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 isolation of genes involved in cancer development is critical for uncovering the molecular basis of cancer. We report here the isolation of the full-length cDNA and chromosomal localization of a new gene frequently deleted in liver cancer (DLC-1) that was identified by representational difference analysis. Loss of heterozygosity was detected for DLC-1 in 7 of 16 primary hepatocellular carcinomas (HCCs) and in 10 of 11 HCC cell lines. Although mRNA for DLC-1 was expressed in all normal human tissues, it was not expressed in 4 of 14 HCC cell lines. Full-length cDNA for DLC-1 of 3800 bp encodes a protein of 1091 amino acids, has 86% homology with rat p122 RhoGAP gene, and was localized by fluorescence in situ hybridization on chromosome 8 at bands p21.3-22. Deletions on the short arm of chromosome 8 are recurrent in liver, breast, lung, and prostate cancers, suggesting the presence of tumor suppressor genes. DLC-1 may be a tumor suppressor gene in liver cancer as well as in other cancers.
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PMID:Cloning, characterization, and chromosomal localization of a gene frequently deleted in human liver cancer (DLC-1) homologous to rat RhoGAP. 960 66

We investigated the expression and deletion of DLC-1 (frequently deleted in liver cancer gene), first reported in 1998 and having a high homology with rat p122RhoGAP in hepatocellular carcinoma (HCC). Six (20%) of 30 human HCC samples and 2 (40%) of 5 HCC cell lines were found to have no detectable DLC-1 expression by reverse transcription-PCR. Homozygous DLC-1 deletion was detected by Southern blotting in two of six HCC samples and in both HCC cell lines with no DLC-1 expression. Transfection of DLC-1 into 5 HCC cell lines (two with DLC-1 deletion and three with intact DLC-1) showed significant growth inhibition in these two HCC cell lines with deleted DLC-1 with both 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assays but not in three other HCC cell lines with intact DLC-1. Our findings suggest that DLC-1 may play an important role in hepatocarcinogenesis.
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PMID:DLC-1 is deleted in primary hepatocellular carcinoma and exerts inhibitory effects on the proliferation of hepatoma cell lines with deleted DLC-1. 1111 37

DLC-1 (deleted in liver cancer 1) is a candidate tumor suppressor gene for hepatocellular carcinoma and other cancers. It is the human homologue of rat p122, which has been shown to function as a GTPase activating protein for RhoA, and it may be involved in signal transduction pathways regulating cell proliferation and adhesion. To establish an animal model for studying the regulation and function of DLC-1, we have undertaken the characterization of the mouse DLC-1 gene. Northern blot analysis shows that the mouse DLC-1 mRNA is widely expressed, with the highest levels in heart, liver, and lung. Mouse genomic clones that contain the entire DLC-1 gene of 47 kb were isolated. The mouse gene consists of 14 exons, and the structural organization is highly similar to that of the human gene. The promoter region of the mouse gene was GC-rich and contained potential binding sites for transcription factors SP1, GCF, and AP-2. A polymorphic microsatellite marker in intron 8 was used for mapping the gene (Arhgap7) to 20 cM on mouse chromosome 8 and for allelotyping of mouse liver tumor DNAs.
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PMID:Gene structure, tissue expression, and linkage mapping of the mouse DLC-1 gene (Arhgap7). 1203 1

The human DLC-1 (deleted in liver cancer 1) gene was cloned from a primary human hepatocellular carcinoma (HCC) and mapped to the chromosome 8p21-22 region frequently deleted in common human cancers and suspected to harbor tumor suppressor genes. DLC-1 was found to be deleted or downregulated in a significant number of HCCs. We expanded our investigations to other cancers with recurrent deletions of 8p22, and in this study examined alterations of DLC-1 in primary human breast tumors, human breast, colon, and prostate tumor cell lines. Genomic deletion of DLC-1 was observed in 40% of primary breast tumors, whereas reduced or undetectable levels of DLC-1 mRNA were seen in 70% of breast, 70% of colon, and 50% of prostate tumor cell lines To see whether DLC-1 expression affects cell growth and tumorigenicity, two breast carcinoma cell lines lacking the expression of endogenous gene were transfected with the DLC-1 cDNA. In both cell lines, DLC-1 transfection caused significant growth inhibition and reduction of colony formation. Furthermore, introduction of the DLC-1 cDNA abolished the in vivo tumorigenicity in nude mice, suggesting that the DLC-1 gene plays a role in breast cancer by acting as a bona fide tumor suppressor gene.
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PMID:DLC-1 gene inhibits human breast cancer cell growth and in vivo tumorigenicity. 1254 65

Aberrant methylation of CpG islands within the promoter regions of tumor suppressor or cancer-related genes is a common mechanism leading to the silencing of gene expression. To determine whether aberrant methylation is a contributing factor to transcriptional inactivation of DLC-1 (deleted in liver cancer-1), a candidate tumor suppressor gene, we examined its methylation status in twelve hepatocellular carcinoma. breast, colon, and prostate tumor cell lines with low or undetectable expression of DLC-1. By Southern blot analysis of DNA digested with the methylation sensitive enzyme HpaII, we found a different degree of promoter hypermethylation in all cell lines with aberrant DLC-1 expression. The hypermethylation status was reversed by the addition of 5-aza-2'-deoxycytidine, a demethylating agent, in one human hepatocellular carcinoma line. These observations suggest that hypermethylation is responsible for abrogating the function of the DLC-1 gene in a subset of liver, breast, colon, and prostate cancers.
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PMID:Promoter hypermethylation of DLC-1, a candidate tumor suppressor gene, in several common human cancers. 1264 48

The DLC-1 gene encoding a regulator of the Rho family of small GTPases is altered in breast, prostate, colon, and liver cancer and has several characteristics of a tumor suppressor gene. DLC-1 overexpression causes inhibition of in vitro growth of liver tumor cells and complete suppression of in vivo tumorigenicity of breast tumor cells. Inactivation and aberrant expression of DLC-1 in human hepatocellular carcinoma (HCC) is frequently associated with hemizygous and homozygous genomic deletion and promoter methylation. Since inactivation of tumor suppressor genes in cancer cells is also commonly associated with point mutation, we evaluated the incidence of mutation of the DLC-1 gene by PCR-SSCP in 17 primary HCC and 18 HCC cell lines. One missense mutation was detected at codon 991 of exon 12 (C-->T transition, Val-->Ile) in an HCC cell line. In addition, two types of polymorphisms were identified: a G-->T at codon 745 of exon 9, a T-->C at 17 bp downstream of exon 2. While the pathogenic relevance of the intronic polymorphism is not known, the low rate of mutation of the DLC-1 gene in HCC implies that genomic deletion and promoter methylation primarily account for the altered expression and tumor suppressive inactivation of the DLC-1 gene.
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PMID:DNA variants of DLC-1, a candidate tumor suppressor gene in human hepatocellular carcinoma. 1279 85

DLC-1 (deleted in liver cancer) gene is frequently deleted in hepatocellular carcinoma. However, little is known about the genetic status and the expression of this gene in gastric cancer. In this study, Northern and Southern analysis showed that seven of nine human gastric cancer cell lines did not express DLC-1 mRNA, but contained the DLC-1 gene. To identify the mechanism of the loss of DLC-1 mRNA expression in these cell lines, we investigated the methylation status of DLC-1 gene by using methylation-specific PCR (MSP) and Southern blot, and found that five of seven DLC-1 nonexpressing gastric cancer cell lines were methylated in the DLC-1 CpG island. Treatment with 5-aza-2'-deoxycytidine (5-Aza-dC) induced DLC-1 mRNA expression in the gastric cancer cell lines that have the methylated alleles. Studies using SNU-601 cell line with methylated DLC-1 alleles revealed that nearly all CpG sites within DLC-1 CpG island were methylated, and that the in vitro methylation of the DLC-1 promoter region is enough to repress DLC-1 mRNA expression, regardless of the presence of transcription factors capable of inducing this gene. In all, 29 of 97 (30%) primary gastric cancers were also shown to be methylated, demonstrating that methylation of the DLC-1 CpG island is not uncommon in gastric cancer. In addition, we demonstrated that DLC-1 mRNA expression was induced, and an increase in the level of acetylated H3 and H4 was detected by the treatment with trichostatin A (TSA) in two DLC-1 nonexpressing cell lines that have the unmethylated alleles. Taken together, the results of our study suggest that the transcriptional silencing of DLC-1, by epigenetic mechanism, may be involved in gastric carcinogenesis.
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PMID:Transcriptional silencing of the DLC-1 tumor suppressor gene by epigenetic mechanism in gastric cancer cells. 1281 68

Hepatocellular carcinoma (HCC) is one of the most common fatal cancers in the world. However, the underlying molecular mechanisms contributing to hepatocarcinogenesis are still unclear. A putative tumor suppressor gene, namely DLC-1 (frequently deleted in liver cancer) was identified and mapped at chromosome 8p21.3-22, a recurrently deleted region in human cancers. The gene exerts inhibitory effects on the cell proliferation of HCC cells. In this study, we investigated the biological function, and genetic and epigenetic status of this gene in human HCC. With in vitro GTPase activating proteins activity assay, we established that DLC-1 protein was a GTPase-activating protein specific for RhoA and Cdc42. Deletion of the DLC-1 gene was frequent in human HCC, as revealed by loss of heterozygosity analysis performed on 100 human HCC cases with markers mapped at the DLC-1 locus, and allelic losses ranging from 44% to 50% of the informative cases. However, somatic mutations of the DLC-1 gene were rare. Moreover, with real-time quantitative PCR, we found that DLC-1 mRNA was significantly underexpressed in HCCs when compared with the corresponding nontumorous livers (P < 0.0001). In addition, the CpG island 5' to the DLC-1 gene was methylated in 3 of 7 HCC cell lines and in 6 (24%) of 25 primary HCCs. These data suggest that transcriptional silencing by hypermethylation may contribute to the inactivation of the DLC-1 gene. Taken together, the results of our study suggest that both genetic and epigenetic alterations play an important role in inactivation of the DLC-1 gene in hepatocarcinogenesis.
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PMID:Genetic and epigenetic alterations of DLC-1 gene in hepatocellular carcinoma. 1463 84

DLC-1 (deleted in liver cancer-1) is a tumor suppressor gene for hepatocellular carcinoma and other cancers. To characterize its functions, we constructed recombinant adenovirus encoding the wild-type DLC-1 and examined its effects on behaviors of a hepatocellular carcinoma cell line (SNU-368), which does not express DLC-1. Here, we found that restoration of DLC-1 expression in the SNU-368 cells caused an inhibition of cell proliferation with an increase of a subG1 population. Furthermore, DLC-1 overexpression induced disassembly of stress fibers and extensive membrane protrusions around cells on laminin-1. DLC-1 overexpression also inhibited cell migration and dephosphorylated focal adhesion proteins such as focal adhesion kinase (FAK), Cas (p130Cas; Crk-associated substrate), and paxillin. These observations suggest that DLC-1 plays important roles in signal transduction pathway regulating cell proliferation, cell morphology, and cell migration by affecting Rho family GTPases and focal adhesion proteins.
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PMID:DLC-1, a GTPase-activating protein for Rho, is associated with cell proliferation, morphology, and migration in human hepatocellular carcinoma. 1729 27

Genomic instability during hepatocarcinogenesis causes changes in signal transduction network. Strategies for identification of new markers/therapeutic targets include discovery of early molecular changes during hepatocarcinogenesis, relevant to preneoplastic lesions progression to full malignancy in rodent models, and evaluation of these changes in human hepatocellular carcinomas (HCCs). Activation of ERB receptor family, MAPK, JAK-STAT, beta-Catenin cascades, c-Myc targets, iNOS-IKK/MAT1A-NF-kB axis, Ornithine decarboxylase, Cyclins and CDKs occurs in human and rodent hepatocarcinogenesis. This is associated with downregulation of the cell cycle inhibitors p16(INK4A) and p53 and TGF-beta/SMAD signaling. Oncosuppressor genes, including p16(INK4A), E-CAD, and DLC-1 are often hypermethylated in humans and rodents. Moreover, protection of cell cycle from p16(INK4A) inhibition by upregulation of CDC37, HSP90, and CRM1 correlates to HCC progression. A body of evidence indicates that inhibition of key genes of aforementioned signaling pathways by antisense or siRNA approaches or specific inhibitors restraints growth of in vitro cultured or in vivo xenografted HCCs. Efforts are currently dedicated to improve transduction efficiency. HCC cells may escape gene therapy by various mechanisms. Attempts to overcome this difficulty include discovery of new therapeutic targets, gene therapy directed to different molecular targets essential for tumor cell survival and specifically directed to HCC subtypes.
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PMID:Dissection of signal transduction pathways as a tool for the development of targeted therapies of hepatocellular carcinoma. 1847 8


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