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)

We investigated expression of insulin-like growth factor II (Igf2) in primary cultured hepatocytes, liver epithelial (LE) cell lines derived from normal hepatocytes, and hepatocellular carcinoma (HCC) cell lines from crosses between C3H/HeJ (C3H) and Mus musculus molossinus mice (MSM). Igf2 mRNA was detected by reverse transcriptase-polymerase chain reaction in primary cultured hepatocytes from 5 d after the start of cultivation and in all 12 LE and 16 HCC cell lines. Analysis of the untranslated region of Igf2 exon 6, which contains polymorphic CA repeats, revealed that 13 of the 16 HCC cell lines had biallelic expression, whereas monoallelic expression was retained in the primary cultured hepatocytes and all 12 LE cell lines. The Igf2 transcripts contained exons 1-3 in all the HCC cell lines but only exons 2 and 3 in cultures of hepatocytes and LE cell lines, indicating difference in promoter use. However, the biallelic HCC cell lines did not have larger amounts of Igf2 mRNA and protein than did the monoallelic lines, suggesting that loss of imprinting may not be directly related to the level of Igf2 expression.
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PMID:Loss of imprinting of the insulin-like growth factor II gene in mouse hepatocellular carcinoma cell lines. 986 54

The soluble form of the insulin-like growth factor II/mannose 6-phosphate (IGF-II/M6-P) receptor has been detected in serum from a variety of mammalian species. We report the development of a highly sensitive quantitative human IGF-II/M6-P receptor immunoassay. Antibodies raised to receptor purified from a human hepatoma cell line by phosphomannan affinity chromatography were used to develop a specific enzyme-linked immunosorbent assay. In this assay, the serum level of soluble receptor for healthy adult subjects was 0.70 +/- 0.23 mg/L. We have shown that soluble receptor is developmentally regulated, with levels in infant (1.12 +/- 0.28 mg/L) and prepubertal (1.18 +/- 0.6 mg/L) subjects dropping by 40% during adolescence (0.73 +/- 0.61 mg/L) and remaining constant throughout adulthood. Further, the receptor is gestationally regulated, with a highly significant association between gestational age and maternal serum receptor levels (r = 0.947; P < 0.0001). Noninsulin-dependent diabetes mellitus (0.98 +/- 0.25 mg/L) and insulin-dependent diabetes mellitus (0.98 +/- 0.25 mg/L) mildly elevated soluble receptor levels, whereas end-stage renal failure (0.75 +/- 0.23 mg/L) and acromegaly (0.79 +/- 0.25 mg/L) did not affect receptor levels. Additionally, we have shown that soluble receptor is present in amniotic fluid, but at a 100-fold lower concentration than serum levels. The ability to quantitate soluble IGF-II/M6-P receptor levels in serum and other fluids provides a valuable tool that will help to further elucidate the role of the receptor in human physiology and disease states.
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PMID:Regulation of soluble insulin-like growth factor II/mannose 6-phosphate receptor in human serum: measurement by enzyme-linked immunosorbent assay. 1002 25

The purpose of this paper was to study the mechanism of synergistic effect in hepatocarcinogenesis induced by hepatitis B virus (HBV) infection and aflatoxin B1 (AFB1) intake. Immunohistochemical staining was used in formalin-fixed, paraffin-embedded sections of cancer and liver tissues. The incidence of hepatocellular carcinomas (HCCs) was 52.9% in experimental tree shrews that received both HBV and AFB1. It was significantly higher than that of animals exposed to HBV (11.1%, Group B), or (AFB1) (15.8%, group C) alone. HCC was not found in the control animals (group D). The expressions of insulin-like growth factor II (IGF-II) were 82.4%, 22.2%, 26.3% and 0 in groups A, B, C and D, respectively. The significant differences of IGF-II were observed between groups A and B, C and D (P < 0.05). The expressions of p21 were 29.4%, 11.1%, 15.8% and 0 in group A, B, C and D, respectively. The positive rate of hepatitis B x antigen (HbxAg) was significantly higher in the group A than that in the group B (52.9% vs. 11.1%, P < 0.05). The parallel relations between the incidence of HCC and the overexpressions of these genes protein have been found in each group. On the other hand, the expressions of these genes in tumour-bearing tree shrews were significantly higher than that in nontumour-bearing animals. These findings suggest a synergistic effects of HBV and AFB1 in activation of these genes in tree shrews. Overexpressions of these genes may take an important role in the course of hepatocarcinogenesis in tree shrews.
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PMID:The expression of insulin-like growth factor II, hepatitis B virus X antigen and p21 in experimental hepatocarcinogenesis in tree shrews. 1037 27

The soluble form of the insulin-like growth factor II (IGF-II)/mannose 6-P (IGF-II/M6P) receptor is released by cells in culture and circulates in the serum. It retains its ability to bind IGF-II and blocks IGF-II-stimulated DNA synthesis in isolated rat hepatocytes. Because these cells are not normally stimulated to divide by IGF-II in vivo, the effect of soluble IGF-II/M6P receptor on DNA synthesis has been further investigated in two cell lines sensitive to IGF-II; mouse 3T3(A31) fibroblasts, stimulated by low levels of IGF-II following priming by epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) and Buffalo rat liver (BRL) cells, which secrete IGF-II and proliferate in the absence of exogenous growth factors. Soluble IGF-II/M6P receptor (0.2-2.0 microgram/ml) purified from a rat hepatoma cell line inhibited DNA synthesis (determined by dThd incorporation) in both cell lines. Basal DNA synthesis was very low in serum-free 3T3 cells, but high in serum-free BRL cells, possibly as a result of autocrine IGF-II production. The inhibitory effect was reversible in cells preincubated with soluble receptor prior to incubation with growth factors and could also be overcome by excess IGF-II. Soluble receptor was more potent in IGF-II-stimulated 3T3 cells and serum-free BRL cells than in BRL cells incubated with serum. Mean inhibition by four preparations of soluble receptor (1 microgram/ml) was 34.7% +/- 4.4% in BRL cells stimulated with fetal calf serum (FCS) (5%) compared to 54.8% +/- 4.2% in serum-free BRL cells (P = 0.05) and 60.6% +/- 6.5% (P = 0.02) in 3T3 cells stimulated by PDGF, EGF, and IGF-II. Soluble receptor had no effect on DNA synthesis in 3T3 cells stimulated with IGF-I. These results demonstrate that soluble receptor, at physiological concentrations, can block proliferation of cells by IGF-II and could therefore play a role in blocking tumor growth mediated by IGF-II.
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PMID:Soluble insulin-like growth factor II/mannose 6-phosphate receptor inhibits DNA synthesis in insulin-like growth factor II sensitive cells. 1056 17

Aflatoxin B1 (AFB1) induced mutation of the p53 gene at codon 249 (p53mt249) is critical during the formation of hepatocellular carcinoma (HCC) following hepatitis B virus (HBV) infection. p53mt249 markedly increases insulin-like growth factor II (IGF-II) transcription largely from promoter 4, accumulating the fetal form of IGF-II. Modulation of the transcription factor binding to IGF-II P4 by wild-type p53 and p53mt249 was identified. Wild-type p53 inhibited binding of transcription factors Sp1 and TBP on the P4 promoter, while p53mt249 enhanced the formation of transcriptional complexes through enhanced DNA-protein (Sp1 or TBP) and protein-protein (Sp1 and TBP) interactions. p53mt249 stimulates transcription factor Sp1 phosphorylation which might be a cause of increased transcription factor binding on the P4 promoter while wild-type p53 does not. Transfection of hepatocytes with p53mt249 impaired induction of apoptosis by the HBV-X protein and TNF-alpha. Therefore, the blocking of apoptosis through enhanced production of IGF-II should provide a favorable opportunity for the selection of transformed hepatocytes. These results explain the molecular basis for the genesis of HCC by p53mt249 which was found to be induced by a potent mutagen, AFB1.
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PMID:Activation of the insulin-like growth factor II transcription by aflatoxin B1 induced p53 mutant 249 is caused by activation of transcription complexes; implications for a gain-of-function during the formation of hepatocellular carcinoma. 1094 25

The possibility that hepatitis C virus core gene product (HCV-core) acts as a transactivator in insulin-like growth factor II (IGF-II) gene transcription was tested. HCV-core protein increases endogenous IGF-II expression from promoter 4 (P4) of the IGF-II gene through two cis-acting elements: Sp1 and Egr1 binding sites. Sp1 and Egr1 both bind to IGF-II P4 and functionally cooperate in mediating the maximal activity of IGF-II P4. HCV-core protein induced the binding of Sp1 and Egr1 on its binding sites on IGF-II P4. In addition, Sp1 and Egr1 were stimulated to phosphorylate by HCV-core, and its DNA binding activity was up-regulated upon HCV-core transfection. Transfection with HCV-core in HepG2 cells stimulated the membrane translocation of protein kinase C (PKC) and the treatment of HCV-core transfected cells with calphostin C, a PKC inhibitor, blocked induction of Sp1 and Egr1 DNA binding activity, and eventually transcriptional transactivations of the IGF-II gene. Increasing the DNA binding activity of the phosphorylated form of Sp1 and Egr1 might be an important mechanism for regulating IGF-II gene expression and for promoting cell division during hepatic carcinogenesis. These results indicate that HCV-core functions as a positive regulator of IGF-II transcription through the PKC pathway and that Sp1 and Egr1 are direct targets of the transcriptional regulation of the IGF-II gene which plays an important role in hepatitis C virus pathogenesis during the formation of hepatocellular carcinoma (HCC).
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PMID:Hepatitis C virus core protein transactivates insulin-like growth factor II gene transcription through acting concurrently on Egr1 and Sp1 sites. 1133 42

A feature of hepatocellular carcinoma (HCC) is that antecedent liver cirrhosis and chronic hepatitis are common precursor conditions and during transition to malignancy some patients develop autoantibodies which were not present during the preceding chronic liver disease phase. Serum samples from such patients can be used to immunoscreen cDNA expression libraries to identify genes encoding the new autoantigens. We demonstrate here the de novo appearance of antibodies to p62, a cytoplasmic protein which has been shown to bind to a developmentally regulated fetal species of insulin-like growth factor II (IGF-II) mRNA. Another antibody appearing during the transition period was against CENP-F, a cell cycle-related nuclear protein with maximum expression in the G2 and M phases of the cell cycle and previously shown to have a high association with malignancy. In three additional patients in whom serial serum samples were examined, new appearance of anti-p62 was detected in two patients and anti-CENP-F in one patient. This study demonstrates that transition to malignancy can be associated with autoantibody responses to certain cellular proteins which might have some role in tumorigenesis.
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PMID:De-novo humoral immune responses to cancer-associated autoantigens during transition from chronic liver disease to hepatocellular carcinoma. 1147 19

p62 is a RNA-binding protein that was isolated by immunoscreening a cDNA expression library with autoantibodies from patients with hepatocellular carcinoma (HCC). This autoantigen binds to mRNA encoding insulin-like growth factor II, which has been found to be overexpressed in HCC and is tumorigenic in transgenic animals. Immunohistochemical analysis of HCC liver showed that 33% (9 of 27) exhibited readily detectable staining of p62 protein in the cytoplasm of all malignant cells in cancer nodules, whereas it was undetectable in adjacent nonmalignant liver cells. In addition one of two patients with cholangiocarcinoma expressed p62 in malignant bile duct epithelial cells. p62 expression was also detected in scattered cells in cirrhotic nodules in contrast to uniform expression in all cells in HCC nodules. In HCC nodules, p62 mRNA was also detected by reverse transcriptase-polymerase chain reaction analysis. Nine normal adult livers did not contain detectable p62 mRNA or p62 protein whereas five fetal livers were all positive for mRNA and protein. The observations show that p62 is developmentally regulated, expressed in fetal, but not in adult liver, and aberrantly expressed in HCC and could be playing a role in abnormal cell proliferation in HCC and cirrhosis by modulating expression of growth factors such as insulin-like growth factor II.
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PMID:Aberrant expression of fetal RNA-binding protein p62 in liver cancer and liver cirrhosis. 1154 87

During a search for trans-acting factors associating with insulin-like growth factor II (IGF-II) mRNAs, we recently identified a family of three IGF-II mRNA-binding Proteins (IMP1, IMP2 and IMP3) that exhibit multiple attachments to IGF-II leader 3 mRNA and the reciprocally imprinted H19 RNA. IMPs contain the unique combination of two RNA recognition motifs (RRMs) and four hnRNP K homology (KH) domains. IMP1 is orthologous to the chicken zipcode-binding protein (ZBP-1), and the mouse c-myc coding region determinant-binding protein (CRD-BP) that associates with beta-actin and c-myc mRNA, respectively. Moreover, the p62 protein identified in hepatocellular carcinoma represents a splice variant of IMP2, and IMP3 is orthologous to the Xenopus Vegetal 1 RNA-binding protein (Vgl-RBP/Vera). IMPs are produced in a biphasic fashion--initially during the early stages of embryogenesis and subsequently later in development. IMPs and their orthologues are predominantly cytoplasmic and are implicated in the transport of their RNA targets towards the leading edge in somatic cells and to the vegetal pole in Xenopus oocytes, respectively. RNA localization is a conserved mechanism of polarizing genetic information in the establishment of asymmetries during both embryogenesis and adult life, enabling local protein synthesis at final destinations within the cell. The identification of developmentally expressed zipcode-binding proteins indicates that RNA trafficking participates in processes such as cell-growth and migration during embryogenesis.
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PMID:A family of IGF-II mRNA binding proteins (IMP) involved in RNA trafficking. 1171 86

Hepatitis B virus (HBV) is a hepatotropic virus that causes acute and chronic hepatocellular injury and hepatocellular carcinoma. To clarify how HBV proteins regulate host cellular gene expression, we used our in-house cDNA microarray and HepG2.2.15 cells, which are derived from HepG2 cells and produce all HBV proteins. Of 2304 genes investigated, several genes were differentially expressed in HepG2.2.15 cells compared with HepG2 cells. These genes included insulin-like growth factor II and alpha-fetoprotein, consistent with previous reports. Furthermore, we previously performed similar microarray analyses to clarify the effects of hepatitis C virus (HCV) proteins on host cells, using a HepG2-derivative cell line, which produces all HCV proteins. Using these two microarray results, we compared the differences in cellular gene expression induced by HBV and HCV proteins. The expression of the majority of genes investigated differed only slightly between HBV and HCV protein-producing cells. However, HBV and HCV proteins clearly regulated several genes in a reciprocal manner. Combined, these microarray results shed new light on the effects of HBV proteins on cellular gene expression and on the differences in the pathogenic activities of these two hepatitis viruses.
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PMID:Differential cellular gene expression induced by hepatitis B and C viruses. 1250 4


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