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)

Deleted in liver cancer 2 (DLC2) is a candidate tumor suppressor frequently found to be deleted in hepatocellular carcinoma. In this study, we determined the subcellular localization of DLC2. Co-localization and biochemical fractionation studies revealed that DLC2 localized to mitochondria. In addition, the DLC2-containing cytoplasmic speckles were in proximity to lipid droplets. A DLC2 mutant containing the steroidogenic acute regulatory protein-related lipid transfer (START) domain only showed a localization pattern identical to that of DLC2. Taken together, we have provided the first evidence for mitochondrial localization of DLC2 through the START domain. These findings might have implications in liver physiology and carcinogenesis.
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PMID:Mitochondrial targeting of growth suppressor protein DLC2 through the START domain. 1636 8

Epigenetic alternation via the promoter hypermethylation of putative tumor suppressor genes has been implicated in the development of hepatocellular carcinoma (HCC). In this study, we investigated the epigenetic changes in two candidate tumor suppressor genes, endothelin receptor type B (EDNRB) and p16, and their relation to the expression of these two genes in HCC. Methylation-specific polymerase chain reaction (MS-PCR) was performed to analyze the promoter methylation status of the EDNRB and p16 genes in tumors and paired non-tumor liver portions of 34 HCC patients. The mRNA expression was assessed by reverse transcription-PCR assay. Hypermethylation of the EDNRB and p16 genes was detected in 29.4% (10/34) and 32.3% (11/34) of HCC patients, respectively. Moreover, the reduction of mRNA expression was correlated to the promoter hypermethylation of the EDNRB and p16 genes. In conclusion, aberrant methylation of EDNRB and p16 genes is highly prevalent in HCC. It suggested that epigenetic alteration of the EDNRB and p16 genes may play an important role in the pathogenesis of HCC.
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PMID:Aberrant methylation of EDNRB and p16 genes in hepatocellular carcinoma (HCC) in Taiwan. 1639 77

The molecular pathogenesis and the genetic aberrations that lead to the progression of hepatocellular carcinoma (HCC) are largely unknown. Here, we demonstrate that the thioredoxin interacting protein (Txnip) gene is a candidate tumor suppressor gene in vivo. We previously showed that the recombinant inbred congenic strain HcB-19 has a spontaneous mutation of the Txnip gene, and we now show that the strain has dramatically increased incidence of HCC, and that the HCC cosegregates with the Txnip mutation. Approximately 40% of the Txnip-deficient mice developed hepatic tumors with an increased prevalence in male mice. Visible tumors develop as early as 8 months of age. Histological analysis confirmed the morphology of HCC in the Txnip-deficient mice. Molecular markers of HCC, alpha-fetoprotein and p53, were increased in tumors of Txnip-deficient mice. The upregulation of p53 preceded tumor development; however, bromodeoxyuridine (BrdU) labeling of normal hepatic tissue of Txnip-deficient mice did not reveal increased cell proliferation. Finally, microarray analyses of tumor, non-tumor adjacent, and normal tissue of Txnip-deficient mice highlighted the genetic differences leading to the predisposition and onset of HCC. Our findings suggest that Txnip deficiency is sufficient to initiate HCC and suggest novel mechanisms in hepatocarcinogenesis.
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PMID:Hepatocellular carcinoma in Txnip-deficient mice. 1660 85

A high frequency of allelic loss affecting chromosome 8p and a minimal region of deletion at p21-22 have been previously reported in hepatocellular carcinoma (HCC), suggesting that at least one tumor suppressor gene is present in this region. In this study, we assessed whether the angiotensin II AT2 receptor interacting protein (ATIP)/mitochondrial tumor suppressor gene (MTUS1), a gene newly identified at position 8p22, may be a candidate tumor suppressor gene mutated in HCC. We searched for alterations in the 17 coding exons of ATIP/MTUS1 by means of denaturating high-performance liquid chromatography and sequencing, in 51 HCC tumors and 58 cell lines for which loss of heterozygosity status was known. Five major nucleotide substitutions were identified, all located in exons used by the ATIP3 transcript which is the only ATIP transcript variant expressed in liver. These nucleotide variations result in amino-acid substitution or deletion of conserved structural motifs (nuclear localisation signal, polyproline motif, leucine zipper) and also affect exonic splicing enhancer motifs and physiological splice sites, suggesting potential deleterious effects on ATIP3 function and/or expression.
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PMID:Mutation analysis of the 8p22 candidate tumor suppressor gene ATIP/MTUS1 in hepatocellular carcinoma. 1665 May 23

DDX3 is a DEAD box RNA helicase with diverse biological functions. Using colony formation assay, our results revealed that DDX3 inhibited the colony formation ability of various tumor cells, and this inhibition might be due to a reduced growth rate caused by DDX3. Additionally, we identified p21(waf1/cip1), a cyclin-dependent kinase inhibitor, as a target gene of DDX3, and the up-regulation of p21(waf1/cip1) expression accounted for the colony-suppressing activity of DDX3. Moreover, DDX3 exerted its transactivation function on p21(waf1/cip1) promoter through an ATPase-dependent but helicase-independent mechanism, and the four Sp1 sites located within the -123 to -63 region, relative to the transcription start site of p21(waf1/cip1) promoter, were essential for the response to DDX3. Furthermore, DDX3 interacted and cooperated with Sp1 to up-regulate the promoter activity of p21(waf1/cip1). To determine the relevance of DDX3 in clinical cancers, the expression profile of DDX3 in various tumors was also examined. A declined expression of DDX3 mRNA and protein was found in approximately 58% to 73% of hepatoma specimens, which led to the reduction of p21(waf1/cip1) expression in a manner independent of p53 status. Additionally, an alteration of subcellular localization from nuclei to cytoplasm was also observed in >70% of cutaneous squamous cell carcinoma samples. Because DDX3 exhibits tumor suppressor functions, such as a growth-suppressive property and transcriptional activation of the p21(waf1/cip1) promoter, and is inactivated through down-regulation of gene expression or alteration of subcellular localization in tumor cells, all these features together suggest that DDX3 might be a candidate tumor suppressor.
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PMID:DDX3, a DEAD box RNA helicase with tumor growth-suppressive property and transcriptional regulation activity of the p21waf1/cip1 promoter, is a candidate tumor suppressor. 1681 30

KLF6 (Zf9, COPEB), an ubiquitous transcription factor, maps to chromosome 10p. Recently, KLF6 was found to have a more generalized role in tumorigenesis as a candidate tumor suppressor gene for some tumors. However, results from other published studies seem not to be in agreement with data from previous studies. Gene-expression analysis is increasingly important in biological research. Loss of expression is one of the mechanisms to functionally inactivate a tumor suppressor gene. To investigate the expression change of KLF6 gene associated with HCC as a step toward a better understanding of the molecular pathophysiology, and to provide the basis for analysis of KLF6 gene in HCC carcinogenesis. We analyzed the expression of KLF6 mRNA in 26 samples of HCC tissues and hepatoma cell lines(Hep3B and HepG2) detected by Real-Time quantitative RT-PCR (qRT-PCR) and conventional RT-PCR assay. To confirm and extend the data obtained at RNA level, we performed detailed immunoblotting analysis on HCC tissues and hepatoma cell lines using a rabbit polyclonal antibody specific for KLF6. NKLF6 detected by qRT-PCR from HCC and corresponding noncancerous tissues was 0.04+/-0.038 and 0.116+/-0.101, respectively. These data demonstrated that KLF6 mRNA level was significantly decreased in HCC, compared with corresponding noncancerous tissues (t =3.683 , P<0.001). The frequency of Hepatoma Cell Lines with KLF6 down-regulation detected by conventional PT-PCR, seems to be consistent with a previous study using real-time PCR assays in tumor samples. KLF6 expression levels were determined by Western blot. Compared to the matched surrounding tissues, a clear decrease of KLF6 protein levels in tumor tissues was observable (t=13.59, P<0.001). Hepatoma cell lines also showed low-level of KLF6 protein (P<0.01) expression. Immunohistochemistry and immunocytochemistry showed a faint diffused staining in the HCC tissues and hepatoma cell lines, and endogenous KLF6 protein was detected mostly in the cytoplasm. KLF6 gene appeared markedly reduced in HCC tissues and hepatoma cell lines. Frequent down-regulation of KLF6 strongly suggested that it is a candidate of tumor suppressor gene for HCC.
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PMID:Loss of expression of Kruppel-like factor 6 in primary hepatocellular carcinoma and hepatoma cell lines. 1755 Jan 40

Multiple regions on the chromosome arm 3p are frequently affected by loss of heterozygosity in human cancers. A candidate tumor suppressor gene is TMEM7, at 3p21.3, which encodes a transmembrane protein. TMEM7 is expressed specifically in the liver, and the encoded protein shares substantial sequence homology with human and mouse 28-kDa interferon-alpha (IFN-alpha) responsive protein. In investigation of the possible role of TMEM7 in development of hepatocellular carcinoma (HCC), we examined TMEM7 expression in 20 primary HCC and 18 HCC cell lines and found recurrent functional alterations. Although TMEM7 mRNA was expressed in normal hepatic cells, downregulation or inactivation of the gene was detected in 85% of primary HCC and 33% of HCC cell lines. To identify the mechanisms responsible, we examined genomic deletion and mutation, and also the effect of inhibitors of DNA methyltransferase and histone deacetylase on cells with low or no endogenous TMEM7 expression. Homozygous deletion of TMEM7 was not detected in 17 pairs of human HCC and corresponding noncancerous liver tissues, nor in any of the 18 HCC cell lines. TMEM7 mutation was not detected in the 18 HCC cell lines (low or normal TMEM7 expression). Treatment of two of six cell lines exhibiting downregulation or loss of TMEM7 with 5-aza-2'-deoxycytidine and trichostatin A yielded additive increase in TMEM7 expression, implicating aberrant DNA methylation and histone deacetylation in transcriptional silencing of this gene. Ectopic expression of TMEM7 in two TMEM7-deficient HCC lines suppressed cell proliferation, colony formation, and cell migration in vitro and reduced tumor formation in nude mice. Treatment of two highly invasive HCC cell lines with IFN-alpha for 7 days significantly increased TMEM7 expression and inhibited cell migration. These findings implicate loss of TMEM7 expression in hepatocarcinogenesis and suggest that modification of TMEM7 expression by IFN-alpha may have therapeutic relevance in a subset of HCC.
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PMID:The interferon-alpha responsive gene TMEM7 suppresses cell proliferation and is downregulated in human hepatocellular carcinoma. 1769 85

The inhibitor of growth (ING) family member 2 (ING2) is a newly discovered member of ING family that can regulate a wide range of cellular processes including cell growth arrest, apoptosis, and DNA repair. Researches have shown that ING2 can activate p53 and p53-mediated apoptotic pathway involved in the hepatocarcinogenesis. To investigate the role of ING2 in hepatocellular carcinoma (HCC) pathogenesis, we analyzed the correlations between the ING2 expression level and clinicopathologic factors and studied its prognostic role in primary HCC. Using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot, ING2 transcription and post-transcription level was found to be downregulated in the majority of tumors compared with matched non-tumors liver tissues (p=0.004 and p=0.014, respectively). The immunohistochemistry data indicated significant reduction of ING2 expression level in 44 of 84 (52.4%) HCC cases. In addition, the expression level of ING2 correlated with tumor size, histopathologic classification, serum AFP (p<0.05). Kaplan-Meier curves demonstrated that patients with reduced ING2 expression were at significantly increased risk for shortened survival time (p=0.009). Using multivariate analysis, ING2 expression was found to be an independent prognostic factor. Our data suggest that ING2 is involved in the progression of HCC, therefore it is considered to be a candidate tumor suppressor gene and its significantly decreased expression in HCC may lead to an unfavorable prognosis.
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PMID:Decreased expression of ING2 gene and its clinicopathological significance in hepatocellular carcinoma. 1816 Feb 12

Hepatocellular adenoma (HCA) is a frequent long-term complication of glycogen storage disease type I (GSD I) and malignant transformation to hepatocellular carcinoma (HCC) is known to occur in some cases. However, the molecular pathogenesis of tumor development in GSD I is unclear. This study was conducted to systematically investigate chromosomal and genetic alterations in HCA associated with GSD I. Genome-wide SNP analysis and mutation detection of target genes was performed in ten GSD Ia-associated HCA and seven general population HCA cases for comparison. Chromosomal aberrations were detected in 60% of the GSD Ia HCA and 57% of general population HCA. Intriguingly, simultaneous gain of chromosome 6p and loss of 6q were only seen in GSD Ia HCA (three cases) with one additional GSD I patient showing submicroscopic 6q14.1 deletion. The sizes of GSD Ia adenomas with chromosome 6 aberrations were larger than the sizes of adenomas without the changes (P = 0.012). Expression of IGF2R and LATS1 candidate tumor suppressor genes at 6q was reduced in more than 50% of GSD Ia HCA that were examined (n = 7). None of the GSD Ia HCA had biallelic mutations in the HNF1A gene. These findings give the first insight into the distinct genomic and genetic characteristics of HCA associated with GSD Ia. These results strongly suggest that chromosome 6 alterations could be an early event in the liver tumorigenesis in GSD I, and may be in general population. These results also suggest an interesting relationship between GSD Ia HCA and steps to HCC transformation.
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PMID:Chromosomal and genetic alterations in human hepatocellular adenomas associated with type Ia glycogen storage disease. 1976 33

The epigenetic silencing of tumor suppressor genes is a crucial event during carcinogenesis and metastasis. Here, in a human genome-wide survey, we identified scavenger receptor class A, member 5 (SCARA5) as a candidate tumor suppressor gene located on chromosome 8p. We found that SCARA5 expression was frequently downregulated as a result of promoter hypermethylation and allelic imbalance and was associated with vascular invasion in human hepatocellular carcinoma (HCC). Furthermore, SCARA5 knockdown via RNAi markedly enhanced HCC cell growth in vitro, colony formation in soft agar, and invasiveness, tumorigenicity, and lung metastasis in vivo. By contrast, SCARA5 overexpression suppressed these malignant behaviors. Interestingly, SCARA5 was found to physically associate with focal adhesion kinase (FAK) and inhibit the tyrosine phosphorylation cascade of the FAK-Src-Cas signaling pathway. Conversely, silencing SCARA5 stimulated the signaling pathway via increased phosphorylation of certain tyrosine residues of FAK, Src, and p130Cas; it was also associated with activation of MMP9, a tumor metastasis-associated enzyme. Taken together, these data suggest that the plasma membrane protein SCARA5 can contribute to HCC tumorigenesis and metastasis via activation of the FAK signaling pathway.
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PMID:Genetic and epigenetic silencing of SCARA5 may contribute to human hepatocellular carcinoma by activating FAK signaling. 2003 95


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