Role of estrogens and epidermal growth factor in hepatocellular carcinoma (HCC)

Abstract

Estrogen (E) and epidermal growth factors (EGF) receptors were assayed in the liver of nine patients with hepatocellular carcinoma (HCC). Total E and nuclear E receptors were decreased significantly in neoplastic tissue as compared to the levels found in surrounding nonneoplastic tissue. The EGF receptor was decreased also in neoplastic tissue. On the basis of binding data, a decrease in the number but not in affinity of both the E and EGF receptors was found. Keywordsestrogen; epidermal growth factor receptors; hepatocellular carcinoma Epidermal growth factor (EGF) is a polypeptide growth factor that was isolated originally from the submaxillary gland. It stimulates DNA synthesis in vitro in a variety of different cells (1)(2)(3). This effect is initiated by the interaction of EGF with a specific plasma membrane receptor (4). During the last five years, several lines of evidence have demonstrated that EGF receptor expression can be altered by hormones such as estrogen (E) (4), growth hormone (5), and thyroid stimulating hormone (TSH) (6) in target tissues for these hormones.The relationship between E and EGF has been studied extensively in normal uterus and in breast cancer tissue (4-7). For example, it has been shown that E stimulates EGF receptor expression in uterine tissue obtained from immature rats (4). In contrast, an inverse relationship exists between the EGF and E receptors content in breast cancer tissues (8). Recently it has been shown that the liver is also a target tissue for sex hormones (9-11). E receptors (ER) appear to play an important role in hepatic regeneration where a strong temporal relationship between increased hepatic DNA synthesis and an increased activity and nuclear distribution of ER have been found. Because both ER and EGF are involved in hepatocyte proliferation, the pattern of E and EGF receptors in tissue samples obtained from patients with hepatocellular carcinoma (HCC) was studied. MATERIALS AND METHODS Liver SpecimensSamples of HCC-containing and normal adjacent liver were collected from patients undergoing resection in Milan, Bari, and Pittsburgh. Both tumor and adjacent normal liver tissue were collected and their identities confirmed by histology. The samples were wrapped in aluminum foil, snap-frozen, and stored at −70° C until assayed for their content of E and EGF receptors. Prior studies using fresh and frozen liver have showed that both the E and EGF receptors are stable during frozen storage. MaterialsRadioactive [2,3,6, H]estradiol ([ 3 H]E 2 ), 90 Ci/mmol and [ 125 I]EGF were purchased from New England Nuclear. The purity of the radiolabeled compounds was assessed periodically by thin-layer or column chromatography (12). Sources of other materials were as described previously (12)(13)(14). Binding StudiesThe preparation of cytosolic, nuclear, and plasma membrane fractions was as described previously (10,15). The methods for the estrogen receptor assay (10) and the EGF binding assay have been described previously (15). Other MethodsProtein concentrations ...

Alternative splicing of estrogen receptor alpha in hepatocellular carcinoma

“…Due to multiple variants of ERa and ERb, the actual role of wtER in HCC was too complex to be defined. Several studies have reported that the expression of wtER was less in tumor tissues than in adjacent normal tissues [19, 20], which was in line with our findings on wtERa. These results indicate that wtERa may exhibit a protective role in HCC [21].…”

Role of sex steroid receptors in pathobiology of hepatocellular carcinoma

“…The early studies used indirect methods of receptor detection based on ligand binding assays. Table 1 gives the details of these studies [13,15,17,[30][31][32][33][34][35][36][37] . These assays were quantitative and measured the amount of receptor in the samples as well as its affinity for the ligand in terms of dissociation constants.…”

Expression of the erb B Oncogene in the Morris Hepatoma 7777

“…Our däta suggest that infcreased expression of the v-erb B related sequences upon serial tumour transplantation is due to a selection of ligand-independent tyrosine kinase activity, because these cells should have a growth advantage in vivo. On the other band, the füll length EGF-receptor mRNA seems to be decreased in some human or rat hepatomas (25,26,27). Therefore, the increased formation of v-erb B related gene transcripts suggests an alternative splicing or a selection of deletion mutations of the EGF receptor gene in Morris hepatoma 7777.…”