UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this paper, the effects of HMBA on the differentiation of human hepatocarcinoma cell line SMMC-7721 were investigated. After treated with 5 mmol/L HMBA, the proliferation of SMMC-7721 cells was inhibited remarkably, the cell growth inhibitory rate amounted to 64.14%, the cell mitotic index was declined by 53.88%. Light microscopy and transmission electron microscopy showed that the morphology and ultrastructure of the cells treated with HMBA undergone restorational alteration. Cytochemistry and immunocytochemistry assay revealed that the activities of gamma-GT declined and the levels of AFP and PCNA downregulated while the activity of TAT increased significantly after HMBA treatment. In the meantime, flow cytometry analysis showed that HMBA could arrest the cells in G0/G1 phase. The results showed that HMBA could effectively inhibit the proliferation, reverse the malignant morphology and ultrastructure, alter the levels of enzymes and antigens, arrest the cells in G0/G1, and induce the differentiation of human hepatocarcinoma SMMC-7721 cells in vitro.
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PMID:[Differentiation of human hepatocarcinoma SMMC-7721 cells induced by HMBA]. 1254 4

The hepatic levels of three protein markers of oxidative stress, polymerase beta, Ref-1, and PCNA, and of the pro-apoptotic protein, Bax, were quantitated after exposure to WY 14,643 (500 ppm in the feed) for 6 or 34 days in a rodent that is susceptible peroxisome proliferator (PP)-induced liver tumors (the Sprague Dawley rat) and in a rodent that is relatively resistant PP-induced liver tumors (the Syrian hamster). The analysis of detergent-extracted whole liver homogenates by immunoblotting showed a marked increase in the abundance of a 45-kDa variant of polymerase beta immunoreactivity and significant increases in the expression of Ref-1 and PCNA in WY 14,643-exposed rats. In contrast. WY 14,643-exposed hamsters expressed only trace levels of the polymerase beta variant and showed significant decreases in the expression of Ref-1 and PCNA. Long-term WY 14,643 exposure was associated with marked decreases in Bax expression in both species. Dose-response studies in the rat showed that the hepatic expression of the polymerase beta and Ref-1 were significantly increased after 6 days of exposure to WY 14,643 at levels of 5 and 50 ppm, respectively. The analysis of subcellular fractions of rat liver showed that the pathological increases in the levels of polymerase beta, Ref-1, and PCNA were especially prominent in mitochondria-enriched particulate liver subfractions. These results indicate that WY 14,643 exposure is associated with an increase in oxidative stress to the liver and that liver mitochondria are a major target of WY 14,643-associated liver damage. Our data are consistent with the hypothesis that the chronic overexpression of mutagenic or oncogenic effectors like polymerase beta and Ref-1 in a setting of increased hepatocyte proliferation and decreased apoptosis may facilitate peroxisome proliferator-induced hepatocellular carcinoma in the rat.
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PMID:Hepatic expression of polymerase beta, Ref-1, PCNA, and Bax in WY 14,643-exposed rats and hamsters. 1256 96

Localization of P-glycoprotein (P-gp) and p53 was immunohistochemically examined in 41 patients with hepatocellular carcinoma (HCC) in order to determine the relationship between the expression of P-gp and p53 and the degree of histological differentiation or cell proliferation in HCC. P-gp showed different patterns of expression between cancerous and cirrhotic liver hepatocytes, and the expression in cancerous tissue also varied according to the degree of histological differentiation. In cirrhotic liver hepatocytes, expression of P-gp was found on bile canalicular membranes. In the case of cancerous tissue, P-gp was localized on the canalicular membranes in well-differentiated HCC showing a trabecular pattern, as recognized cirrhotic liver hepatocytes. In moderately differentiated HCC showing pseudo-glandular patterns, predominant expression of P-gp was found on the luminal side of cell membranes of the glandular ducts. The P-gp expression rate was 87.5% in well-differentiated HCC, 84% in moderately differentiated HCC, and 37.5% in poorly differentiated HCC, indicating a marked decrease with decreasing degree of differentiation. On the other hand, the rate of mutation of p53, a tumor suppressor gene, was 12.5% in well-differentiated HCC, 52.0% in moderately differentiated HCC, and 85.5% in poorly differentiated HCC, showing a significant increase with decreasing degree of differentiation (P<0.005). The labeling index (LI) of proliferating cell nuclear antigen (PCNA) tended to increase with the progression of chronic liver disease, with a markedly high value of 24.0+/-1.5% in cases of HCC. The PCNA LI was 15.6+/-11.9% in well-differentiated HCC, 23.1+/-15.1% in moderately differentiated HCC, and 50.1+/-13.3% in poorly differentiated HCC, which indicated a significantly increase in poorly differentiated HCC (P<0.001). Thus, it became apparent that abnormal expressions of P-gp and p53 and the cell proliferation in HCC vary according to the degree of histological differentiation of the malignancy. This suggests that more effective chemotherapy for HCC can be potentially developed by considering the pattern and level of expression of P-gp as a mechanism of drug resistance and the extent of histological differentiation.
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PMID:Immunohistochemical studies on the expression of P-glycoprotein and p53 in relation to histological differentiation and cell proliferation in hepatocellular carcinoma. 1264 52

Cyclooxygenase-2 (COX-2) has been suggested to be associated with carcinogenesis. Recently, many studies have shown increased expression of COX-2 in a variety of human malignancies, including hepatocellular carcinoma (HCC). Therefore, it becomes important to know more about what determines COX-2 expression. In this work, we have studied the effect of PPARdelta activation on COX-2 expression using a selective agonist (GW501516) in human hepatocellular carcinoma (HepG2) cells. Activation of PPARdelta resulted in increased COX-2 mRNA and protein expression. The mechanism behind the induction seems to be increased activity of the proximal promoter of the COX-2 gene, spanning nucleotides -327 to +59. The increased COX-2 protein expression and promoter activity induced by the GW501516 was also confirmed in the monocytic cell line THP-1. Induced levels of COX-2 have previously been associated with resistance to apoptosis and increased cell proliferation in many cell types. In HepG2 cells, we observed a dose-dependent increase in cell number by GW501516 treatment for 72h. The levels of PCNA, used as an indicator of cell division were induced, and the cell survival promoting complex p65 (NF-kappaB) was phosphorylated under GW501516 treatment. We conclude that PPARdelta activation in HepG2 cells results in induced COX-2 expression and increased cellular proliferation. These results may suggest that PPARdelta plays an important role in the development of HCC by modulating expression of COX-2.
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PMID:PPARdelta activation induces COX-2 gene expression and cell proliferation in human hepatocellular carcinoma cells. 1290 77

Inhibitors of differentiation and DNA binding-1 (Id-1) have been demonstrated to oppose Ets-mediated activation of p16INK4a. As p16INK4a protein is inactivated in hepatocellular carcinoma (HCC), we aimed to investigate the role of Id-1 in regulating p16INK4a expression during the development of HCC in HCC patients and direct ectopic Id-1 introduction into the PLC/PRF/5 HCC cell line. Sixty-two HCC samples were recruited for evaluation of Id-1 and proliferating cell nuclear antigen (PCNA) protein expression. The messenger RNA (mRNA) expression of Id-1 and p16INK4a was detected by quantitative reverse transcription-polymerase chain reaction. For in vitro Id-1 transfection, five Id-1 transfected clones were isolated and the effect of ectopic Id-1 introduction was investigated by 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, flow cytometry, immunostaining and western blot. Our results showed that Id-1 was over-expressed in HCC specimens both at mRNA and protein levels. Over-expression of Id-1 protein was correlated with PCNA (r = 0.334, P = 0.033). HCC samples showing low Id-1 protein expression had a lower Id-1 mRNA level (340.2 versus 1467%, P = 0.039) and higher p16INK4a expression (195 versus -78.6%, P = 0.039) than samples with high Id-1 protein expression. In the PLC/PRF/5 HCC cell line study, ectopic Id-1 expression resulted in proliferation of HCC cells and an increased percentage of S phase cells and PCNA expression. The results showed that over-expression of Id-1 induces cell proliferation in HCC through inactivation of p16INK4a/retinoblastoma pathway. In conclusion, the results provided an insight for the understanding of the role of Id-1 in functional inactivation of p16INK4a in HCC.
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PMID:Over-expression of Id-1 induces cell proliferation in hepatocellular carcinoma through inactivation of p16INK4a/RB pathway. 1294 53

Interferon (IFN)-alpha treatment is a common therapy for chronic viral hepatitis and contributes to preventing hepatocarcinogenesis. However, it is not clear whether IFN-alpha directly inhibits the clonal expansion of pre-neoplastic hepatocytes. To clarify the mechanism by which IFN-alpha prevents hepatocarcinogenesis, we examined the effect of IFN-alpha in a chemically induced hepatocarcinogenesis model initiated by diethylnitrosamine (DEN) and promoted by 2-acetylaminofluorene (2-AAF) and partial hepatectomy, in which hepatocellular carcinoma (HCC) arises through pre-neoplastic foci without inflammation or fibrosis. The protocols of IFN-alpha administration were started simultaneously with chemical initiation and lasted for either 4 or 40 weeks. The pre-neoplastic foci and neoplastic HCC were evaluated at 4 or 40 weeks after chemical initiation, respectively. The effects of IFN-alpha were assessed by the expression of tumor-related genes and cell cycle-related genes in the pre-neoplastic foci, using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). As a result of IFN-alpha treatment, the numbers and average volume of pre-neoplastic foci were reduced. The proliferating cell nuclear antigen index and the expression of G(1) cyclins were also reduced in the pre-neoplastic foci in the IFN-treated group. The expression of p21, which is an inhibitor of cyclin-kinase complexes was higher in the foci of the IFN-treated group, while p53 expression was not altered in this group, compared with the control group. IFN-alpha also suppressed the tumor development at 40 weeks after initiation. And in the long-term IFN-alpha-treated group, both the tumor numbers and average tumor size were markedly more reduced than those in the short-term-treated group. Therefore, it was demonstrated that longer treatment with IFN-alpha was more effective, compared with shorter treatment. In conclusion, it was shown that IFN-alpha directly prevented and delayed hepatocarcinogenesis through the suppression of pre-neoplastic cell proliferation and that it may partially depend on p21 induction through a p53-independent pathway.
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PMID:IFN-alpha prevents the growth of pre-neoplastic lesions and inhibits the development of hepatocellular carcinoma in the rat. 1463 63

Survivin is a recently described anti-apoptosis protein and regulator of cell division. Its expression and localization in hepatocellular carcinoma (HCC) and in normal liver tissue has not been fully elucidated. We examined the expression of survivin, Fas, proliferating cell nuclear antigen (PCNA), and apoptosis in 47 specimens of hepatocellular carcinoma (HCC) and surrounding nonmalignant hepatic tissues. To further determine the relationship between survivin expression and cell proliferation and apoptosis, we performed double immunostaining for survivin and PCNA TUNEL staining in the same HCC specimens. Positive immunostaining for survivin was present in 35 of 47 (74%) HCCs. Twenty-two of 35 survivin-positive HCCs (63%) showed punctate nuclear staining in HCC cells, and the remaining 13 showed predominant cytoplasmic staining. In contrast, nonmalignant hepatocytes showed only cytoplasmic staining. HCC cells had significantly higher PCNA-labeling and apoptotic indices compared with the case of nonmalignant hepatic tissue (P<0.001). Furthermore, nucleus-positive HCC specimens for survivin showed the highest PCNA labeling index. The nuclear localization of survivin in HCC cells correlated with tumor cell de-differentiation with the exception of the HepG2 cell line. Survivin expression was inversely associated with apoptosis and was strongly associated with Fas expression (P=0.01). All 4 HCC cell lines examined showed survivin expression and punctate nuclear localization. Our results indicate that survivin is localized to the cytoplasm in quiescent nonmalignant liver cells to suppress apoptosis and translocates into the nucleus in HCC cells. In conclusion, translocation of survivin from the cytoplasm to the nucleus may constitute an important regulatory mechanism for cell proliferation and differentiation in HCC.
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PMID:Nuclear translocation of survivin in hepatocellular carcinoma: a key to cancer cell growth? 1465 13

Reactive oxygen species may be involved in the progression of chronic liver disease and the occurrence of hepatocellular carcinoma (HCC). To clarify whether clinicopathological findings in liver diseases are related to oxidative DNA damage, hepatic expression of the 8-hydroxy-2'-deoxyguanosine (8-OHdG) was examined in 75 liver disease patients, which included 32 chronic hepatitis (CH), 13 liver cirrhosis (LC) and 30 HCC patients. The CH patients had higher 8-OHdG-positive hepatocytes than LC (P < 0.05). In CH and LC, the number of 8-OHdG-positive hepatocytes was correlated with alanine aminotransferase and asparate aminotransferase (P < 0.01 and P < 0.05, respectively). Of 30 HCC cases, 25 cases (83%) showed stronger immunoreactivity than non-cancerous counterparts. The patients with poorly differentiated HCC had a larger tumor size and higher levels of AFP, and exhibited higher labeling indices of PCNA-, TUNEL- and 8-OHdG-positive cells than those with well and moderately differentiated HCC. Our findings suggest that oxidative DNA damage is increased in association with necroinflammation in chronic liver disease and determination of 8-OHdG is useful in assessing high-grade malignancy in HCC.
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PMID:Expression of 8-hydroxy-2'-deoxyguanosine in chronic liver disease and hepatocellular carcinoma. 1470 94

A complementary way for the assessment of HCC prognosis is represented by the analysis of molecular markers. Thus, immunohistochemical assessment of proliferation can describe tumor aggressiveness, probability of local recurrence or metastasis potential, being very useful for the assessment of recurrence-free survival and survival until death. The aim of our study was to assess proliferating cell nuclear antigen activity in HCC and dysplastic nodules as compared with surrounding non-neoplasic areas. Immunohistochemical techniques were thus performed on the samples obtained by ultrasound-guided liver biopsies or intraoperative biopsies, in 32 patients with HCC, as well as in 3 patients with dysplastic nodules occurring in liver cirrhosis. Expression of PCNA within extranodular areas of the HCC patients in the absence or presence of cirrhosis, was increasing from 40% to 70%, respectively. PCNA expression further increased within intranodular areas of dysplastic nodules and HCC, to 100% and 96.88%, respectively. A progressive increase of the mean values of PCNA-LI was also observed from extranodular areas without or with cirrhosis, towards intranodular areas of dysplastic nodules and HCC (4.2%, 6.8%, 27.9%, 31.9%, respectively). Dysplastic nodules can thus be considered lesions with a high-proliferation rate, representing an early stage of hepatocarcinogenesis. This supported the current recommendations for borderline hepatocellular nodules identified by ultrasound, which indicate an aggressive treatment similar to malignant lesions. In summary, we demonstrated a progressively increasing rate of cellular proliferation, from extranodular non-neoplasic areas to intranodular areas (dysplastic nodules and HCC), as reflected by an increased expression of proliferating cell nuclear antigen labelling index.
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PMID:Immunohistochemical assessment of proliferating cell nuclear antigen in primary hepatocellular carcinoma and dysplastic nodules. 1475 12

Methionine adenosyltransferase (MAT) is an essential enzyme because it catalyzes the formation of S-adenosylmethionine (SAMe), the principal biological methyl donor. Of the two genes that encode MAT, MAT1A is mainly expressed in adult liver and MAT2A is expressed in all extrahepatic tissues. Mice lacking MAT1A have reduced hepatic SAMe content and spontaneously develop hepatocellular carcinoma. The current study examined the influence of chronic hepatic SAMe deficiency on liver regeneration. Despite having higher baseline hepatic staining for proliferating cell nuclear antigen, MAT1A knockout mice had impaired liver regeneration after partial hepatectomy (PH) as determined by bromodeoxyuridine incorporation. This can be explained by an inability to up-regulate cyclin D1 after PH in the knockout mice. Upstream signaling pathways involved in cyclin D1 activation include nuclear factor kappaB (NFkappaB), the c-Jun-N-terminal kinase (JNK), extracellular signal-regulated kinases (ERKs), and signal transducer and activator of transcription-3 (STAT-3). At baseline, JNK and ERK are more activated in the knockouts whereas NFkappaB and STAT-3 are similar to wild-type mice. Following PH, early activation of these pathways occurred, but although they remained increased in wild-type mice, c-jun and ERK phosphorylation fell progressively in the knockouts. Hepatic SAMe levels fell progressively following PH in wild-type mice but remained unchanged in the knockouts. In culture, MAT1A knockout hepatocytes have higher baseline DNA synthesis but failed to respond to the mitogenic effect of hepatocyte growth factor. Taken together, our findings define a critical role for SAMe in ERK signaling and cyclin D1 regulation during regeneration and suggest chronic hepatic SAMe depletion results in loss of responsiveness to mitogenic signals.
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PMID:Impaired liver regeneration in mice lacking methionine adenosyltransferase 1A. 1503 34

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