EGF promotes DKK1 transcription in hepatocellular carcinoma by enhancing the phosphorylation and acetylation of histone H3

2020 ◽  
Vol 13 (657) ◽  
pp. eabb5727
Author(s):  
Jie Niu ◽  
Wei Li ◽  
Chao Liang ◽  
Xiao Wang ◽  
Xin Yao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nuclear Translocation ◽  
Histone H3 ◽  
Growth Factor Receptor ◽  
Transcript Level ◽  
Metastatic Progression ◽  
Chemically Induced ◽  
Epidermal Growth ◽  
Dual Inhibition ◽  
Dickkopf 1

The protein Dickkopf-1 (DKK1) is frequently overexpressed at the transcript level in hepatocellular carcinoma (HCC) and promotes metastatic progression through the induction of β-catenin, a Wnt signaling effector. We investigated how DKK1 expression is induced in HCC and found that activation of the epidermal growth factor receptor (EGFR) promoted parallel MEK-ERK and PI3K-Akt pathway signaling that converged to epigenetically stimulate DKK1 transcription. In HCC cell lines stimulated with EGF, EGFR-activated ERK phosphorylated the kinase PKM2 at Ser37, which promoted its nuclear translocation. Also in these cells, EGFR-activated Akt phosphorylated the acetyltransferase p300 at Ser1834. Subsequently, PKM2 and p300 mediated the phosphorylation and acetylation, respectively, of histone H3 at the DKK1 promoter, which synergistically enhanced DKK1 transcription. The mechanism was supported with mutational analyses in cells and in a chemically induced HCC model in rats. The findings suggest that dual inhibition of the MEK and PI3K pathways might suppress the expression of DKK1 and, consequently, tumor metastasis in patients with HCC.

scholarly journals PKM2-Induced the Phosphorylation of Histone H3 Contributes to EGF-Mediated PD-L1 Transcription in HCC

2020 ◽  
Vol 11 ◽  
Author(s):  
Xiao Wang ◽  
Chao Liang ◽  
Xin Yao ◽  
Ruo-Han Yang ◽  
Zhan-Sheng Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Histone H3 ◽  
Growth Factor Receptor ◽  
Transcriptional Level ◽  
Mrna And Protein Expression ◽  
Normal Rat ◽  
Epidermal Growth ◽  
Hcc Cells

High expression of programmed death-ligand-1 (PD-L1) in hepatocellular carcinoma (HCC) cells usually inhibits the proliferation and functions of T cells, leading to immune suppression in tumor microenvironment. However, very little has been described regarding the mechanism of PD-L1 overexpression in HCC cells. In the present study, we found epidermal growth factor (EGF) stimulation promoted the expression of PD-L1 mRNA and protein in HCC cells. Inhibition of epidermal growth factor receptor (EGFR) could reverse EGF-induced the expression of PD-L1 mRNA and protein. Subsequently, we also observed that the phosphorylation level of Pyruvate kinase isoform M2 (PKM2) at Ser37 site was also increased in response to EGF stimulation. Expression of a phosphorylation-mimic PKM2 S37D mutant stimulated PD-L1 expression as well as H3-Thr11 phosphorylation in HCC cells, while inhibition of PKM2 significantly blocked EGF-induced PD-L1 expression and H3-Thr11 phosphorylation. Furthermore, mutation of Thr11 of histone H3 into alanine abrogated EGF-induced mRNA and protein expression of PD-L1, Chromatin immunoprecipitation (ChIP) assay also suggested that EGF treatment resulted in enhanced H3-Thr11 phosphorylation at the PD-L1 promoter. In a diethylnitrosamine (DEN)-induced rat model of HCC, we found that the expression of phosphorylated EGFR, PKM2 nuclear expression, H3-Thr11 phosphorylation as well as PD-L1 mRNA and protein was higher in the livers than that in normal rat livers. Taken together, our study suggested that PKM2-dependent histone H3-Thr11 phosphorylation was crucial for EGF-induced PD-L1 expression at transcriptional level in HCC. These findings may provide an alternative target for the treatment of hepatocellular carcinoma.

Interrupted crosstalk between natural killer cells and anti-epidermal growth factor receptor: a possible role in hepatocellular carcinoma treatment failure

2021 ◽  
Vol 21 ◽  
Author(s):  
Hadeer Abosalema ◽  
Shahenda Mahgoub ◽  
Mohamed Emara ◽  
Nahla Kotb ◽  
Sameh Soror
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Major Health Problem ◽  
Advanced Stages ◽  
Epidermal Growth ◽  
First Time ◽  
Late Stages

: Hepatocellular carcinoma (HCC) is a major health problem worldwide. Most patients are diagnosed for the first time at late stages; this leads to a very poor prognosis. It is challenging to discover strategies for treatment at these advanced stages. Recently, monoclonal antibodies (mAbs) targeting specific cellular signaling pathways in HCC have been developed. Unfortunately, they still have a low survival rate, and some of them failed clinically to produce effective responses even if they showed very good results against HCC in preclinical studies. This review focuses on and discusses the possible causes for the failure of mAbs, precisely anti-Epidermal Growth Factor Receptor (EGFR) mAb and the crosstalk between this mAb and patients' NK cells.

scholarly journals Immunohistochemical Expression of Epidermal Growth Factor Receptor in Hepatocellular Carcinoma

PRILOZI ◽  
2018 ◽  
Vol 39 (2-3) ◽  
pp. 21-28
Author(s):  
Dafina Nikolova ◽  
Viktorija Chalovska ◽  
Magdalena Genadieva Ivanova ◽  
Emilija Nikolovska ◽  
Ance Volkanovska ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tumor Cells ◽  
Liver Tissue ◽  
Vascular Invasion ◽  
Tumor Tissue ◽  
Growth Factor Receptor ◽  
Epidermal Growth

Abstract Introduction: Epidermal growth factor receptor (EGFR) signaling plays an important role in various cancers, including hepatocellular carcinoma (HCC). We aimed to evaluate immunoexpression of EGFR in HCC and surrounding non-tumor liver tissue and to correlate it to multiple clinicopathologic data. Material and Methods: We analyzed 60 patients with HCC for multiple clinicopathologic characteristics and survival. Presence of the immunosignal and the percentage of positive tumor cells at the whole tumor tissue sample and adjacent cirrhotic liver tissue were semi-quantitatively determined. Results: Nineteen patients (31.67%) were female and 41 (68.33%) were male ranging in age from 31 to 85 years, median 61.88±10.51. Mean survival time for female patients was 8.86±1.76 months, for male 13.03±1.50 months and overall survival was 11.6051±1.19 months. The most patients had: T2 status (41.67%), no enlarged lymph nodes (90%), vascular invasion (63.33%) and well differentiated (43.33%) tumors. EGFR immunoexpression was determined in range from 0% to 100% in both tumor and non-tumor tissue with mean value of 39.58% in tumor and 86.86% in cirrhotic tissue (p<0.00). Higher percent of tumor EGFR positive cells were found in cases with higher T status, higher levels of AFP and poorly differentiated carcinoma, but not significantly. Lower percent of tumor EGFR positive cells were found in patients with vascular invasion and enlarged lymph nodes, but also not significantly. EGFR expression in tumor tissue significantly influenced survival of the patients (p<0.05). Conclusion: The study showed that expression of EGFR in lower percentage of tumor cells was associated to favorable prognosis, making it a potential prognostic marker and therapeutic target.

scholarly journals Correction: Yes and Lyn play a role in nuclear translocation of the epidermal growth factor receptor

Oncogene ◽  
2018 ◽  
Vol 38 (13) ◽  
pp. 2435-2435
Author(s):  
M. Iida ◽  
T. M. Brand ◽  
D. A. Campbell ◽  
C. Li ◽  
D. L. Wheeler
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Nuclear Translocation ◽  
Growth Factor Receptor ◽  
Epidermal Growth
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