UMLS:C0019204 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of studies have shown that various vitamins K, specifically vitamin K2, possessed antitumor activity on various types of rodent- and human-derived neoplastic cell lines. However, there are only a small number of reports demonstrating in vivo antitumor effects of vitamins K. Furthermore, the mechanism of antitumor effects of vitamins K still remains to be examined. In the present study, we examined the antitumor effects of vitamins K2, K3 and K5 on PLC/PRF/5 human hepatocellular carcinoma (HCC) cells in vivo. Furthermore, to examine the mechanism of antitumor actions of these vitamins K, mRNA expression levels of various G1 phase-related cell cycle molecules were evaluated by using a real-time reverse transcription-polymerase chain reaction (RT-PCR) method. HCC-bearing animals were produced by implanting PLC/PRF/5 cells subcutaneously into athymic nude mice, and drinking water containing vitamin K2, K3 or K5 was given to the animals. Treatments with vitamins K2, K3 and K5 were shown to markedly inhibit the growth of HCC tumors. To examine the mechanism of in vivo antitumor effects of vitamins K, total RNA was extracted from HCC tumors, and the expression of G1 phase-related cell cycle molecules was quantitatively examined. Real-time RT-PCR demonstrated that the expression of the cell cycle-driving molecule, cyclin-dependent kinase 4 (Cdk4), in HCC was significantly reduced by the treatments with vitamin K2, K3 and K5. Conversely, the expression of the cell cycle-suppressing molecules, Cdk inhibitor p16INK4a and retinoblastoma, in HCC was significantly enhanced by the treatments with vitamins K2, K3 and K5. These results indicate that vitamins K2, K3 and K5 exert antitumor effects on HCC by regulating the expression of G1 phase-related cell cycle molecules. These results also indicate that vitamins K2, K3 and K5 may be useful agents for the treatment of patients with HCC.
...
PMID:Vitamins K2, K3 and K5 exert in vivo antitumor effects on hepatocellular carcinoma by regulating the expression of G1 phase-related cell cycle molecules. 1601 Apr 34

Reports elsewhere demonstrated that Epimedin C, a constituent isolated from the leaves of Epimedium sagittatum, possessed anti-tumor activity. However, its mechanism of action remains unresolved. Using SK-Hep-1 cells, a poorly-differentiated hepatoma subline, as an experimental model, we present evidence here that the anti-tumor activity of Epimedin C may involve cell cycle blockage. Immunoblotting analyses demonstrated that Epimedin C caused a decreased expression of hyperphosphorylated retinoblastoma (Rb) protein, cyclin D1, c-Myc, and c-Fos. In parallel, we measured the kinase activities and found that CDK2 and CDK4 were suppressed with commensurate increased levels of CDK inhibitors, p21(Cip1) and p27(Kip1). These data suggested that Epimedin C arrested the proliferation of these cells at G0/G1 phase through inhibition of CDK2 and CDK4 activities via an increased induction of p21(Cip1) and p27(Kip1). Alternatively, we investigated whether the anti-proliferative effect of Epimedin C on these cells might involve MAP kinase cascade. Using western blotting technique, we demonstrated that Epimedin C also selectively decreased ERK1/2 phosphorylation. Among the downstream effectors of ERK examined, we found that Epimedin C selectively decreased the expression of c-Fos, but not c-Jun. By EMSA assay, we further demonstrated that decreased c-Fos resulted in the downregulation of AP-1/DNA binding activity. Taken together, the molecular mechanisms of anti-tumor activity of Epimedin C may be proceeded by the combined effects of the cell cycle blockage via either the inhibition of CDK2 and CDK4 activities, with commensurate increase in their inhibitors, p21(Cip1) and p27(Kip1) or negatively modulates the ERK/c-Fos/AP-1 signaling pathway.
...
PMID:Molecular mechanism of cell cycle blockage of hepatoma SK-Hep-1 cells by Epimedin C through suppression of mitogen-activated protein kinase activation and increased expression of CDK inhibitors p21(Cip1) and p27(Kip1). 1611 86

Insulin-like growth factor binding protein-3 (IGFBP-3) is a mediator of growth suppression signals and a putative tumor suppressor gene. The growth suppression mechanisms of IGFBP-3 have not been well clarified. We examined the expression of IGFBP-3 transcripts in human hepatocellular carcinoma (HCC) and the relationship between IGFBP-3 expression and the transforming growth factor-beta (TGF-beta) and/or retinoblastoma (Rb) signaling pathways. In situ hybridization revealed IGFBP-3 transcripts in cancer cells in 6 of 57 (10%) HCCs, including moderately and poorly differentiated HCCs with intrahepatic metastasis. In contrast, all lung metastatic nodules of 4 HCCs showed IGFBP-3 transcripts in cancer cells. The cDNA microarray showed that genes for the TGF-beta pathway and Rb were up-regulated in IGFBP-3-expressing HCCs. In 6 HCCs presenting IGFBP-3, immunohistochemical analyses showed abnormalities in the TGF-beta and/or Rb pathways; the loss of phosphorylated-Smad2 was observed in 2, and overexpression of phosphorylated-Rb was observed in the remaining 4 HCCs. The present study suggests that IGFBP-3 mediates growth suppression signals via the TGF-beta and/or Rb pathways in HCC.
...
PMID:IGFBP-3 expression in hepatocellular carcinoma involves abnormalities in TGF-beta and/or Rb signaling pathways. 1621 Dec 16

The biological significance of hypermethylation of p16 gene promoter in human hepatocellular carcinoma (HCC) cells remains to resolved. In order to clarify the significance of methylation of p16 gene promoter, we examined the methylation status of p16 gene in association with phosphorylation of retinoblastoma gene product (pRb) and cell growth in human HCC cell lines. The presence of methylation was examined by methylation-specific PCR. Expression and phosphorylation of p16 and pRb were examined by Western blot analysis. Genetic changes were analyzed by multiplex PCR and DNA sequencing. The effect of demethylation of p16 was assessed by cell growth. p16 gene promoter was methylated in HuH7 and HLF cells. The demethylating agent, 5-aza-2-deoxycytidine (5-Aza-CdR), upregulated p16 mRNA in HuH6 and HuH7 cells. 5-Aza-CdR increased p16 protein expression in HuH6, HuH7, and HLF cells, and it clearly decreased the phosphorylation level of pRb in HuH6, HuH7 and PLC/PRF/5 cells. Treatment with 5-Aza-CdR inhibited the growth of HuH7 cells. Homozygous deletion and significant mutations were absent. Methylation in the p16 promoter region is biologically significant, being associated with phosphorylation of pRb and cell growth in human HCC cells.
...
PMID:Effect of promoter methylation of the p16 gene on phosphorylation of retinoblastoma gene product and growth of hepatocellular carcinoma cells. 1625 59

HBx and MHBst products from hepatitis B virus-DNA (HBV-DNA), which become transcriptional transactivators of cellular and viral genes, are known to play causative roles in the development of hepatocellular carcinoma (HCC). However, the biomolecular mechanism(s) for their roles in hepatocarcinogenesis in vivo remain poorly understood. To identify authentic cellular genes involved in HBx and MHBst-transactivated carcinogenesis,we used mRNA differential display polymerase chain reaction (DD-PCR). We examined HBx and MHBs-positive or -negative HCC, which had chromosomally integrated HBV DNA, vs nontumor tissues, respectively, and differentially expressed genes in either type of HCC were identified and compared with each other. Using 240 different combinations of three one-base anchored oligo-dT primers and 80 arbitrary 13mers, 16 genes were differentially expressed in the HBx and MHBs-positive HCC including RoRNA hY1, glutamine synthetase, factor H homologue 3' end, voltage-dependent anionc hannel 3 (VDAC3), three ribosomal proteins, four mitochondrial genes, and four novel genes. Unexpectedly, upregulated genes in association with functional HBV proteins were different from those reportedly transactivated by HBV viral proteins in vitro. Ten genes were downregulated, including three novel genes. In contrast, 15 genes in HCC tissue negative for HBx and MHBs-expression were preferentially expressed including pancreatic secretory trypsin inhibitor (PSTI), H19, guanidine nucleotide-binding protein alpha-1 subunit (GNAZ), carbamyl phosphate synthetase I (CPS I), insulin-like growth factor (IGF)-II, and 10 ribosomal proteins genes. Eighteen genes were downregulated including acute phase genes, a novel gene, and particularly the retinoblastoma susceptibility gene. Only two genes (ribosomal protein P0 and L37a) were commonly upregulated in both types of HCC tissues. These results suggest that cellular genes involved in the viral protein-transactivation may generally differ from those not associated with transactivation in established HCC, and that the specific oncogenic coordination through the transactivation by viral proteins which works in experiments in vitro, may play only a potential role in hepatocarcinogenesis in vivo. In addition, the functional analyses of the eight novel genes identified in this study might be valuable to further understand the mechanism(s) of hepatocarcinogenesis.
...
PMID:Differentially expressed genes associated with hepatitis B virus HBx and MHBs protein function in hepatocellular carcinoma. 1626 27

The ubiquitous transcription factor Yin Yang 1 (YY1) is known to have a fundamental role in normal biologic processes such as embryogenesis, differentiation, replication, and cellular proliferation. YY1 exerts its effects on genes involved in these processes via its ability to initiate, activate, or repress transcription depending upon the context in which it binds. Mechanisms of action include direct activation or repression, indirect activation or repression via cofactor recruitment, or activation or repression by disruption of binding sites or conformational DNA changes. YY1 activity is regulated by transcription factors and cytoplasmic proteins that have been shown to abrogate or completely inhibit YY1-mediated activation or repression; however, these mechanisms have not yet been fully elucidated. Since expression and function of YY1 are known to be intimately associated with progression through phases of the cell cycle, the physiologic significance of YY1 activity has recently been applied to models of tumor biology. The majority of the data are consistent with the hypothesis that YY1 overexpression and/or activation is associated with unchecked cellular proliferation, resistance to apoptotic stimuli, tumorigenesis and metastatic potential. Studies involving hematopoetic tumors, epithelial-based tumors, endocrine organ malignancies, hepatocellular carcinoma, and retinoblastoma support this hypothesis. Molecular mechanisms that have been investigated include YY1-mediated downregulation of p53 activity, interference with poly-ADP-ribose polymerase, alteration in c-myc and nuclear factor-kappa B (NF-kappaB) expression, regulation of death genes and gene products, and differential YY1 binding in the presence of inflammatory mediators. Further, recent findings implicate YY1 in the regulation of tumor cell resistance to chemotherapeutics and immune-mediated apoptotic stimuli. Taken together, these findings provide strong support of the hypothesis that YY1, in addition to its regulatory roles in normal biologic processes, may possess the potential to act as an initiator of tumorigenesis and may thus serve as both a diagnostic and prognostic tumor marker; furthermore, it may provide an effective target for antitumor chemotherapy and/or immunotherapy.
...
PMID:Transcription factor YY1: structure, function, and therapeutic implications in cancer biology. 1631 46

The retinoblastoma tumor-suppressor protein (Rb) plays a critical role in controlling cellular proliferation and apoptosis by regulating E2F transcription factors. Rb is a key target of oncoproteins expressed by DNA tumor viruses, but RNA viruses are not known to regulate Rb function. Here, we show that Rb abundance is negatively regulated in cells containing replicating genomic RNA from hepatitis C virus, a human virus strongly associated with hepatocellular carcinoma. The viral RNA-dependent RNA polymerase NS5B forms a complex with Rb, targeting it for degradation and resulting in reduction of Rb abundance, activation of E2F-responsive promoters, and cell proliferation. NS5B contains a conserved Leu-x-Cys/Asn-x-Asp motif that is homologous to Rb-binding domains in the oncoproteins of DNA viruses. This domain overlaps the polymerase active site, and mutations within it abrogate Rb binding and reverse the effects of NS5B on E2F promoter activation and cell proliferation. These findings suggest a unique link between an oncogenic RNA virus implicated in the development of liver cancer and a critically important tumor-suppressor protein.
...
PMID:Down-regulation of the retinoblastoma tumor suppressor by the hepatitis C virus NS5B RNA-dependent RNA polymerase. 1633 62

Thyroid hormone (triiodothyronine, T3) regulates growth, development and differentiation. To examine the influence of T3 on hepatoma cell growth, thyroid receptor (TR)alpha1 or TRbeta1 over-expressing HepG2 cell lines were used. Growth of the HepG2-TR stable cell line was inhibited by over 50% following treatment with T3. However, transforming growth factor (TGF)-beta neutralizing antibody, but not the control antibody can reverse the cell growth inhibition effect of T3. Flow cytometric analysis indicated that the growth inhibition was apparent at the transition point between the G1 and S phases of the cell cycle. The expression of major cell cycle regulators was used to provide further evidence for the growth inhibition. Cyclin-dependent kinase 2 (cdk2) and cyclin E were down-regulated in HepG2-TR cells. Moreover, p21 protein or mRNA levels were up-regulated by around 5-fold or 7.3-fold respectively following T3 treatment. Furthermore, phospho-retinoblastoma (ppRb) protein was down-regulated by T3. The expression of TGF-beta was studied to delineate the repression mechanism. TGF-beta was stimulated by T3 and its promoter activity was enhanced six- to eight-fold by T3. Furthermore, both T3 and TGF-beta repressed the expression of cdk2, cyclin E and ppRb. On the other hand, TGF-beta neutralizing but not control antibody blocked the repression of cdk2, cyclin E and ppRb by T3. These results demonstrated that T3 might play a key role in liver tumor cell proliferation.
...
PMID:Mediation of the inhibitory effect of thyroid hormone on proliferation of hepatoma cells by transforming growth factor-beta. 1646 23

The p16 protein is a cyclin-dependent kinase (CDK) inhibitor, which plays an important role in the regulation of the cell cycle by inactivating the cyclin-dependent kinase (CDK) that phosphorylates the retinoblastoma (Rb) protein. Overexpression of p16 protein has been found in many types of human malignancy. Autoantibody response to p16 in cancer has not been reported. This study determined the extent and frequency of autoantibodies to p16 in diverse malignancies. p16 recombinant protein was expressed in E. Coli BL21 (DE3) cells, and purified using GST fusion protein purification system. In further studies, p16 recombinant proteins were used as antigens in enzyme-linked immunoassay (ELISA) and Western blotting. Sera from 479 cancer patients and 82 normal individuals were analyzed. Autoantibodies to p16 were found in 11.7% in cancer, with significant difference from the normal individuals (p<0.05). The results in this study also showed that the frequency of antibodies to p16 is relatively higher in nasopharyngeal cancer (28.6%), breast cancer (17.1%) and hepatocellular carcinoma (HCC, 21.4%). Of the 56 ELISA positive sera with the anti-p16 antibodies, 85.7% (48/56) had positive reactions in Western blotting. The antigen-antibody absorption experiment was also performed to confirm the specificity of the anti-p16 antibody. In order to increase the frequency of antibody detection in cancer, a combination of three tumor-associated antigens (TAAs) p16, p53 and c-myc were used. Increased frequencies at p<0.01 were found for antibodies to p16 in breast, esophageal, and nasopharyngeal cancer as well as HCC. For antibodies to c-myc, increased frequencies at p<0.01 were found in breast, cervical, colorectal and lung cancer. For antibodies to p53, increased frequencies at p<0.01 were only found in breast cancer. With the successive addition of three TAAs, there was a stepwise increase of positive anti-body reaction up to 44% in breast cancer and 43% in nasopharyngeal cancer. In summary, the results in this study suggest that the combination of antibodies might acquire higher sensitivity for early cancer diagnosis. It is conceivable that auto-antibody profiles involving different panels or arrays of TAAs might be developed in the future and the results could be useful for cancer diagnosis.
...
PMID:Humoral immune response to p16, a cyclin-dependent kinase inhibitor in human malignancies. 1701

The known molecular players in cell-cycle control are much studied, not only to learn more about this intricate system, but also to understand the molecular features of oncogenic transformation. Infrequently, new players are discovered that change the interpretation of cell-cycle control. Gankyrin is one such player and was discovered in yeast two-hybrid screens as a new proteasomal subunit that interacts specifically with the S6b (rpt3) AAA (ATPase associated with various cellular activities) ATPase, which, with five other AAAs, are present in the so-called base of the 19 S regulator of the 26 S proteasome. Gankyrin is also the first liver oncogene. Gankyrin is found in other complexes that contain Rb (retinoblastoma protein) and the ubiquitin protein ligase Mdm2 (murine double minute 2). Gankyrin increases the hyperphosphorylation of Rb and therefore activates E2F-dependent transcription of DNA synthesis genes. Additionally, gankyrin, by binding to Mdm2, increases the ubiquitylation and degradation of p53 and prevents apoptosis. Gankyrin controls the functions of two major tumour suppressors and, when overexpressed, causes hepatocellular carcinoma.
...
PMID:Gankyrin, the 26 S proteasome, the cell cycle and cancer. 1705 88

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>