Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0345904 (liver cancer)
 15,188 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

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

The deleted in liver cancer (DLC-1) gene at chromosome 8p21-22 is altered mainly by genomic deletion or aberrant promoter methylation in a large number of human cancers such as breast, liver, colon and prostate and is known to have an inhibitory effect on breast and liver tumor cell growth. Given the high frequency of deletion involving region 8p21-22 in human non-small cell lung carcinoma (NSCLC), we examined alterations of DLC-1 in a series of primary tumors and tumor cell lines and tested effects of DLC-1 on tumor cell growth. A significant decrease or absence of the DLC-1 mRNA expression was found in 95% of primary NSCLC (20/21) and 58% of NSCLC cell lines (11/19). Transcriptional silencing of DLC-1 was primarily associated with aberrant DNA methylation, rather than genomic deletion as 5-aza-2'-deoxycytidine induced reactivation of DLC-1 expression in 82% (9/11) NSCLC cell lines showing downregulated DLC-1. It was further evidenced by an aberrant DLC-1 promoter methylation pattern, which was detected by Southern blotting in 73% (8/11) of NSCLC cell lines with downregulation of the gene. The transfer of DLC-1 into three DLC-1 negative cell lines caused a significant inhibition in cell proliferation and/or a decrease in colony formation. Furthermore, stable transfer of DLC-1 abolished tumorigenicity in nude mice of two cell lines, suggesting that DLC-1 plays a role in NSCLC by acting as a bona fide new tumor suppressor gene.
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PMID:DLC-1 operates as a tumor suppressor gene in human non-small cell lung carcinomas. 1466 Oct 59

Tensin is a family of multidomain scaffold proteins that bind the cytoplasmic tail of beta-integrins and localize to adhesions that anchor stress fibers in cells. Tensin expression is suppressed in cancer, especially metastatic cancer. The N-terminal domain of tensin1 associates with protein phosphatase-1alpha (PP1alpha) and mediates PP1alpha localization to adhesions. Here, we show F302A mutation in a KVXF motif of tensin1 abrogates binding to PP1alpha. The SH2 domain in tensin family member c-ten requires R474 to bind a RhoGAP called DLC-1 (deleted in liver cancer). We mutated the corresponding residue in tensin1, R1488A, and showed this reduces association with DLC-1. Unexpectedly, tensin1 F302A also had reduced association with DLC-1. Expression of tensin1 F302A or R1488A showed similar dominant phenotypes, with reduced cell polarization, lowered MLC20 phosphorylation and reduced levels of RhoA(GTP) compared with cells expressing tensin1 WT. However, migration and invasion of metastatic MDA MB 231 breast cancer cells were differentially affected by tensin1 mutated at F302A or R1488A. Cancer cells stably expressing F302A tensin1 showed increased migration and invasion compared with cells stably expressing either R1488A tensin1 or WT tensin1. This suggests that PP1alpha bound to tensin1 has additional effects in reducing migration and invasion that are not mediated through DLC-1. Our results show the importance of PP1alpha binding to tensin1 for the regulation of cell polarization, migration, and invasion.
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PMID:Tensin1 requires protein phosphatase-1alpha in addition to RhoGAP DLC-1 to control cell polarization, migration, and invasion. 1982 1

Deleted in liver cancer-1(DLC-1) gene expression is frequently down-regulated or deleted in many types of human cancer. To evaluate whether DLC-1 could be a therapeutic target for non-Hodgkin lymphoma (NHL), we examined the expressions of DLC-1 in Burkitt's lymphoma (BL) cell lines and tested the effects of DLC-1 on cellular growth and migration in BL cells. DLC-1 expression was not detectable in two human BL cell lines, Raji and Daudi, by reverse transcription-PCR. The transfer of DLC-1 into Raji and Daudi cell lines caused a significant inhibition in cell proliferation. This inhibitory effect on cell proliferation in BL cell lines was accompanied by induction of apoptosis. Furthermore, restoration of DLC-1 expression in BL cells had a significant inhibitory effect on migration. Our findings suggest that DLC-1 may play an important role in lymphoma by acting as a bona fide new tumor suppressor gene.
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PMID:DLC-1 as a modulator of proliferation, apoptosis and migration in Burkitt's lymphoma cells. 2088 54

Deleted in liver cancer-1 (DLC-1) has been isolated from primary hepatocellular carcinoma and demonstrated to be a potential tumor suppressor gene. The aim of the present study was to observe the effect of the DLC-1 gene on pancreatic cancer cell growth and evaluate the feasibility of using the DLC-1 gene in gene therapy for pancreatic cancer. A recombinant plasmid (pcDNA3.1/DLC-1) was transfected into PANC-1 cells by liposomes and then the pre-established human PANC-1 pancreatic carcinoma cells were injected into athymic nude mice via the tail vein. The results showed that the overexpression of DLC-1 in the PANC-1 cells inhibited cell proliferation in vitro, while the act of introducing DLC-1 reduced tumorigenicity in the nude mice. The findings suggest that DLC-1 may have an effect on the pathogenesis of pancreatic cancer. The DLC-1 gene may be a promising target in gene therapy for pancreatic cancer.
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PMID:Deleted in liver cancer-1 inhibits cell growth and tumorigenicity in human pancreatic cancer. 2413 59

The hepatitis B virus core protein (HBc), also named core antigen, is well-known for its key role in viral capsid formation and virus replication. Recently, studies showed that HBc has the potential to control cell biology activity by regulating host gene expression. Here, we utilized miRNA microarray to identify 24 upregulated miRNAs and 21 downregulated miRNAs in HBc-expressed HCC cells, which were involved in multiple biological processes, including cell motility. Consistently, the in vitro transwell assay and the in vivo tail-vein injection model showed HBc promotion on HCC metastasis. Further, the miRNA-target gene network analysis displayed that the deleted in liver cancer (DLC-1) gene, an important negative regulator for cell motility, was potentially targeted by several differentially expressed miRNAs in HBc-introduced cells. Introduction of miRNAs mimics or inhibitors and 3'UTR luciferase activity assay proved that miR-382-5p efficiently suppressed DLC-1 expression and its 3'-UTR luciferase reporter activity. Importantly, cotransfection of miR-382-5p mimics/inhibitors and the DLC-1 expression vector almost abrogated HBc promotion on cell motility, indicating that the miR-382-5p/DLC-1 axis is important for mediating HBc-enhanced HCC motility. Clinical HCC samples also showed a negative correlation between miR-382-5p and DLC-1 expression level. Furthermore, HBc-positive HCC tissues showed high miR-382-5p level and reduced DLC-1 expression. In conclusion, our findings revealed that HBc promoted HCC motility by regulating the miR-382-5p/DLC-1 axis, which might provide a novel target for clinical diagnosis and treatment.
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PMID:Hepatitis B core protein promotes liver cancer metastasis through miR-382-5p/DLC-1 axis. 2898 93


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