) model. The current study investigates this unexpected role of EGFR in promoting AILI using a hepatocyte-specific EGFR deletion mouse model. Hepatocyte-specific EGFR-deficient mice were generated by administering AAV8-TBG-CRE in EGFRfl/fl mice and were subsequently treated with a severely toxic dose (500 mg/kg) of APAP. Liver injury, regeneration and associated signaling pathways were assessed at different time intervals. EGFR deletion significantly attenuated the progression of liver injury (beyond 12hr post-APAP) without altering early liver injury (up to 6 hr) following APAP overdose. Consistently, the key injury initiating events such as APAP-protein adducts formation and early JNK activation remained intact in EGFR-deficient mice. However, EGFR deletion restricted prolonged JNK activation and its mitochondrial translocation, resulting in reduced propagation of mitochondrial damage and release of cell death drivers. Further, the replenishment of antioxidant glutathione (GSH), which is known to limit the progression of liver injury, was strikingly faster in EGFR-deficient mice. RNA-seq analysis and consequent validation revealed marked upregulation of autophagy and its transcriptional regulator TFEB, a key response to remove damaged mitochondria, in EGFR-deficient mice. Paradoxically, EGFR deletion also promoted compensatory liver proliferative response secondary to decreased progression of liver injury. Overall, hepatocyte-specific EGFR deletion halted the progression of AILI. Our study established an unexpected death promoting function of EGFR in AILI progression, which has wide implications in liver biology.
2025-11-13 | GSE309115 | GEO
Project description:Hepatocyte-specific epidermal growth factor receptor (EGFR) deletion attenuates acetaminophen-induced liver injury in mice
| PRJNA1333989 | ENA
Project description:Hepatocyte-specific epidermal growth factor receptor (EGFR) deletion attenuates acetaminophen-induced liver injury in mice [RNA-seq Illumina]
| PRJNA1333992 | ENA
Project description:Hepatocyte-specific epidermal growth factor receptor (EGFR) deletion attenuates acetaminophen-induced liver injury in mice [RNA-seq AVITI]
| PRJNA1333980 | ENA
Project description:The mechanisms and biological implications of coordinated receptor tyrosine kinase coactivation remain poorly appreciated. Epidermal growth factor receptor (EGFR) and c-Met are frequently coexpressed in cancers, including those associated with hepatocyte growth factor (HGF) overexpression, such as malignant astrocytoma. In a previous analysis of the HGF-induced transcriptome, we found that two EGFR agonists, transforming growth factor-alpha and heparin-binding epidermal growth factor-like growth factor (HB-EGF), are prominently up-regulated by HGF in human glioma cells. We now report that stimulating human glioblastoma cells with recombinant HGF induces biologically relevant EGFR activation. EGFR phosphorylation at Tyr(845) and Tyr(1068) increased 6 to 24 h after cell stimulation with HGF and temporally coincided with the induction of transforming growth factor-alpha (~5-fold) and HB-EGF (~23-fold) expression. Tyr(845) and Tyr(1068) phosphorylation, in response to HGF, was inhibited by cycloheximide and actinomycin D, consistent with a requirement for DNA transcription and RNA translation. Specifically, blocking HB-EGF binding to EGFR with the antagonist CRM197 inhibited HGF-induced EGFR phosphorylation by 60% to 80% and inhibited HGF-induced S-G(2)-M transition. CRM197 also inhibited HGF-induced anchorage-dependent cell proliferation but had no effect on HGF-mediated cytoprotection. These findings establish that EGFR can be activated with functional consequences by HGF as a result of EGFR ligand expression. This transcription-dependent cross-talk between the HGF receptor c-Met and EGFR expands our understanding of receptor tyrosine kinase signaling networks and may have considerable consequences for oncogenic mechanisms and cancer therapeutics.
| S-EPMC2839502 | biostudies-literature
Project description:Fibroblast growth factor receptor 4 (FGFR4) is known to induce cancer cell proliferation, invasion, and antiapoptosis through activation of RAS/RAF/ERK and PI3K/AKT pathways, which are also known as major molecular bases of colon cancer carcinogenesis related with epidermal growth factor receptor (EGFR) signaling. However, the interaction between FGFR4 and EGFR signaling in regard to colon cancer progression is unclear. Here, we investigated a potential cross-talk between FGFR4 and EGFR, and the effect of anti-EGFR therapy in colon cancer treatment. To explore the biological roles of FGFR4 in cancer progression, RNA sequencing was carried out using FGFR4 transfected colon cell lines. Gene ontology data showed the upregulation of genes related to EGFR signaling, and we identified that FGFR4 overexpression secretes EGFR ligands such as amphiregulin (AREG) with consequent activation of EGFR and ErbB3. This result was also shown in in vivo study and the cooperative interaction between EGFR and FGFR4 promoted tumor growth. In addition, FGFR4 overexpression reduced cetuximab-induced cytotoxicity and the combination of FGFR4 inhibitor (BLU9931) and cetuximab showed profound antitumor effect compared to cetuximab alone. Clinically, we found the positive correlation between FGFR4 and AREG expression in tumor tissue, but not in normal tissue, from colon cancer patients and these expressions were significantly correlated with poor overall survival in patients treated with cetuximab. Therefore, our results provide the novel mechanism of FGFR4 in connection with EGFR activation and the combination of FGFR4 inhibitor and cetuximab could be a promising therapeutic option to achieve the optimal response to anti-EGFR therapy in colon cancer.
| S-EPMC7469799 | biostudies-literature
Project description:Myeloid cells, including macrophages, play important roles as first responders to cardiac injury and stress. Epidermal growth factor receptor (EGFR) has been identified as a mediator of macrophage responsiveness to select diseases, though its impact on cardiac function or remodeling following acute ischemic injury is unknown. We aimed to define the role of myeloid cell-specific EGFR in the regulation of cardiac function and remodeling following acute myocardial infarction (MI)-induced injury. Floxed EGFR mice were bred with homozygous LysM-Cre (LMC) transgenic mice to yield myeloid-specific EGFR knockout (mKO) mice. Via echocardiography, immunohistochemistry, RNA sequencing and flow cytometry, the impact of myeloid cell-specific EGFR deletion on cardiac structure and function was assessed at baseline and following injury. Compared with LMC controls, myeloid cell-specific EGFR deletion led to an increase in cardiomyocyte hypertrophy at baseline. Bulk RNASeq analysis of isolated cardiac Cd11b+ myeloid cells revealed substantial changes in mKO cell transcripts at baseline, particularly in relation to predicted decreases in neovascularization. In response to myocardial infarction, mKO mice experienced a hastened decline in cardiac function with isolated cardiac Cd11b+ myeloid cells expressing decreased levels of the pro-reparative mediators Vegfa and Il10, which coincided with enhanced cardiac hypertrophy and decreased capillary density. Overall, loss of EGFR qualitatively alters cardiac resident macrophages that promotes a low level of basal stress and a more rapid decrease in cardiac function along with worsened repair following acute ischemic injury.
| S-EPMC10758753 | biostudies-literature
Project description:Epidermal growth factor receptor (EGFR) plays a crucial role in hepatocyte proliferation. Its role in acetaminophen (APAP)-mediated hepatotoxicity and subsequent liver regeneration is completely unknown. Role of EGFR after APAP-overdose in mice was studied using pharmacological inhibition strategy. Rapid, sustained and dose-dependent activation of EGFR was noted after APAP-treatment in mice, which was triggered by glutathione depletion. EGFR-activation was also observed in primary human hepatocytes after APAP-treatment, preceding elevation of toxicity markers. Treatment of mice with an EGFR-inhibitor (EGFRi), Canertinib, 1h post-APAP resulted in robust inhibition of EGFR-activation and a striking reduction in APAP-induced liver injury. Metabolic activation of APAP, formation of APAP-protein adducts, APAP-mediated JNK-activation and its mitochondrial translocation were not altered by EGFRi. Interestingly, EGFR rapidly translocated to mitochondria after APAP-treatment. EGFRi-treatment abolished mitochondrial EGFR activity, prevented APAP-mediated mitochondrial dysfunction/oxidative-stress and release of endonucleases from mitochondria, which are responsible for DNA-damage/necrosis. Treatment with N-acetylcysteine (NAC), 4h post-APAP in mice did not show any protection but treatment of EGFRi in combination with NAC showed decrease in liver injury. Finally, delayed treatment with EGFRi, 12-h post-APAP, did not alter peak injury but caused impairment of liver regeneration resulting in sustained injury and decreased survival after APAP overdose in mice. Impairment of regeneration was due to inhibition of cyclinD1 induction and cell cycle arrest. Our study has revealed a new dual role of EGFR both in initiation of APAP-injury and in stimulation of subsequent compensatory regeneration after APAP-overdose.
| S-EPMC6020708 | biostudies-literature
Project description:Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) are two extensively studied membrane-bound receptor tyrosine kinase proteins that are frequently overexpressed in many cancers. As a result, these receptor families constitute attractive targets for imaging and therapeutic applications in the detection and treatment of cancer. This review explores the dynamic structure and structure-function relationships of these two growth factor receptors and their significance as it relates to theranostics of cancer, followed by some of the common inhibition modalities frequently employed to target EGFR and VEGFR, such as tyrosine kinase inhibitors (TKIs), antibodies, nanobodies, and peptides. A summary of the recent advances in molecular imaging techniques, including positron emission tomography (PET), single-photon emission computerized tomography (SPECT), computed tomography (CT), magnetic resonance imaging (MRI), and optical imaging (OI), and in particular, near-IR fluorescence imaging using tetrapyrrolic-based fluorophores, concludes this review.
| S-EPMC7922143 | biostudies-literature