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

Chemoresistance is a major problem in the treatment of hepatocellular carcinoma. Certain p53 mutants may enhance drug resistance in cancer cells. To determine whether two frequently occurring p53 mutants, R248Q and R273C, would increase the drug resistance of liver cancer cells, stable cell lines expressing these specific p53 mutants were established by transfecting the p53-null Hep3B cells with mutant p53 expression vectors, and then treating them with the anticancer drugs doxorubicin and paclitaxel. The cells expressing the p53 mutant, R248Q, but not R273C, displayed cross-resistance to both drugs, in contrast to the control cells expressing the vector alone. Moreover, both the expression and the activity of the multiple drug resistance gene product, P-glycoprotein, were elevated in p53 mutant R248Q-expressing cells. Reduced uptake of doxorubicin was also observed in the R248Q-expressing cells. These results suggest that expression of the p53 mutant, R248Q, in liver cancer cells may enhance their drug resistance and that upregulation of P-glycoprotein activity may contribute to this protective effect.
 ...
PMID:Mutant p53 expression enhances drug resistance in a hepatocellular carcinoma cell line. 1500 24

We studied the transcriptional activity of p53 protein in 50 tissues of hepatocellular carcinoma (HCC) using a yeast functional assay. In this assay, red yeast colonies indicate that p53 protein cannot bind to its specific domain and has lost its transcriptional activity. We also clarified whether mutant p53 protein could inactivate wild-type p53 protein in a transdominant manner using a modified yeast assay. In addition, we examined whether immunohistochemically detectable p53 protein was functionally inactive. The incidence of p53 inactivation was significantly higher in tumors with capsular invasion. Out of 21 tumors diagnosed with p53 mutations, 11 exhibited >75% red colonies, and all contained missense mutations. In these tumors, p53 function was lost because there was supposedly no intact p53 gene on either allele. One missense mutant produced <60% red colonies, but it was also considered inactive as a p53 protein heterotetramer because of its transdominant activity. In 7 of the remaining 9 tumors, p53 was considered to be mutated on one allele and intact on the other. All of these 7 tumors contained nonsense or frameshift mutations and had no transdominant activity, which suggested that p53 function remained intact. Alternately, immunohistochemical analysis demonstrated that all of the tumors with missense mutations were positively immunostained, whereas those that contained nonsense or frameshift mutations were negatively stained. Consequently, positively immunostaining tumors mostly coincided with p53-inactive tumors. These yeast-based assays suggested that p53 function was retained in some mutant cases. Immunohistochemistry was helpful in screening functionally inactive p53 protein in HCCs.
 ...
PMID:Loss of p53 transcriptional activity in hepatocellular carcinoma evaluated by yeast-based functional assay: comparison with p53 immunohistochemistry. 1501 92

The morbidity and mortality experienced by cancer patients is mainly due to the invasion and metastasis of the primary tumor. Recently, a potential metastasis-associated gene and its product, the metastatic tumor antigen 1 (MTA1), were identified; this gene has been found to be overexpressed in a variety of cancers. MTA1 is also known as a potent co-repressor of estrogen receptor element transcription in breast cancer cells. The expression of MTA1 in hepatocellular carcinoma (HCC) and its potential relationship to metastasis and to estrogen receptor alpha (ER-alpha) expression has not been examined, forming the basis for this study. Paraffin sections of 45 HCC specimens, 4 different HCC cell lines, and normal hepatocyte cell line (h NHeps) were immunostained with MTA1 and ER-alpha antibodies. In addition, we examined, by Western blotting, the MTA1 and ER-alpha expression levels in 4 human HCC lines (HepG2 [wild p53], HLE, HLF, and HuH-7 [mutant p53]). MTA1 was overexpressed in HCC cells versus nonmalignant hepatocytes in 31 of 45 HCC specimens (69%). Its expression was predominantly localized to the nucleus or cytoplasm of HCC cells. Nineteen of 20 HCC (95%) specimens with vascular invasion displayed strong MTA1 expression. Overexpression of MTA1 also significantly correlated with large tumor size. The cytoplasmic and nuclear immunoreactivity for ER-alpha was present in HCC specimens in 46% and 12%, respectively. Expression of MTA1 inversely correlated with the nuclear localization of ER-alpha. There was no marked difference in MTA1 and ER-alpha expression levels between HCC cell line expressing wild-type p53 and cell line with mutated p53 HCC. In conclusion, these findings indicate that overexpression of MTA1 is associated with HCC growth and vascular invasion. Nuclear translocation of ER-alpha inversely correlated with MTA1 expression, suggesting negative regulatory mechanisms.
 ...
PMID:Overexpression of metastatic tumor antigen 1 in hepatocellular carcinoma: Relationship to vascular invasion and estrogen receptor-alpha. 1511 22

Norcantharidin (NCTD), the demethylated analogue of cantharidin, has been used to treat human cancers in China since 1984. It was recently found to be capable of inducing apoptosis in human colon carcinoma, hepatoma and glioblastoma cells by way of an elusive mechanism. In this study, we demonstrated that NCTD also induces apoptosis in human oral cancer cell lines SAS (p53 wild-type phenotype) and Ca9-22 (p53 mutant) as evidenced by nuclear condensation, TUNEL labeling, DNA fragmentation and cleavage of PARP. Apoptosis induced by NCTD was both dose- and time-dependent. We found NCTD did not induce Fas and FasL, implying that it activated other apoptosis pathways. Our data showed that NCTD caused accumulation of cytosolic cytochrome c and activation of caspase-9, suggesting that apoptosis occurred via the mitochondria mediated pathway. NCTD enhanced the expression of Bax in SAS cells consistent with their p53 status. Moreover, we showed that NCTD downregulated the expression of Bcl-2 in Ca9-22 and Bcl-XL in SAS. Our results suggest that NCTD-induced apoptosis in oral cancer cells may be mediated by an increase in the ratios of proapoptotic to antiapoptotic proteins. Since oral cancer cells with mutant p53 or elevated Bcl-XL levels showed resistance to multiple chemotherapeutic agents, NCTD may overcome the chemoresistance of these cells and provide potential new avenues for treatment.
 ...
PMID:Norcantharidin-induced apoptosis in oral cancer cells is associated with an increase of proapoptotic to antiapoptotic protein ratio. 1559 95

The hepatitis C virus (HCV) core protein plays important roles in hepatocarcinogenesis through modulation of cellular proliferation, apoptosis, and immunological responses. The roles of core protein in apoptosis have been conflicting; both proapoptotic and anti-apoptotic roles have been reported from different experimental conditions. Nonetheless, the overcoming apoptosis is a key molecular event to development of hepatocellular carcinoma. We investigated whether the HCV core-expressing cells are susceptible to apoptosis after cellular stress. Furthermore, we focused on the possibility that the presence of mutant p53 can render cells resistant to apoptosis. Our data clearly indicated that core-expressing cells showed increased apoptotic cell death through caspase-3 activation pathways after genotoxic stress without modulation of Bcl-2 family proteins. However, core-expressing cells, when transiently transfected with mutant p53, showed markedly increased resistance upon apoptosis after genotoxic stress. Thus, our data suggest that even though HCV core-expressing cells are susceptible to apoptosis after genotoxic stress, cells are resistant to apoptosis under mutant p53, implying a functional abnormality of p53 giving a chance to overcome apoptosis and ultimately cells develop into hepatocellular cell carcinoma.
 ...
PMID:Modulation of cell death sensitivity by mutant p53 in HCV core-expressing cells. 1570 41

VEGF, a potent angiogenic growth factor, is up-regulated in many tumors including human breast tumors and stimulates growth of vascular networks that support tumor growth and metastasis. We previously reported that natural and synthetic progestins (P) increased VEGF mRNA and protein levels in progesterone receptor (PR) containing T47-D human breast cancer cells in a PR dependent manner, but not in PR positive ZR-75 and MCF-7, or in PR negative MDA-MB-231 cells. This indicated that factors beside PR are involved in progesterone-dependent VEGF regulation. We, therefore, tested additional tumor cell lines reported to contain PR for progestin-dependent VEGF induction. Out of nine PR-positive breast tumor cell lines, progestins induced VEGF in three cell lines that lack wild-type p53 (T47-D, BT-474, and HCC-1428) but not in cell lines that contained the wild-type p53 protein. The T47-D and BT-474 cells express mutant p53, while the p53 protein is absent HCC-1428 cells. The anti-progestin RU-486 blocked progestin-dependent induction of VEGF in T47-D and BT-474 cells but not in HCC-1428 cells. However, RU-486 partially blocked medroxyprogesterone acetate-dependent induction of VEGF in HCC-1428 cells. Estrogen receptor (ER) and PR agonists and antagonists also induce VEGF in HCC-1428 cells and this effect was partially blocked by anti-estrogen ICI-182, 780. Progestin-dependent VEGF induction was completely inhibited by PRIMA-1-activated p53 in all cell-types, but progestin-dependent transcription of a progesterone-regulated minimal promoter was only partially inhibited. PRIMA-1 induced activation of p53 in tumor cell lines was confirmed with a p53-responsive p21 reporter plasmid and by detecting increased levels of p21 proteins in cell lysates. PRIMA-1 induced p53 protein in the HCC-1428 cells while levels of mutant p53 protein in T47-D and BT-474 remained unaltered. Progestin-dependent induction of VEGF was also inhibited by stable transfection of wild-type p53 in T47-D cells. These results are consistent with the hypothesis that wild-type p53 blocks progestin-dependent induction of VEGF in breast cancer cells and this may be a novel anti-angiogenic mechanism for controlling the growth of progestin-dependent tumors.
 ...
PMID:p53-dependent inhibition of progestin-induced VEGF expression in human breast cancer cells. 1586 Feb 60

To study the antitumor activity of alkaloid extracted from Oxytropis ochrocephala and its possible mechanism, we observed the effect of alkaloid on tumor weight and expression of PCNA and p53 in mice bearing H(22) hepatocellular carcinoma by means of immunohistochemistry SP method. After treatment with alkaloid from Oxytropis ochrocephala, the results showed that alkaloid administration (25 and 50 mg/kg body weight, p.o.) could inhibit H(22) hepatocellular carcinoma growth to various extent, and the rates of inhibition were 48.5% and 57.7% respectively (p<0.01). The antitumor activity of the alkaloid is in a dose dependent manner, with no signs of toxicity to weight, kidney and liver. The sections of tumor showed the number of tumor cell decreased and nucleus appeared putrescence such as nucleus atrophy, disintegrating and dissolving. Meanwhile, the expression of PCNA and mutant p53 protein positive cell numbers in mice bearing H(22) hepatocellular carcinoma also suppressed by alkaloid (p<0.05). It suggested that Alkaloid from Oxytropis ochrocephala showed antitumor effect and its possible mechanism might be associated with the expression inhibition of PCNA and mutant p53 protein. Further studies are needed to explore the antitumor activity of the other compounds of Oxytropis ochrocephala and to specify their possible mechanism of action.
 ...
PMID:The effect of alkaloid from Oxytropis ochrocephala on growth inhibition and expression of PCNA and p53 in mice bearing H22 Hepatocellular Carcinoma. 1607 18

A systemic vitamin K analog, compound 5 (Cpd 5), possesses the ability to inhibit cell growth of tumor cells. Therefore, we investigated the effect of Cpd 5 in human hepatocellular carcinoma (HCC) cell lines and evaluated its role in apoptosis. Human HCC cell lines were cultured and treated with Cpd 5. Apoptosis was assessed using DAPI staining and Annexin-V membrane staining. The expression of caspases, XIAP and Bcl-xL was also investigated. Cpd 5 decreased cell viability in a dose-dependent manner in two HCC cells (HLE and SK-Hep1) containing mutant p53, but not in the HepG2 cell line, which contained wild-type p53. Cpd 5-treated HLE and SK-Hep1 cells showed typical apoptotic features, nuclear condensation and nuclear fragmentation upon DAPI staining. Positive membranous staining for Annexin-V was also seen in these cells. Both caspase-8 and caspase-3 activities were up-regulated slightly. Pro-caspase-8 protein levels decreased slightly in both cells. Although the expression of Bcl-xL was not influenced by Cpd 5, that of XIAP decreased in HLE cells. However, the pan-caspase inhibitor, zVAD, could not significantly prevent Cpd 5-induced apoptosis and Cpd 5 could not augment TRAIL-induced apoptosis. These results demonstrate that Cpd 5 induced apoptosis in human HCC cell lines, mainly independently of caspase activities. This may contribute to its highly potent cytotoxicity toward HCC cells.
 ...
PMID:Vitamin K analog (compound 5) induces apoptosis in human hepatocellular carcinoma independent of the caspase pathway. 1609 31

RTN4-C gene is a member of RTNs. To investigate its expression in human hepatocellular carcinoma tissues and study its function on SMMC7721 cells, RT-PCR was conducted to detect its expressions in human hepatocellular carcinoma tissues. RTN4-C-pcDNA3. 1 plasmid was reconstructed and stably transfected into SMMC7721 cells by Lipofect AMINE. Growth curve of SMMC7721 measured by MTT and apoptosis indentified with acridine orange staining were examined to demonstrate the effect of RTN4-C on SMMC7721. Immunocytochemical analysis for mutant p53, c-Fos, Hsp70 proteins were conducted. The results showed that the transfected SMMC7721 cells grew more slowly than control and the average inhibition rate at the 1st, 2nd and 3rd day were 33.8% +/- 0.026, 56.2% +/- 0. 094, 34.8% +/- 0.077 respectively. In transfected SMMC7721 cell line, the apoptosis was strengthened,mutant p53 protein tranferred from nucleus to cytoplasm and c-Fos, Hsp70 proteins were decreased. Our data indicated RTN4-C gene was expressed differently in hepatocellular carcinoma and its paracancerous tissues. By tranferring mutant p53 protein from nucleus to cytoplasm and decreasing c-Fos, Hsp70 protein expression, RTN4-C inhibited SMMC7721 cells growth and promoted its apoptosis.
 ...
PMID:RTN4-C gene expression in hepatocellular carcinoma and its influence on SMMC7721 cell growth and apoptosis. 1620 Dec 30

Hepatocellular carcinoma (HCC) is a common human malignancy that is often associated with risk factors such as aflatoxin-B1 (AFB1) exposure and Hepatitis-B virus infection in developing countries. There is a strong correlation between these risk factors and mutation of the tumor-suppressor gene p53 at codon 249. In vitro experiments have also shown that treatment of human liver cells with AFB1 results in p53 mutations. A tumor-promoting role for mutant p53 was demonstrated using transgenic mice models, in which HCC development was accelerated upon AFB1-exposure. However, wild-type mice in which AFB1 alone was used to induce liver cancers have failed to recapitulate p53 mutations, raising the possibility that mouse DNA context may not be appropriate for the generation of AFB1-induced p53 mutations. We have now tested this hypothesis using the Hupki mice (human p53 knock-in) in which the mouse DNA-binding domain has been replaced by the homologous human p53 segment. Mice were followed for 80 weeks after AFB1 injection for survival and HCC formation. Hupki mice were found to be more susceptible to AFB1 than wild-type mice. Moreover, only 19% of wild-type mice developed HCCs compared to 44% in Hupki mice. However, none of the liver tumors and normal tissues from Hupki mice contained any mutations in the DNA-binding domain of p53. These findings suggest that the human DNA context of the p53 gene alone may not be the sole determinant of AFB1-induced mutagenesis. Furthermore, humanized p53 appears not to be as effective as murine p53 in the mouse cellular environment in preventing malignant transformation.
 ...
PMID:Aflatoxin-B exposure does not lead to p53 mutations but results in enhanced liver cancer of Hupki (human p53 knock-in) mice. 1655 86


<< Previous 1 2 3 4 5 6 7 8 9 Next >>