Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CIP1/WAF1, a critical downstream effector of tumor suppressor p53, encodes a cyclin-dependent kinase inhibitor. By Northern blot analysis, the CIP1/WAF1 mRNA level in the tumor was significantly lower than that in the corresponding normal liver from 19 Japanese patients with hepatocellular carcinoma (P < 0.05). In the tumor from only one out of 19 patients (5%), somatic mutations of the CIP1/WAF1 as well as that of p53 gene were identified by RT-PCR/SSCP analysis. These results suggest that the decreased CIP1/WAF1 expression is involved in the carcinogenesis or the progression of hepatocellular carcinoma.
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PMID:Decreased expression and rare somatic mutation of the CIP1/WAF1 gene in human hepatocellular carcinoma. 902 46

Laminin-overlay to the culture of a human hepatocellular carcinoma cell line, HuH-7, resulted in changes in the cell behavior; suppression of the cell growth, conversion of the cell morphology, and the elevated secretion of cellular AFP in the culture medium, implying that the cells had undergone apparent differentiation in vitro. Together with the behavioral changes, the cells showed positive immunohistochemical staining of the anti-p 21/WAF 1 antibody over the cell nucleus and the amount of p 21/WAF-1 proteins was increased in the cells. p53 protein was detected both in the control cells and the cells with the laminin overlay. These findings indicate that the laminin-dependent changes in the cell behavior are closely associated with the activation of the cyclin-dependent kinase inhibitor, p 21/WAF-1, and that? is uncoupled with the p 53 expression.
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PMID:[Laminin-dependent growth arrest of human hepatic carcinoma cell line, HuH-7, in association with expression of p21/WAF-1 protein]. 912 52

Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), which belongs to the EGF family, is produced as a membrane-anchored form (pro-HB-EGF) and later processed to a soluble form (sHB-EGF). It is known that high expression of pro-HB-EGF occurs in hepatoma tissues, although its biological meaning remains unknown. We established two types of hepatoma cell lines (AH66tc), which stably produce pro-HB-EGF and sHB-EGF, respectively. While sHB-EGF-producing cells (sHB-AH) showed rapid growth, pro-HB-EGF-producing cells (pHB-AH) showed markedly suppressed cell growth as compared with the parental cells. Transforming growth factor beta or serum-starved conditions induced apoptosis of mock and sHB-AH as well as the parental cells, but not of pHB-AH. The resistance to apoptosis upon serum-starved treatment was correlated with an increase in the rate of the G1 phase in the cell cycle due to up-regulation of the cyclin-dependent kinase inhibitor p21. The mechanism underlying this resistance of pHB-AH to apoptosis was thought to be related to the prolonged half-life of the EGF receptor followed by continuous phosphorylation of the tyrosine residues. These observations demonstrate a unique function of pro-HB-EGF that is not observed for the mature form and show that pro-HB-EGF may act as a tumor survival factor in hepatoma cells.
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PMID:Membrane-anchored heparin-binding epidermal growth factor-like growth factor acts as a tumor survival factor in a hepatoma cell line. 916 71

The molecular mechanisms of hepatocarcinogenesis are poorly understood. Only very recently has there been a suggestion of familial hepatocellular carcinoma (HCC). We have analyzed the status of the p16INK4(MTS1) gene, a cyclin-dependent kinase inhibitor, in 26 patients with HCC of different etiologies. Four patients carried hemizygous germ-line point mutations of the p16INK4(MTS1) gene, suggesting the existence of familial HCC involving this gene. The wild-type allele was lost in the tumor in 2 of these 4 patients. Three of the patients carrying a germ-line mutation had non-cirrhosis-associated HCC. No somatic mutations of p16INK4(MTS1) were observed in the 26 cases of HCC. The most common somatic alteration of the p16INK4(MTS1) gene in HCC was de novo methylation, which was detected in 48% of the cases. Low levels (21%) of p16INK4(MTS1) gene allele loss were observed. Altogether, these results indicate that alteration of the p16INK4(MTS1) gene plays an important role in the genesis of HCC.
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PMID:Germ-line mutations of the p16INK4(MTS1) gene occur in a subset of patients with hepatocellular carcinoma. 918 56

The cyclin-dependent kinase inhibitor p21/WAF1 is regulated by p5S3-dependent and p53-independent pathways. In addition, p21/WAF1 binds with proliferating cell nuclear antigen (PCNA) and inhibits the action of PCNA. To investigate the possible role of p21/WAF1 in human hepatocellular carcinomas (HCCs), we examined the expression of p21/WAF1 and its relation with PCNA and p53 expression in 97 surgically resected HCCs by immunohistochemistry and with the mutation status of p53 in 26 HCCs. p53 mutation status was examined by direct DNA sequencing using 3 sets of primers covering exons 5-9. Six of the 26 tumors showed p53 point mutations and only 33% of these HCCs demonstrated p21/WAF1 expression. In contrast, 75% of HCCs without p53 mutations showed p21/WAF1 expression. Of all 97 HCCs, p21/WAF1 expression was significantly higher in the tumors than in corresponding non-tumorous liver. When the tumors were stratified into 2 groups by the median tumor p21/WAF1 score, those with higher expression were found to have a lower incidence of multiple tumor nodules (p = 0.008) and tumor microsatellite formation (p = 0.050). The tumor p21/WAF1 score was positively associated with tumor PCNA expression (p = 0.036) but not with tumor p53 expression. Thus, in HCC, expression of p21/WAF1 is in part dependent on p53 status, but a p53-independent pathway also plays a significant role in the regulation of p21/WAF1 expression. High p21/WAF1 expression is significantly associated with solitary tumor nodules and, to a lesser extent, tumor microsatellites but may not be enough to suppress tumor progression.
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PMID:p21/WAF1, p53 and PCNA expression and p53 mutation status in hepatocellular carcinoma. 969 37

p21, a potent cyclin-dependent kinase inhibitor, has been known to induce cell cycle arrest in response to DNA-damaging agents. Although p21 has been reported to play an important role in the regulation of apoptosis, the postulated role for p21 in apoptosis is still controversial. Previously, we reported that p21 was induced in a p53-independent manner during ceramide-induced apoptosis in human hepatocarcinoma cell lines. In the present study, we investigated the precise role of p21 in ceramide-induced apoptosis in human hepatocarcinoma cells by using a tetracycline-inducible expression system. Overexpression of p21 by itself did not induce apoptosis in p53-deficient Hep3B cells. However, Hep3B/p21 cells were more sensitive to ceramide-induced apoptosis. In these cells, p21 overexpression did not result in G1 arrest. The expression level of Bax was increased in Hep3B/p21 cells treated with ceramide and its expression was more accelerated under the p21-overexpressed condition compared to that of the p21-repressed condition. Overexpression of Bax induced apoptosis in Hep3B cells. On the other hand, the levels of p21 and Bax protein were increased by ceramide in another hepatocarcinoma cell line, SK-Hep-1, while the Bcl-2 protein level was not changed. Overexpression of Bcl-2 not only suppressed apoptosis but also completely prevented induction of p21 and Bax caused by ceramide in SK-Hep-1 cells. Furthermore, overexpression of p21 antagonized the death-protective function of Bcl-2 and upregulated expression of Bax protein. These results suggest that p21 promotes ceramide-induced apoptosis by enhancing the expression of Bax, thereby modulating the molecular ratio of Bcl-2:Bax in human hepatocarcinoma cells.
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PMID:p21 promotes ceramide-induced apoptosis and antagonizes the antideath effect of Bcl-2 in human hepatocarcinoma cells. 1058 63

Progression through the cell cycle is controlled by the induction of cyclins and activation of cognate cyclin-dependent kinases. The human hepatitis B virus-X (HBV-X) protein functions in gene expression alterations, in the sensitization of cells to apoptotic killing and deregulates cell growth arrest in certain cancer cell types. We have pursued the mechanism of growth arrest in Hep3B cells, a p53-mutant human hepatocellular carcinoma (HCC) cell line. In stable or transient HBV-X transformed Hep3B cells, HBV-X increased protein and mRNA levels of the cyclin-dependent kinase inhibitor (CDKI) p21(waf1/cip1) increased binding of p21(waf1/cip1) with cyclin-dependent kinase 2 (CDK2), markedly inhibited cyclin E and CDK2 associated phosphorylation of histone H1 and induced the activation of a p21 promoter reporter construct. By using p21 promoter deletion constructs, the HBV-X responsive element was mapped to a region between -1185 and -1482, relative to the transcription start site. Promoter mutation analysis indicated that the HBV-X responsive site coincides with the ets factor binding sites. These data indicate that in human hepatocellular carcinoma cells, HBV-X can circumvent the loss of p53 functions and induces critical downstream regulatory events leading to transcriptional activation of p21(waf1/cip1). As a consequence, there is an increased chance of acquisition of mutations which can enhance the genesis of hepatomas. Our results also emphasize the chemotherapeutic potential of p21(waf1/cip1) inhibitors, particularly in the HBV-X infected hepatoma which lacks functional p53.
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PMID:Hepatitis B virus-X protein upregulates the expression of p21waf1/cip1 and prolongs G1-->S transition via a p53-independent pathway in human hepatoma cells. 1091 95

In primary hepatocytes and HepG2 hepatoma cells, prolonged activation of the p42/44 mitogen-activated protein kinase (MAPK) pathway is associated with a reduction in DNA synthesis, mediated by increased expression of the cyclin-dependent kinase inhibitor protein p21 (Cip-1/WAF1/mda6) (p21). This study was performed to evaluate the contribution of transcriptional and post-transcriptional regulation in this response. Prolonged activation of the MAPK pathway in wild-type or p21 null hepatocytes caused a large decrease and increase, respectively, in DNA synthesis. Prolonged activation of the MAPK pathway in either wild-type or p21 antisense HepG2 cells also caused large decreases and increases, respectively, in DNA synthesis. MAPK signaling increased the phosphorylation of the transcription factors Ets2, C/EBPalpha, and C/EBPbeta, and rapidly increased transcription from the p21 promoter via multiple Ets- and C/EBP-elements within the enhancer region. Eight hours after MAPK activation, loss of C/EBPbeta or Ets2 function significantly reduced MAPK-stimulated transcription from the p21 promoter and abolished increased p21 protein expression. At this time, MAPK signaling increased both p21 mRNA and p21 protein stabilities that were also demonstrated to be essential for a profound increase in p21 protein levels. Thirty-six hours after MAPK activation, transcription from the p21 promoter was still significantly reduced in cells without either C/EBPbeta or Ets2 function; however, these cells were now capable of exhibiting a partial increase in p21 protein expression. In contrast, loss of C/EBPalpha function modestly reduced MAPK-stimulated transcription from the p21 promoter but strongly inhibited the ability of prolonged MAPK activation to increase protein levels of p21. This data suggested that prolonged enhancement of p21 protein levels may be under posttranscriptional control. In agreement with this hypothesis, prolonged MAPK signaling further increased p21 mRNA stability at 36 h, compared with the 8-h time point. Our data argue that MAPK signaling increased p21 promoter activity via multiple transcription factors, which alone were insufficient for a robust prolonged increase in p21 protein levels in primary hepatocytes, and that to increase p21 protein levels also required enhanced stabilization of p21 mRNA and p21 protein. Collectively, these data suggest that loss of transcription factor and mRNA/protein stabilization functions correlates with an inability of MAPK signaling to cause growth arrest versus proliferation in primary hepatocytes.
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PMID:A role for both Ets and C/EBP transcription factors and mRNA stabilization in the MAPK-dependent increase in p21 (Cip-1/WAF1/mda6) protein levels in primary hepatocytes. 1098 90

The p27 cyclin-dependent kinase inhibitor is a negative regulator of cell-cycle progression. In many human epithelial malignancies, decreased expression of p27 correlates with high grade, early recurrence, and poor prognosis. To evaluate the prognostic significance of p27 in hepatocellular carcinoma (HCC), we studied 54 HCCs along with corresponding nontumoral tissue. Immunohistochemistry (IHC) and Western blot (WB) analysis before and after immunoprecipitation with Cdk2 were performed on paraffin-embedded tissues and protein homogenates, respectively, to compare localization and expression of the p27 protein and to determine the total and active (Cdk2-bound) fractions of p27. Correlations were analyzed between IHC-assessed levels of p27, survival, and major clinical and pathological variables. IHC revealed no p27 expression in the majority of hepatocytes from normal and cirrhotic liver, whereas 14 HCCs (26%) were high p27 expressers (>50% positive cells), 26 (48%) low expressers (<50% positive cells), and 14 (26%) negative. High IHC signals of p27 correlated with Cdk2-bound p27 as assessed by immunoprecipitation-WB; by contrast, WB alone displayed similar levels of p27 protein in all normal and tumoral samples. High IHC p27 expression correlated with prolonged survival (P = 0.027), whereas the presence of cirrhosis was associated with poor outcome (P = 0.029). We conclude that with respect to their nonneoplastic counterparts, a subset of HCCs acquire significant p27 expression and that high expression of p27 is a favorable independent prognostic parameter for HCC.
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PMID:Acquired expression of p27 is a favorable prognostic indicator in patients with hepatocellular carcinoma. 1105 Dec 45

IFN regulatory factor-1 (IRF-1) regulates the IFN system, inhibits cell growth, and has tumor-suppressor activities. p21 is a universal cyclin-dependent kinase inhibitor, the induction of which depends on both p53 and IRF-1 in mouse embryonic fibroblasts. The expression of p21 in hepatocellular carcinomas (HCCs) is regulated by wild-type p53. We examined the expressions of IRF-1 and p21 in 32 HCCs by quantitative reverse transcription-PCR and the mutation p53 gene in 32 HCCs by single-strand conformation polymorphism and direct sequencing. The expression of IRF-1 mRNA in 15 of 32 HCCs was lower than that in adjacent noncancerous tissue. IRF-1 mRNA expression was reduced in 0 of 3 specimens of well-differentiated HCC, 9 of 21 (42%) specimens of moderately differentiated HCC, and 6 of 8 (75%) specimens of poorly differentiated HCC. IRF-1 mRNA expression was significantly lower in tumors with portal thrombus than in those without portal thrombus (P = 0.003). p53 mutations were detected in 7 of 32 HCCS: p21 expression was reduced in 6 of the 7 (86%) HCCs with p53 mutations. In contrast, p21 expression was reduced in 13 of 25 (52%) HCCs with wild-type p53. IRF-1 expression was reduced in 7 of 13 (53%) HCCs with both wild-type p53 and reduced expression of p21. These results suggest that IRF-1 may be a tumor-suppressor gene for HCC and that IRF-1 is related to p21 expression in HCC with wild-type p53.
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PMID:Tumor-suppressor effect of interferon regulatory factor-1 in human hepatocellular carcinoma. 1135 Aug 97


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