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)

Gag-related proteins were precipitated from 35S-methionine-labelled cells of the PR-2 line derived from a hepatoma induced by virus MC29. Immunoprecipitates were incubated with viral protease p15 and the cleavage products of P110 were analysed in SDS-PAGE. The major cleavage fragment of P110 is a protein with mol. wt. of 56 000. Preparative isolation of the non-gag fragments from protein P110 by means of a gag immunosorbent showed that the 56K fragment did not contain any gag specific antigenic determinants. This finding was also confirmed by performing immunization with this fragment. Cleavage of protein P110 and the properties of cleavage products are discussed.
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PMID:In vitro cleavage of gag-myc fused protein P110 of a defective leukaemia virus MC29 by retroviral protease p15. 629 16

The tumor suppressor gene CDKN2A (MTS1/p16), located on chromosome 9p21, is inactivated in a variety of tumors including melanomas and tumors of the biliary tract, pancreas, and stomach. The aim of the present study was to determine whether this gene is inactivated in hepatocellular carcinoma (HCC). Twenty-three primary HCCs and four HCC cell lines were examined. Loss of heterozygosity (LOH) analysis was performed using eight polymorphic markers immediately surrounding CDKN2A, and showed a contiguous region of loss, with the two most commonly deleted markers being D9S1604, located between the p16 and p15 genes, at which 7 of 13 informative tumors (54%) showed loss, and D9S171, with 4 of 14 LOH (29%). Exons 1, 2, and 3 of CDKN2A were amplified by polymerase chain reaction to detect homozygous deletions, and single-strand conformation polymorphism (SSCP) analysis was performed to screen for mutations. No homozygous deletions were detected in any sample. SSCP and sequence analysis showed the same nucleotide change at codon 148 in four tumors. This has been reported elsewhere as a polymorphism. One of these four tumors also contained a mutation at codon 119, resulting in the substitution of an acidic amino acid for a basic one. It is concluded that CDKN2A is infrequently deleted or mutated in HCC. The region of allelic loss upstream from CDKN2A might result in inactivation of regulatory sequences important in the expression of this gene; alternatively, a second tumor suppressor gene may be present in the region 9p21-22, proximal to CDKN2A. These possibilities require further investigation.
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PMID:Frequency of mutation and deletion of the tumor suppressor gene CDKN2A (MTS1/p16) in hepatocellular carcinoma from an Australian population. 904 4

The tumor suppressor genes p53, retinoblastoma (RB), p16, and p15 encode proteins that regulate the cell cycle cooperatively by controlling the transition from G1 to S phase and may play an important role in cell growth and differentiation. To screen for abnormalities in these genes in cancer, we performed genetic analysis in six human pancreatic cancer and five hepatoma cell lines, by single-strand conformation polymorphism (SSCP) analysis, direct sequencing, and the reverse transcriptase-polymerase chain reaction (RT-PCR). All six pancreatic cancer cell lines had p53 mutations, with the concomitant loss of the other normal allele, encoding wild-type p53. Frequent homozygous deletions were found in p16 and p15, but the RB gene was expressed. Four of the five hepatoma cell lines had p53 mutations with loss of the normal allele and aberrant RB. There were no deletions of p16 and p15 in any of the hepatoma cell lines. These findings suggest that alterations in the p53, p16, and p15 genes are common in human pancreatic cancer cell lines, while p53 or RB mutations are common in hepatoma cell lines. Alterations of these tumor suppressor genes may thus be important features in organ-specific carcinogenesis.
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PMID:Alterations in the tumor suppressor genes p53, RB, p16/MTS1, and p15/MTS2 in human pancreatic cancer and hepatoma cell lines. 905 94

In cycling cells, the retinoblastoma protein (pRb) is un- and/or hypo-phosphorylated in early G1 and becomes hyper-phosphorylated in late G1. The role of hypo-phosphorylation and identity of the relevant kinase(s) remains unknown. We show here that hypo-phosphorylated pRb associates with E2F in vivo and is therefore active. Increasing the intracellular concentration of the Cdk4/6 specific inhibitor p15(INK4b) by transforming growth factor beta treatment of keratinocytes results in G1 arrest and loss of hypo-phosphorylated pRb with an increase in unphosphorylated pRb. Conversely, p15(INK4b)-independent transforming growth factor beta-mediated G1 arrest of hepatocellular carcinoma cells results in loss of Cdk2 kinase activity with continued Cdk6 kinase activity and pRb remains only hypo-phosphorylated. Introduction of the Cdk4/6 inhibitor p16(INK4a) protein into cells by fusion to a protein transduction domain also prevents pRb hypo-phosphorylation with an increase in unphosphorylated pRb. We conclude that cyclin D:Cdk4/6 complexes hypo-phosphorylate pRb in early G1 allowing continued E2F binding.
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PMID:Hypo-phosphorylation of the retinoblastoma protein (pRb) by cyclin D:Cdk4/6 complexes results in active pRb. 938 Jun 98

CDKN2A (p16INK4A/MTS1) and CDKN2B (p15INK4B/MTS2) have recently been shown to be potent inhibitors of the cyclin D/cyclin-dependent kinase-4 complex. Both genes are candidates for the putative tumour suppressor genes located at chromosome 9p21 and are frequently inactivated in many human cancers through homozygous deletion. More recently, another reported pathway of inactivation involves loss of transcription associated with de novo methylation of the 5' CpG island of p16/MTS1 and p15/MTS2 in human cancers. We examined a total of 34 tumours from 30 hepatocellular carcinoma (HCC) patients for deletion, mutation and DNA methylation of these two genes by polymerase chain reaction (PCR) amplification, sequence analysis and Southern blot. Homozygous deletions of P16/MTS1 exon 1 were only identified in 1 of 30 cases (3%). Homozygous deletions of p15 exon 1 or exon 2 were found in 7 of 30 cases (13%). Automated sequencing analysis of p16 exon 1 and 2 and p15 exon 1 and 2 failed to demonstrate mutations in either p16 or p15 in any of these specimens. No aberrant 5' CpG island hypermethylation of p16 or p15 was found in any of the primary tumours by Southern blot. These data suggest that the p16/MTS1 gene has a limited role in HCC. However, deletions of the p15/MTS2 gene are found in 13% HCC and might be involved in a subset of HCC.
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PMID:Infrequent mutations and no methylation of CDKN2A (P16/MTS1) and CDKN2B (p15/MTS2) in hepatocellular carcinoma in Taiwan. 989 70

Hepatocellular carcinoma (HCC) is a common malignancy worldwide and highly associated with chronic virus-B or -C infection and cirrhosis. Molecular studies have shown high frequency of loss of heterozygosity (LOH) in some specific chromosome regions, but LOH on chromosome 9 in HCC has not been thoroughly investigated. In our investigation of chromosome 9 with 19 polymerase-chain-reaction (PCR)-based polymorphic microsatellite markers, 30 of 48 HCC tissue samples (63%) had LOH, and a distinct common deletion region and a region of loss were identified. The first region was located at the 9p21 region and the minimal deletion region was located between loci D9S1747 and D9S1748. This is a region of approximately 200 kb which includes the p16 tumor-suppressor gene. A region of loss was located on 9p13 to 9q33. The putative tumor-suppressor gene for nevoid-basal-cell-carcinoma syndrome (NBCCS) at 9q22.3 resides within this region. In addition to LOH, 4 HCC cases showed possible homozygous deletions at 9p21 with markers D9S1748, D9S1752 and D9S171 by multiplex PCR analysis. In 3 cases, the minimal region of possible homozygous deletion was approximately 300 kb and was defined between markers D9S1747 and D9S1752. Since this deletion region includes both the p15 and the p16 tumor-suppressor genes, these genes were possibly inactivated by homozygous deletion in HCC. In addition, a second region of possible homozygous deletion was present on the centromeric side of 9p21. However, these changes are not associated with age, gender, size or tumor-cell differentiation. Our data also suggest that inactivation of the p16 and the p15 genes and the possibility of other unknown tumor-suppressor genes located on these defined deleted regions of chromosome 9 may be involved in the pathogenesis of HCC.
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PMID:Frequent allelic loss on chromosome 9 in hepatocellular carcinoma. 1020 42

Transforming growth factor beta (TGF-beta)-mediated G(1) arrest previously has been shown to specifically target inactivation of cyclin D:cyclin-dependent kinase (Cdk) 4/6 complexes. We report here that TGF-beta-treated human HepG2 hepatocellular carcinoma cells arrest in G(1), but retain continued cyclin D:Cdk4/6 activity and active, hypophosphorylated retinoblastoma tumor suppressor protein. Consistent with this observation, TGF-beta-treated cells failed to induce p15(INK4b), down-regulate CDC25A, or increase levels of p21(CIP1), p27(KIP1), and p57(KIP2). However, TGF-beta treatment resulted in the specific inactivation of cyclin E:Cdk2 complexes caused by absence of the activating Thr(160) phosphorylation on Cdk2. Whole-cell lysates from TGF-beta-treated cells showed inhibition of Cdk2 Thr(160) Cdk activating kinase (CAK) activity; however, cyclin H:Cdk7 activity, a previously assumed mammalian CAK, was not altered. Saccharomyces cerevisiae contains a genetically and biochemically proven CAK gene, CAK1, that encodes a monomeric 44-kDa Cak1p protein unrelated to Cdk7. Anti-Cak1p antibodies cross-reacted with a 45-kDa human protein with CAK activity that was specifically down-regulated in response to TGF-beta treatment. Taken together, these observations demonstrate that TGF-beta signaling mediates a G(1) arrest in HepG2 cells by targeting Cdk2 CAK and suggests the presence of at least two mammalian CAKs: one specific for Cdk2 and one for Cdk4/6.
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PMID:Transforming growth factor beta targeted inactivation of cyclin E:cyclin-dependent kinase 2 (Cdk2) complexes by inhibition of Cdk2 activating kinase activity. 1061 20

To investigate the role p15 gene plays in the pathogenesis of human primary hepatocarcinoma, 35 human hepatocarcinomas, 35 cases of adjacent non-cancerous liver cirrhosis and the blood cells of 10 normal human were analyzed for somatic mutation in p15 gene with PCR-SSCP. One case of adjacent non-cancerous liver cirrhosis showed abnormal migration single strand. In the hepatocarcinomas and in the other cases of adjacent non-cancerous liver cirrhosis, no mutation was found. Cloning and sequencing of the amplified abnormal migration single strand DNA revealed that it contained a wild type exon 2 of p15 gene in 345 bp length. The results indicate that the inaction of p15 gene by point mutation is a very uncommon event in human hepatocarcinoma.
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PMID:[Mutation analysis of the p15 gene exon 2 in human primary hepatocarcinoma]. 1074 27

We prospectively analyzed p15 methylation patterns in 25 surgically resected tumors and 130 plasma, serum, and buffy coat samples from hepatocellular carcinoma (HCC) patients, controls with chronic hepatitis/cirrhosis, and healthy subjects. Using methylation-specific PCR, we demonstrated for the first time p15 promoter methylation in 64% of tumors and 25% (4 of 16) of patients' plasma and serum samples. Concurrent p15 and p16 methylation was shown in 48% of tumors, and p15/p16 methylation was detected in the plasma/serum of 92% (11 of 12) of patients. Of note, 75% of 12 patients with concurrent tumor methylation developed clinical metastasis/recurrence (P = 0.027). In buffy coat samples, p15 methylation was detected in all eight patients with tumor p15 methylation, suggesting the presence of circulating tumor cells. None of the control samples were methylation positive. Our data underscore the important role(s) of p15 and p16 methylation in hepatocarcinogenesis and tumor progression. Among 92% (23 of 25) of patients with tumor p15/p16 methylation, circulating tumor DNA and HCC cells were detected in the peripheral blood of 87% (20 of 23) of patients. The combination of these epigenetic markers may prove valuable for noninvasive HCC diagnosis and disease monitoring.
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PMID:Frequent p15 promoter methylation in tumor and peripheral blood from hepatocellular carcinoma patients. 1099 38

This paper provides a review of the known genetic diagnostic indicators of liver cancer. The correlation between the genetic diagnosis and clinical outcome in patients with hepatocellular carcinoma (HCC) has been widely reported, based on the detection of liver-specific mRNA or tumor DNA in the blood. Our results suggest that an alteration of alpha-fetoprotein (AFP) mRNA in peripheral blood from HCC patients during the perioperative period might permit the prediction of early recurrence after surgery. The presence of circulating HCC cells may be indicative of metastasis if liver-specific AFP mRNA is detected in the peripheral blood. However, some studies showed that sensitive RT-PCR might possibly give rise to false positivity because nontumor hepatocytes would also express low levels of AFP mRNA. Recently, quantification of AFP mRNA for HCC cell detection using real-time PCR or semiquantitative RT-PCR has proven useful in the prediction of metastasis/recurrence. On the other hand, circulating liver tumor DNA such as p16 and p15 methylation and mitochondrial mutations in the plasma and serum of liver cancer patients might be useful for monitoring, similar to the tumor markers. In future, HCC-specific genes and genes sensitive to radiation and chemotherapy are expected to have wide-spread clinical applications.
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PMID:[Genetic detection and clinical applications in patients with hepatocellular carcinoma]. 1209 98


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