Taken together, our results indicate that SNX5 promotes HCC cell proliferation and metastasis via inhibiting the endocytosis and degradation of EGFR, thereby activating the ERK1/2 signaling pathway.
By crossing Twist1a-ERT2 with xmrk (a homolog of hyperactive form of epidermal growth factor receptor) transgenic zebrafish, which develops hepatocellular carcinoma, ~80% of the double transgenic zebrafish showed spontaneous cell dissemination of mCherry-labelled hepatocytes from the liver to the entire abdomen region and the tail region.
In conclusion, this work reveals a new tumour suppressor function for EGFR counteracting TGF-β-mediated epithelial to amoeboid transitions in HCC, supporting a rational for targeting the TGF-β pathway in patients with low EGFR expression.
Since MYC amplification is frequently identified in HCC, co-occurring with EGFR amplification, our findings suggest that targeting EGFR signaling might be essential for JQ1 therapy in advanced HCC.
Our research suggests that in addition to the metabolic manner, TKT can promote the development of HCC in a non-metabolic manner via its nuclear localization and EGFR pathway.
Here we report that CD317, a surface molecule with a unique topology, activated EGFR in hepatocellular carcinoma (HCC) cells by regulating its localization on the plasma membrane.
Importantly, we provide <i>in vitro</i> and <i>in vivo</i> evidence that UVRAG ubiquitination at lysine residues 517 and 559 or prevention of Ser522 phosphorylation by D4476, a CSNK1A1 inhibitor, enhances the lysosomal degradation of EGFR, which significantly inhibits hepatocellular carcinoma (HCC) growth.
This is the first report showing that YTHDF2 may act as a tumor suppressor to repress cell proliferation and growth via destabilizing the EGFR mRNA in HCC.
Either inhibition of tyrosine kinase activity of EGFR with Erlotinib/Icotinib or inhibition of KLF4 expression with short hairpin RNA recovered the response of three SR HCC cell lines to sorafenib, suggesting the critical roles of EGFR tyrosine kinase and KLF4 on inducing SR. Luciferase activity and chromatin immunoprecipitation assays further determined that KLF4 promoted EGFR expression through inducing its transcription by directly binding to its promoter.
The IC<sub>50</sub> values of the compounds against carcinoma cells varied from 16.90 µM (in resistant U87MG.ΔEGFR glioblastoma cells) to 48.67 µM (against HepG2 hepatocarcinoma cells) for 1, from 7.85 µM (in U87MG.ΔEGFR cells) to 14.44 µM (in resistant MDA-MB231/BCRP breast adenocarcinoma cells) for 2, from 4.96 µM (towards U87MG.ΔEGFRcells) to 7.76 µM (against MDA-MB231/BCRP cells) for 4, and from 0.07 µM (against MDA-MB231 cells) to 2.15 µM (against HepG2 cells) for doxorubicin.
Besides, The Cancer Genome Atlas analyses of HCCs were performed to determine the association of MCM3AP-AS1 and epidermal growth factor receptor (EGFR) with overall survival.
Cx32 facilitated HCC progression by blocking chemotherapy-induced apoptosis in vitro and in vivo via interacting with Src and thus promoting the phosphorylation of EGFR, subsequently activating the EGFR signaling pathway.
In addition, somatic mutations including those in genes encoding colony-stimulating factor 1 receptor (5.1%), epidermal growth factor receptor (6.8%), <i>RET</i> proto-oncogene (3.4%), Erb-B2 receptor tyrosine kinase 4 (<i>ERBB4</i>; 1.7%) and serine/threonine kinase 11 (<i>STK11</i>, also known as liver kinase B1; 6.8%) were also identified at a low frequency in patients with HCC.
Furthermore, the analysis of human hepatocellular carcinoma specimens obtained from the GEO database showed that the expression of EGFR and Met correlated with that of Grb2.