Expression and biosynthetic variation of the epidermal growth factor receptor in human hepatocellular carcinoma-derived cell lines.

Abstract

Expression of the epidermal growth factor (EGF) was analyzed in six human hepatocellular carcinomaderived and one human hepatoblastoma-derived cell line, each of which retained the differentiated phenotype and functions of the parenchymal hepatocyte. The level of receptor expression of each hepatoma cell line was imilar to that of the normal human fibroblast, approximately 10 molecules per cell. However, NPLC/PRF/5, a subline of the PLC/PRF/5 cell line obtained following reestablishment of a xenograft tumor in vitro, was found to express 4 x 106 high-affinity EGF receptor molecules per cell. Proliferation of the NPLC/PRF/5 cell line was inhibited in the presence of nanomolar quantities of ligand. Receptor overexpression was found to result from EGF receptor gene amplification without apparent rearrangement of the EGF receptor coding sequences. Although cell-specific variability in posttranslational processing of EGF receptor N-linked oligosaccharides in the hepatoma cell lines was found, no difference between the receptors in PLC/PRF/5 and NPLC/PRF/5 was observed and no aberrant receptor-related species were detected. EGF receptor gene amplification in the NPLC/PRF/5 cell line is probably a reflection of genome instability and selection of variants with augmented growth potential in limiting concentrations of EGF in vivo. When viewed in this light, EGF receptor overexpression could represent a manifestation of tumor progression in the EGF-responsive hepatocyte.The adult parenchymal hepatocyte is a long-lived differentiated cell which can be stimulated to proliferate in a compensatory growth model. Although the molecular interactions which lead to liver cell proliferation are unknown, insulin, glucagon, and epidermal growth factor (EGF) are known to be necessary to the regenerative process (41). To determine whether abnormalities in the receptor for one growth factor implicated in the regulation of proliferation of the normal hepatocyte could be a factor in hepatocellular carcinogenesis, we examined the display of the EGF receptor in a series of hepatoma-derived cell lines. Increased expression of the EGF receptor has been observed in primary tumors and cell lines derived from human glioblastomas (31), pancreatic tumors (27), squamous cell carcinomas (22), and breast tumors (44). Hepatocellular carcinoma is a common tumor in areas of the world where hepatitis B virus (HBV) is endemic, but despite the frequent and stable integration of the HBV genome in these tumor cells, no viral transforming gene product and no common site of HBV integration within the host cell genomes have been identified (6, 12, 20a, 43, 49, 52). In the present analysis, we found that EGF receptor expression in the hepatoma-derived cell lines did not differ from that in normal cells, with the exception of one laboratory-derived subline of the PLC/PRF/5 hepatoma-derived cell line which expresses 20-fold more receptors per cell than the parental cell line, the result of EGF receptor gene amplification. Although receptor affinity for EGF was sim...

Expression of high‐ and low‐affinity epidermal growth factor receptors in human hepatoma cell lines

“…These data are at variance with those of others which suggest that either EGF-R expression is decreased in hepatoma cells [27], or that abnormal expression of the EGF-R of HCC-cells is not among the factors responsible for the aberrant cell proliferation [15]. EGF has been observed to inhibit growth in vitro of a variety of carcinoma-derived cell lines [28][29][30][31], most of which exhibit high levels of high-affinity EGF receptors as a consequence of gene amplification.…”

“…A further aspect of HCC cells in culture has been reported concerning their response to polypeptide mitogens [13][14][15], thus indicating that at least in some cases epidermal growth factor (EGF) can play a major role in conditioning the growth characteristics of these cells.…”

The role of signaling pathways in the development and treatment of hepatocellular carcinoma

“…Expression of both IGF and IGF receptor is upregulated in HCC and human cirrhotic liver (Alexia et al, 2004) Similarly, EGF and related growth factors are commonly overexpressed in HCC (Yeh et al, 1987;Carlin et al, 1988;Kira et al, 1997;Ito et al, 2001).…”

Epidermal Growth Factor–PEG Functionalized PAMAM-Pentaethylenehexamine Dendron for Targeted Gene Delivery Produced by Click Chemistry

“…27À29 The epidermal growth factor receptor (EGFR) is highly expressed in a wide variety of human tumors, such as lung, breast and hepatocellular cancers. 30 The binding of EGF to EGFR triggers the fast internalization of EGF conjugated polyplexes. 31 Our previous studies demonstrated that the EGF-PEG conjugated polyethylenimine (EGF-PEG-PEI) polyplexes delivered pDNA or dsRNA into targeted cells or tumor xenograft much more efficiently than EGF free ones.…”