The expression of EGF receptors, EGF-like factors and c-myc in ovarian and cervical carcinomas and their potential clinical significance.
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The expression of the epidermal growth factor receptor (EGF-R) and the c-myc oncogene was investigated in different specimens of ovarian and cervical carcinomas. The EGF-Rs were analyzed by EGF binding assay, immunohistochemistry and Northern blotting. For analysis of c-myc expression, we used Northern blotting and immunohistochemistry. Furthermore, tissue concentrations of EGF-like factors (EGF-F) were measured in the same tumor and non-malignant specimens. The biochemical determination of EGF-R demonstrated that EGF specific binding sites were detected in 36% of ovarian (n = 140) and 81% of cervical carcinomas (n = 42). High amounts of EGF-R (greater than 10 fmol/mg specific binding) were found in 8% of the ovarian and 41% of the cervical carcinomas. Increased expression of EGF-R specific mRNA was detectable in 7/21 ovarian and in 5/7 cervical carcinomas. A positive correlation between the amounts of EGF-R mRNA, the EGF-R binding data and the staining index of EGF-R immunohistochemistry was found. The EGF-R immunohistochemistry demonstrates that only the tumor cells produce increased amounts of EGF-R, while the stromal cells are EGF-R negative. Low amounts of EGF-R specific mRNA were also detected in biochemically EGF-R negative tumors. The c-myc specific mRNA signal was found in all cases investigated. It is shown that the c-myc expression was increased in 10/21 ovarian and 5/7 cervical carcinomas. There was no positive correlation between the amounts of EGF-R and c-myc mRNAs. The product of myc, as detected by immunohistochemistry, is found in tumor as well as in stromal cells. The levels of EGF-F were measured in extracts of 63 ovarian and 12 cervical carcinomas and in 21 non-malignant tissues. About 30% of the tumor extracts contained higher EGF-F levels (4-15 ng/mg) than those found in the non-malignant specimens. Tumors with high EGF-F levels expressed high amounts of c-myc RNA. The EGF-R status (n = 111) and the EGF-F levels (n = 63) were related to the prognosis of survival for patients with ovarian carcinomas. EGF-R positive (EGF-R(+)) ovarian carcinomas had a significantly higher response rate to chemotherapy. The survival time of the EGF-R(+) group is reduced compared to the EGF-R negative (EGF-R(-)) group if only patients in remission are used to construct survival curves. Furthermore, a poor prognosis for survival was noticed for ovarian carcinoma patients with high EGF-F levels.Cite
To investigate the mechanism of silicosis by observing the effects of silica on the expression of plasminogen activator inhibitor-1 (PAI-1) and activator protein-1 (AP-1) in human alveolar epithelial cells type II (A549).A549 cell and SiO(2) (200 microg /ml) were co-cultured for 0, 4, 8, 16 and 24 h respectively. The reverse transcriptase polymerase chain reaction (RT-PCR), Western blotting and SP immunocytochemistry were used for detections of the PAI-1 mRNA and protein expression. The nucleoprotein and total protein expression of AP-1 were investigated by Western blotting.The expression levels of PAI-1 mRNA and protein were increased in a time-dependent manner(r(mRNA) = 0.911, r(protein) = 0.902, P < 0.05). The expressions of PAI-1 mRNA and protein in experimental groups were higher than that in control group (P < 0.05) and was the highest in 24 h group [(0.73 +/- 0.01) vs (0.36 +/- .03)]. The nucleoprotein expressions of c-jun/c-fos in experimental groups were also higher than in control group (P < 0.05), and the nucleoprotein expression level of c-jun was the highest in 4 h group [(1.54 +/- 0.02) vs (0.56 +/- 0.03)]; the nucleoprotein expression level of c-fos was the highest in 8 h group [(0.36 +/- 0.01) vs (0.15 +/- 0.01)]. Both c-jun and c-fos expression were decreased after 16 h, but the total protein expression of c-jun/c-fos had no difference in all experimental groups. The positive signal of PAI-1 was located in cytoplasm and nucleus.SiO(2) could induce PAI-1 expression of A549 in a time-dependent manner, and AP-1 activation can be observed in early time.
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In Cebus apella monkey, as with other mammalian species tested to date, two different forms of haem oxygenase, HO-1 and HO-2, are detected. With the use of cDNA fragment corresponding to HO-1 nucleotides +71 to +833, blot hybridization of RNA revealed the presence of only one HO-1 mRNA of approx. 1.8 kb in both rat and monkey liver, kidney and brain. With the use of a full-length HO-2 DNA probe, blot hybridization of RNA isolated from the same rat organs revealed the presence of two HO-2 homologous transcripts of approx. 1.3 kb and approx. 1.9 kb. The same probe detected only one message of approx. 1.7 kb in monkey organs. The rat 1.3 kb mRNA has been previously shown [Rotenberg & Maines (1990) J. Biol. Chem. 265, 7501-7506] to encode HO-2 (36 kDa). The monkey 1.7 kb mRNA and the rat 1.3 kb mRNA encode proteins with similar molecular masses and immunochemical properties as indicated by Western-immunoblotting analysis. In rat organs the relative abundance of the two mRNAs differed as follows: in the liver the 1.3 kb mRNA was by far the most abundant form; in the brain equal amounts of the two mRNAs were detected, whereas in the kidney the 1.3 kb mRNA was somewhat more abundant. The protein encoded by the 1.8 kb HO-1 mRNA in the monkey did not exhibit immunochemical reactivity with antibody to rat HO-1 in Western blotting and direct e.l.i.s.a. analysis. The data suggest that, at the primary structural level, both HO-1 and HO-2 share extensive base sequence similarity in the rat and the Cebus apella monkey. The HO-1 protein, however, appears to undergo differential post-translational and/or conformational modifications in the two species, whereas the secondary structure of HO-2 protein and antigenic epitopes are conserved among the two mammalian species.
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We have investigated whether the expression of Epidermal Growth Factor Receptors (EGF-Rc) evaluated by immunohistochemical technique, may influence the prognosis of patients with prostate cancer. EGF-Rc were positive in 20/76 (26.3%) of tumors. There was no correlation between EGF-Rc and other prognostic factors such as tumor size, Gleason score, metastases at diagnosis, DNA content and S-Phase fraction (SPF). In patients with locally advanced tumors EGF-Rc expression was significantly correlated with the presence of metastases at diagnosis (p=0.038). Both disease-free survival (DFS) and overall survival (OS) did not differ between patients with receptor-positive and receptor-negative tumors. It is concluded that the immunohistochemical localization of EGF-Rc is of limited prognostic value in prostate cancer.
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An immunohistochemical examination by the avidin-biotin-peroxidase complex method was carried out to assess the expression of oncogene-related products, i.e., ras p 21 protein, fes p 85 protein and epidermal-growth-factor (EGF) receptors, in human gastrointestinal malignancies. The presence of ras p 21, fes p 85 and EGF receptors was detected in 48%, 62%, and 62% of 29 colorectal carcinomas and in 65%, 65% and 40% of 20 gastric cancers, respectively. More than one oncogene protein was demonstrated in 18 of 29 colorectal carcinomas and in 10 of 20 gastric cancers. These results suggest that multiple oncogenes are important in the occurrence and progress of gastrointestinal malignancies.
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The specific binding of [125I]epidermal growth factor ([126I]EGF) to hepatic microsomal membranes was about 2-fold higher in adult male than in adult female rats. Scatchard analysis of the binding data showed that the sex difference in EGF binding was due to the difference in EGF receptor concentration rather than to a change in receptor affinity. From the developmental study, an apparent sex difference in EGF binding was observed from the pubertal period (4 weeks of age). Castration of adult male rats slightly, but significantly, decreased the EGF receptor level; and moreover, treatment of adult females with testosterone increased it only slightly. On the other hand, castration of neonatal male rats decreased the EGF receptor content almost to the female level. The decreased level of the receptor was completely restored by the combination of neonatal and pubertal treatments with testosterone. Neonatal or pubertal treatment alone of castrated animals had no significant effect on the decreased level of EGF receptors. These effects of testosterone were similarly observed when normal female rats were treated with the steroid. Moreover, hypophysectomy of the rats resulted in the marked decrease in EGF receptors only in the male animals. Treatment of hypophysectomized rats with either testosterone or T3 had no apparent effect on the EGF receptors. The membrane protein, cross-linked with [125I]EGF, had a mol wt of 170,000, and this protein (EGF receptor) was phosphorylated basally or by the addition of EGF. The rate of affinity labeling, or phosphorylation of EGF receptors, was in good agreement with the results of the EGF binding study. These results strongly suggest that the EGF receptor level in rat liver plasma membranes is in part regulated by the hypothalamopituitary unit and that neonatal androgens are essential for this regulation, probably through their effects on the hypothalamus. (Endocrinology122: 1707–1714, 1988)
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Objective To study the localizations and the quantity of GnRH receptor in stomach of Sprague-Dawley (SD) rats under stress.Methods The model of stress SD rats was established by fear. Then, stomachs were taken from the rats in acute stress group (2h-12h), chronic stress group (1d-4w) and the control group respectively.The localizations and the quantity of GnRH receptor in stomachs were detected using immunohistochemistry and Western blotting.Results The results of immunohistochemistry showed that immunoreactivity of GnRH receptor was displayed in the gastric parietal cells and the epithelial cells of the gastric pits in stomachs of rats in all groups. The immunoreactive materials were distributed in membrane and cytoplasm of all positive cells, but not in nuclei. Meanwhile, the results of Western blotting showed that the number of GnRH receptor decreased significantly when SD rats were in stress from 2h to 2w (P0.01). The number of GnRH receptor decreased significantly when stressed from 3w to 4w (P0.01).Conclusion The expression of GnRH receptor changed with the time under stress, suggesting that GnRH receptor might regulate digestive function under stress.
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Epidermal growth factor receptors were measured in biopsies from patients with newly diagnosed bladder cancer. Two methods to detect these receptors were compared: immunohistochemical staining of frozen sections, and a ligand binding study using radiolabeled epidermal growth factor and tumor cell membranes. We studied 101 patients by immunohistochemistry and 47 patients by both methods. An association was found between immunohistochemical positivity for epidermal growth factor receptors and high tumor stage (p less than 0.001). Thus, most of the muscle invasive tumors were positive (35 of 49, 71 per cent) and more stage pT1 tumors were positive (8 of 18, 44 per cent) than were stage pTa tumors (5 of 34, 15 per cent, p less than 0.05). The ligand binding study was slightly more sensitive in detecting receptors than immunohistochemistry (30 of 47, 64 per cent and 25 of 47, 53 per cent, respectively). Greater amounts of receptors were found in muscle invasive tumors compared to tumors not invading muscle (p less than 0.05). A significant association was found between the 2 methods in the detection of receptors (p less than 0.001) and no discrepancies were found between the 2 methods in tumors containing high levels of receptors. Immunohistochemistry provides a satisfactory method to detect receptors in tumors with high levels of receptors, although ligand binding is more sensitive in tumors with low levels of receptors.
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Objective To investigate the expression of DAPK,an apoptosis-related serine/threonine kinase gene,in tissue of primary gastric cancer(GC) at mRNA and protein levels and to evaluate the clinical implication.Methods DAPK mRNA expression was determined using RT-PCR,and the protein expression was measured using immunohistochemical staining in 62 GC tissues and adjacent normal tissues.The expression of DAPK protein level was further determined using Western-blotting.Results DAPK mRNA and protein expressions by Western blotting in GC were reduced significantly than those in corresponding normal tissues.Immunohistochemical staining revealed that expression of DAPK was significantly lower in GC than that in matched normal tissues.Furthermore,there was a significant correlation between DAPK mRNA and protein expressions,stage classification and lymph node metastasis of GC.Conclusion Expression of DAPK was significantly reduced in tissue of GC at mRNA and protein levels,and the expression was related to the stage classification and lymph node metastasis of GC.
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The association of Jumonji domain-containing 6 (JMJD6) with the prognosis of various types of cancer has been demonstrated, except in intrahepatic cholangiocarcinoma (ICC). The present study aimed to clarify the impact of JMJD6 on ICC. The liver specimens of 51 patients who underwent surgery for ICC were analyzed for JMJD6 expression using immunohistochemistry staining. The relationship between clinicopathological factors and JMJD6 expression was investigated. The cellular activity was also evaluated in JMJD6 knocked down cells with Transwell migration assay and viability assay. In the immunohistochemistry staining of clinical samples, high expression of JMJD6 was seen in 32 of 51 samples. High expression was also associated with improved overall survival (OS) and recurrence-free survival (RFS) (P=0.0033 and 0.048, respectively). Further analyses revealed that higher JMJD6 expression was one of the improved independent prognostic factors of OS and RFS. Expression of JMJD6 was knocked down in commercial culture cell lines of ICC, and RNA and protein were extracted to analyze the downstream gene expression using RNA-sequencing and western blotting. JMJD6 knockdown was associated with higher programmed death-ligand 1 (PD-L1) expression in RNA-sequencing and western blotting. In addition, PD-L1 expression was higher in JMJD6 low expression clinical samples when measured using immunohistochemistry staining. In conclusion, high expression of JMJD6 was an independent favorable prognostic factor of ICC. JMJD6 may influence the prognosis of ICC through the regulation of PD-L1 expression.
Intrahepatic Cholangiocarcinoma
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