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)

The case of a variant of hepatocellular carcinoma is described, which, based on its unique histology, we propose to term, medullary-like hepatocellular carcinoma. It developed in a 56-year-old male patient with liver cirrhosis, and consisted of large, amphophilic cells with a solid growth pattern. The tumour was densely infiltrated with lymphocytes and plasma cells. Lymphocytes formed a mixture of B and T cells, and plasma cells were polytypic. In addition, numerous S-100 protein-reactive stellate cells were observed at the tumour border, where marked apoptosis of hepatocellular carcinoma cells was evident. In areas of dense lymphoplasmacytic infiltration, part of the tumour cells had lost their intercellular connections and their beta-catenin reactivity. Some tumour cells expressed FasL, but not Fas. The tumour exhibited several foci of regression, showing small remnants of damaged tumour cells within dense infiltrations. The patient is alive without evidence of disease 25 months after resection. Medullary-like hepatocellular carcinoma is a lesion which mimics several features known for other medullary carcinomas, including a marked immune response which may be responsible for partial regression of this tumour.
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PMID:Hepatocellular carcinoma with an unusual medullary-like histology and signs of regression ("medullary-like hepatocellular carcinoma"). 1246 3

Mutations in the adenomatous polyposis coli (APC) gene and K-ras occur in the majority of human colorectal cancers. Loss of functional APC protein activates the Wnt signal transduction pathway, allowing the nuclear accumulation of beta-catenin, which then binds to T-cell factor-4 (Tcf-4), causing increased transcriptional activation of downstream target genes. We investigated the hypothesis that the activation of the WNT pathway regulates cyclooxygenase-2 (COX-2). COX-2 was down-regulated after the induction of full-length APC in the HT29-APC cell line. We identified a Tcf-4-binding element (TBE) in the COX-2 promoter that specifically bound to Tcf-4 in an electrophoretic mobility shift assay. COX-2 promoter luciferase activity is down-regulated by APC in a promoter reporter construct containing the, TBE but not with mutant TBE. Mutant beta-catenin expression up-regulated the COX-2 promoter activity and the endogenous COX-2 mRNA expression in HuH7, hepatocellular carcinoma cell line, which is partially abrogated by cotransfection with a dominant-negative Tcf-4 expression vector. Although beta-catenin alone did not increase COX-2 protein to detectable levels in HuH7 cells, coexpression of both mutant beta-catenin and mutant K-ras increased COX-2 protein expression, which is consistent with the previous reports that K-ras can stabilize COX-2 mRNA. Taken together, our data support the hypothesis that COX-2 is down-regulated by APC and up-regulated by nuclear beta-catenin accumulation, and additionally implicate the Wnt signal transduction pathway in colon and liver carcinogenesis.
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PMID:Regulation of cyclooxygenase-2 expression by the Wnt and ras pathways. 1256 20

To identify the genes responsible for carcinogenesis and progression of hepatocellular carcinoma (HCC), we screened differentially expressed genes in several human HCC cell lines. Among these genes, Gpr49 was up-regulated in PLC/PRF/5 and HepG2. Gpr49 is a member of the glycoprotein hormone receptor subfamily, which includes the thyroid-stimulating hormone receptor (TSHR). However, Gpr49 remains to be an orphan G-protein-coupled receptor. By real-time quantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis, overexpression (>3-fold increase compared with the corresponding noncancerous liver tissue) of Gpr49 mRNA was observed in 18 of 38 (47%) HCCs compared with corresponding noncancerous livers. Clinicopathologically, overexpression of Gpr49 was frequently observed in HCC with mutation in beta-catenin exon 3 (14 of 16 cases, 87.5%). Moreover, introduction of mutant beta-catenin into mouse hepatocytes in culture caused up-regulation of the Gpr49 mouse homologue. Therefore, Gpr49 is likely to be a target gene activated by Wnt-signaling in HCC. In conclusion, although much is still unknown, Gpr49 may be critically involved in the development of HCCs with beta-catenin mutations and has the potential to be a new therapeutic target in the treatment of HCC.
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PMID:Overexpression of orphan G-protein-coupled receptor, Gpr49, in human hepatocellular carcinomas with beta-catenin mutations. 1260 49

To investigate the genetic mechanism of metastatic spread in hepatocellular carcinoma (HCC), we analyzed genomic changes in lung or liver metastases and the corresponding primary tumors (83 tumor samples) in 18 patients who underwent orthotopic liver transplantation. We studied the incidence of microsatellite instability (MSI) and loss of heterozygosity (LOH) involving 8 highly polymorphic microsatellite markers and the polyA tract, Bat26. We also sought alterations of p53 and beta-catenin gene mutations. High MSI (>30-40% of the loci analyzed) was found only in primary tumors (11%), whereas LOH was observed in 50% of primary and in 39% of recurrent tumors. p53 mutations were found in 2 cases of primary HCC but not in the corresponding metastases. P53 was overexpressed in 4 primary HCC (22%) and 7 metastases (39%). The percentage of beta-catenin gene mutations was low (6%). Lung metastases retained the D16S402 microsatellite abnormalities observed in the primary tumors, whereas recurrent liver tumor did not (p = 0.02). In conclusion, LOH and P53 protein overexpression, rather than mutations in the p53 or beta-catenin genes or MSI, seem to be involved in the spreading of HCC, suggesting the presence of metastasis suppressor genes in the vicinity of the chromosomal loci in question.
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PMID:Analysis of chromosomal instability in pulmonary or liver metastases and matched primary hepatocellular carcinoma after orthotopic liver transplantation. 1264 Jun 82

Hepatoblastomas (HBs) represent the most frequent malignant liver tumors of childhood; yet little is known about the molecular pathogenesis and the alterations in expression patterns of these tumors. We used a suppression subtractive hybridization approach to identify new candidate genes that may play a role in HB tumorigenesis. cDNA species derived from corresponding liver and fetal liver were subtracted from HB cDNAs, and a series of interesting candidates were isolated that were differentially expressed. One of the transcripts overexpressed in HB was derived from the human Dickkopf-1 (hDkk-1) gene, which encodes a secreted protein acting as a potent inhibitor of the wingless/WNT signaling pathway. We examined the hDkk-1 expression levels in 32 HB biopsy specimens and in the corresponding liver samples, in 4 HB cell lines, and in a panel of other tumors and normal tissues using a differential PCR approach and Northern blotting. Eighty-one percent of the HBs but none of the normal pediatric or fetal liver tissues showed hDkk-1 expression. hDkk-1 transcripts were also present in 5 of 6 Wilms' tumors but only weakly detectable in 2 of 20 hepatocellular carcinoma samples and in 1 of 5 medulloblastoma cell lines; transcripts were absent in malignant gliomas and breast cancer. The central effector molecule in the WNT developmental control pathway is the beta-catenin protein. Interestingly, activating mutations of the beta-catenin gene have previously been identified in 48% of HBs, and more than 85% of HBs show accumulation of beta-catenin protein as the indicator for an activated pathway. The overexpression of the inhibitor Dkk-1 may therefore be related to uncontrolled wingless/WNT signaling and may represent a negative feedback mechanism. hDkk-1 expression represents a novel marker for HBs and Wilms' tumors.
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PMID:Overexpression of human Dickkopf-1, an antagonist of wingless/WNT signaling, in human hepatoblastomas and Wilms' tumors. 1264 43

Mutational activation of beta-catenin and cyclin D1 over-expression are a frequent change in mouse hepatic tumors. Although activated beta-catenin may bind to T cell factor (TCF) family members and transcriptionally activate the cyclin D1 gene, either beta-catenin or cyclin D1 may be activated by various pathways independently of beta-catenin mutations. In this study, we investigated beta-catenin activation and mutations, cyclin D1 expression, H-ras mutations and phosphorylation of extracellular signal regulated protein kinases 1/2 (ERK1/2), Akt and glycogen synthetase kinase 3beta (GSK3 beta) in mouse hepatic carcinogenesis. Nuclear/cytoplasmic staining of beta-catenin, a sign of beta-catenin activation, was frequently observed in association with the high nuclear cyclin D1 labeling index in the hepatic tumors at the late stage of carcinogenesis. The beta-catenin activation was further suggested by the fact that all hepatocellular carcinoma (HCC) cell lines examined showed the nuclear beta-catenin/TCF4 complex together with cyclin D1 over-expression. However, the fact that only 31.8% (7/22) of the lesions with the nuclear/cytoplasmic beta-catenin staining showed beta-catenin mutations indicated that beta-catenin was activated not only by its own mutations but also by other reason(s). On the other hand, there was no correlation between the beta-catenin/cyclin D1 activation and the H-ras mutations or phosphorylation of Akt, GSK3 beta and ERK1/2, although GSK3 beta was frequently over-expressed in the tumors. These results indicate that, although beta-catenin and cyclin D1 activation are well correlated, the Akt/GSK3 beta and ras/ERK1/2 pathways may not play a major role in the beta-catenin/cyclin D1 activation.
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PMID:Cyclin D1 over-expression correlates with beta-catenin activation, but not with H-ras mutations, and phosphorylation of Akt, GSK3 beta and ERK1/2 in mouse hepatic carcinogenesis. 1266 2

Alteration of beta-catenin expression has been implicated in the development of hepatocellular carcinoma (HCC). It has been also reported that beta-catenin can influence the tumor cell proliferation or cyclin D1 expression, one of the target factors of betacatenin. We performed an immunohistochemical analysis of beta-catenin and cyclin D1 in 77 patients with resected HCCs, and examined the relationships between the expressions of beta-catenin and cyclin D1, and other pathologic parameters including the mitotic index. Altered expressions of beta-catenin including nonnuclear overexpression and nuclear expression were detected in 58.4% of HCCs (45/77) and showed significant correlations with large tumor size, poor histologic grade, and high tumor stage. The mean mitotic index of HCCs with nuclear expression (3.2 +/- 3.0) and nonnuclear overexpression (2.7 +/- 2.5) was significantly higher than that of tumors with no overexpression (1.7 +/- 1.4) (p=0.018 and 0.038, respectively), however, no correlation was noted between the expressions of cyclin D1 and beta-catenin. In addition, nonnuclear overexpression out of two altered expression patterns was more frequent (37.7% versus 20.8%) as well as pathologically more significant than nuclear expression. These results indicate that the altered expression of beta-catenin in HCC may play an important role in tumor progression by stimulating tumor cell proliferation, and nonnuclear overexpression may have pathologic significance in HCC.
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PMID:Expression of beta-catenin in hepatocellular carcinoma in relation to tumor cell proliferation and cyclin D1 expression. 1269 18

The Wnt signaling pathway, named for its most upstream ligands, the Wnts, is involved in various differentiation events during embryonic development and leads to tumor formation when aberrantly activated. Molecular studies have pinpointed activating mutations of the Wnt signaling pathway as the cause of approximately 90% of colorectal cancer (CRC), and somewhat less frequently in cancers at other sites, such as hepatocellular carcinoma (HCC). Ironically, Wnts themselves are only rarely involved in the activation of the pathway during carcinogenesis. Mutations mimicking Wnt stimulation-generally inactivating APC mutations or activating beta-catenin mutations-result in nuclear accumulation of beta-catenin which subsequently complexes with T-cell factor/lymphoid enhancing factor (TCF/LEF) transcription factors to activate gene transcription. Recent data identifying target genes has revealed a genetic program regulated by beta-catenin/TCF controlling the transcription of a suite of genes promoting cellular proliferation and repressing differentiation during embryogenesis, carcinogenesis, and in the post-embryonic regulation of cell positioning in the intestinal crypts. This review considers the spectra of tumors arising from active Wnt signaling and attempts to place perspective on recent data that begin to elucidate the mechanisms prompting uncontrolled cell growth following induction of Wnt signaling.
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PMID:Caught up in a Wnt storm: Wnt signaling in cancer. 1278 68

Constitutive activation of WNT signalling through beta-catenin, which leads to increased transcription of TCF/beta-catenin target genes, is crucial in the development of many human tumour types including colorectal carcinoma and hepatoma. Its role in urothelial cancer (TCC) is unclear, since typical activating mutations are not found. We therefore determined the activity of a beta-catenin/TCF-dependent promoter in proliferating normal uroepithelial cells and seven TCC cell lines, using a hepatoma line with oncogenic beta-catenin as a control. Neither normal urothelial cells nor TCC lines exhibited activity under normal growth conditions. In normal cells and 5/7 TCC lines, even transfection of activated beta-catenin did not restore promoter activity, suggesting repression of beta-catenin/TCF activity. TCF mRNAs and total beta-catenin protein levels did not differ qualitatively between inducible and noninducible cell lines, but E-cadherin expression was lacking or low in inducible TCC lines. In these, cotransfection of E-cadherin diminished activation of the TCF-dependent promoter by beta-catenin. Our results make constitutive WNT/beta-catenin signalling in TCC appear unlikely, thereby explaining the lack of reported mutations. However, decreased E-cadherin expression occurring in many TCC, often as a consequence of promoter hypermethylation, may confer inappropriate responsiveness to WNT factors.
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PMID:E-cadherin involved in inactivation of WNT/beta-catenin signalling in urothelial carcinoma and normal urothelial cells. 1279 39

Wnt signaling mediated by beta-catenin plays crucial roles in the development of hepatocellular carcinoma and other cancers such as colorectal cancer. beta-Catenin associates with T-cell factor (TCF) transcription factors and functions as a transcriptional activator in the nucleus. By protein interaction screening, we identified EBP50, a cytoplasmic protein with 2 PDZ domains, as a beta-catenin-associating molecule. EBP50 interacted with beta-catenin through its carboxyl-PDZ domain in vitro and in vivo. Northern blot and RT-PCR analysis revealed an increase of EBP50 messenger RNA (mRNA) in hepatocellular carcinoma (HCC) cell lines and surgical specimens of human HCC. Over-expression of EBP50 protein with focal nuclear localization was detected in human HCC. In human HCC and colorectal cancer cell lines, EBP50 enhanced beta-catenin/TCF-dependent transcription in a dose-dependent manner. In an HCC cell line, over-expression of the carboxyl PDZ domain resulted in a decrease of endogenous beta-catenin/TCF transactivation. EBP50 promoted beta-catenin-mediated transactivation only in cells in which beta-catenin was already stabilized, suggesting that EBP50 may work with stabilized beta-catenin for transcriptional regulation. In conclusion, the EBP50/beta-catenin complex promotes Wnt signaling, and over-expression of EBP50 may work cooperatively with beta-catenin in the development of liver cancer.
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PMID:EBP50, a beta-catenin-associating protein, enhances Wnt signaling and is over-expressed in hepatocellular carcinoma. 1283


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