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)

A patient with liver cirrhosis who progressed to hepatocellular carcinoma was found to develop novel antinuclear antibodies. The serum was used to isolate full-length cDNA clones encoding related proteins of 530 amino acids (representative clone HCC1.4) and 524 amino acids (representative clone HCC1.3). Affinity-purified antibodies eluted from recombinant proteins recognized a 64-kD nuclear protein in Western blotting and decorated the nucleoplasm in a speckled-network fashion in immunofluorescence, colocalizing with antibodies to pre-mRNA splicing factor SC35 and uridine-rich small nuclear RNAs. The deduced amino acid sequence contained an arginine/serine-rich (RS) domain and three-ribonucleoprotein consensus sequence domains, two classes of motifs present in several splicing factors. A repeating octapeptide of Arg-Ser-Arg-Ser-Arg(Lys)-Glu(Asp)-Arg-Lys(Arg) was present in RS region of HCC1. This octapeptide sequence called RS-ERK motif was also found in splicing factors U2AF 35- and 65-kD proteins and 70-kD U1 small nuclear ribonucleoprotein. The molecular features and immunolocalization data suggest that the HCC1 autoantigen may be associated with splicing activities and are consistent with observations that autoantibody responses frequently target molecules involved in important cellular biosynthetic functions.
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PMID:Novel nuclear autoantigen with splicing factor motifs identified with antibody from hepatocellular carcinoma. 822 58

Human 'acute-phase' serum amyloid A protein (A-SAA) is a major acute-phase reactant (APR) and an apolipoprotein of high density lipoprotein 3 (HDL3). We have examined several parameters of A-SAA biosynthesis in PLC/PRF/5 hepatoma cells in response to monocyte conditioned medium (MoCM) and dual treatment with interleukin-1 beta and interleukin-6 (IL-1 beta + IL-6). Treatment of PLC/PRF/5 cells with MoCM or IL-1 beta + IL-6 caused a dramatic and rapid increase in A-SAA mRNA and protein synthesis; A-SAA mRNA was first detectable at 3 h, with peak levels reached by 24 h. A-SAA mRNA accumulation is accompanied by a gradual and homogeneous decrease in the length of the A-SAA poly(A) tail; the poly(A) tail shortening does not apparently affect the intrinsic stability of A-SAA mRNA. Analysis of RNA isolated from the ribonucleoprotein, monosome and polysome fractions of cytokine-treated PLC/PRF/5 cells showed that most A-SAA mRNA was associated with small polyribosomes, regardless of time post-stimulus, suggesting that the translational efficiency of A-SAA mRNA is constant throughout cytokine-driven induction. Moreover, the transit time of A-SAA protein out of the cell is also constant throughout the time course of induction. These data provide evidence of a paradox with regard to the transcriptional upregulation of A-SAA by IL-1 beta + IL-6 and the relative synthesis of A-SAA protein and suggest a role for post-transcriptional control of A-SAA biosynthesis during the acute phase.
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PMID:Biosynthesis of human acute-phase serum amyloid A protein (A-SAA) in vitro: the roles of mRNA accumulation, poly(A) tail shortening and translational efficiency. 838 77

Telomerase, a ribonucleoprotein that directs the synthesis of telomeric DNA repeats and compensates for the telomeric losses that occur with cell division, is absent from most mortal cells but is present in immortal cells. Telomerase activity is thought to be essential for continuous cell division as seen in malignant tumor cells, and its inhibition could be a strategy for anti-cancer therapy. We prepared a hammerhead ribozyme (teloRZ) directed against the RNA component of human telomerase and tried to find if it could serve as an inhibitor of telomerase. TeloRZ showed a specific cleavage activity against a synthesized portion of the telomerase RNA component used as the substrate. Furthermore, when added to cell extracts from HepG2 or Huh-7, human hepatocellular carcinoma derived lines, teloRZ inhibited the telomerase activity in both. These findings support the potential application of ribozymes capable of telomerase inhibition as new therapeutic agents directed against immortalized cancer cells.
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PMID:Hammerhead ribozyme-mediated inhibition of telomerase activity in extracts of human hepatocellular carcinoma cells. 875 2

Telomerase is a ribonucleoprotein enzyme that elongates telomeric DNA. It has been reported that most immortal cell lines express telomerase, whereas in adult normal tissues telomerase activity is not detected. So, in malignant tumors telomerase is thought to be activated to maintain their immortality. In this study, we examined telomerase activity in 12 cases of hepatocellular carcinoma (HCC) with the use of PCR-based assay and analyzed the relationship of telomerase activity to clinicopathological features. In 11 of 12 HCC nodules telomerase activity was detected, of which 9 cases showed strong activity. There was no significant correlation between telomerase activity and clinicopathological features of HCC. Telomerase activity among 6 well-differentiated HCCs was strong in 3 (50%), weak in 2 (33%), and undetected in 1 (17%). All of 6 moderately-differentiated HCCs (100%), however, showed strong activity. As regards tumor size, 4 of 5 HCCs (80%) less than 3 cm in diameter showed strong telomerase activity. On the other hand, weak telomerase activity was detected in only 2 of 12 (17%) noncancerous liver tissues surrounding HCC nodules. The assay of telomerase activity may be a useful diagnostic marker of HCC regardless of tumor size, and the activity may be expressed even at early stage.
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PMID:Clinical significance of telomerase activity in hepatocellular carcinoma. 897 88

Telomerase is a ribonucleoprotein that stabilizes telomeres and allows unlimited cell division. It has been reported that most cancer cells evince reactivated telomerase. We examined telomerase activity in 29 patients with hepatocellular carcinoma (HCC) by a polymerase chain reaction-based semiquantitative assay. Of 24 HCCs, telomerase activity was positive in 23 (95.8%), of which 16 showed strong activity. In 11 well differentiated HCCs, telomerase activity was strong in 5, weak in 5, and undetected in 1 and in 13 moderately differentiated HCCs, it was strong in 11 and weak in 2. Five of 6 HCCs less than 2 cm in diameter expressed strong telomerase activity, while weak telomerase activity was detected in 7 of 19 (36.8%) resected noncancerous liver tissues from the HCC patients. Five of these 7 patients (71%) manifested recurrence within 6 months after surgery. The recurrence rate in these patients whose noncancerous liver tissue was positive for telomerase activity was significantly higher than that in patients in whom it was negative (P = 0.017). These results suggest that the presence of telomerase activity may be a useful diagnostic marker of HCC, regardless of tumor size, and that its detection in resected noncancerous liver tissues may serve as a useful predictor of postoperative recurrence.
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PMID:Telomerase activity in hepatocellular carcinoma as a predictor of postoperative recurrence. 943 18

A thymidylate synthase (TS)-ribonucleoprotein (RNP) complex composed of TS protein and the mRNA of the tumor suppressor gene p53 was isolated from cultured human colon cancer cells. RNA gel shift assays confirmed a specific interaction between TS protein and the protein-coding region of p53 mRNA, and in vitro translation studies demonstrated that this interaction resulted in the specific repression of p53 mRNA translation. To demonstrate the potential biological role of the TS protein-p53 mRNA interaction, Western immunoblot analysis revealed nearly undetectable levels of p53 protein in TS-overexpressing human colon cancer H630-R10 and rat hepatoma H35(F/F) cell lines compared to the levels in their respective parent H630 and H35 cell lines. Polysome analysis revealed that the p53 mRNA was associated with higher-molecular-weight polysomes in H35 cells compared to H35(F/F) cells. While the level of p53 mRNA expression was identical in parent and TS-overexpressing cell lines, the level of p53 RNA bound to TS in the form of RNP complexes was significantly higher in TS-overexpressing cells. The effect of TS on p53 expression was also investigated with human colon cancer RKO cells by use of a tetracycline-inducible system. Treatment of RKO cells with a tetracycline derivative, doxycycline, resulted in 15-fold-induced expression of TS protein and nearly complete suppression of p53 protein expression. However, p53 mRNA levels were identical in transfected RKO cells in the absence and presence of doxycycline. Taken together, these findings suggest that TS regulates the expression of p53 at the translational level. This study identifies a novel pathway for regulating p53 gene expression and expands current understanding of the potential role of TS as a regulator of cellular gene expression.
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PMID:Thymidylate synthase protein and p53 mRNA form an in vivo ribonucleoprotein complex. 989 Oct 91

The aim of the study was to clarify the role of telomerase component genes in hepatocarcinogenesis and to examine both the relationship between the expression of telomerase component genes and histological differentiation in hepatocellular carcinoma (HCC) and the relationship between expression levels of telomerase component genes and telomerase activity in HCCs. Telomerase is a ribonucleoprotein enzyme composed of a template RNA and several proteins. Recently, three such telomerase component genes have been identified: human telomerase reverse transcriptase (hTERT); human telomerase RNA component (hTERC); and telomerase-associated protein 1 (TEP1). The expression of these components was evaluated in 34 HCCs and 24 non-cancerous liver tissues by reverse transcriptase-polymerase chain reaction (RT-PCR). Expression of hTERT mRNA was detected in most HCCs, but not in the non-cancerous tissues (P<0.01). Expression of hTERC was detected in both HCCs and non-cancerous tissues, but the expression level in HCCs was higher than that in non-cancerous tissues (P<0.01) and tended to increase as histological differentiation became less marked. The expression level of hTERT mRNA correlated with relative telomerase activity (P<0.01). These results suggest that telomerase reactivation during hepatocarcinogenesis might be regulated by only hTERT and an increase in telomerase activity level in tumour progression might be regulated by both hTERT and hTERC.
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PMID:Expression of telomerase component genes in hepatocellular carcinomas. 1071 26

Telomerase, a ribonucleoprotein enzyme associated with cellular immortality, consists of human telomerase RNA component (hTERC), human telomerase protein 1 (hTEP1), and human telomerase reverse transcriptase (hTERT). In this study, the expression of these subunits was examined in non-neoplastic livers [13 cases of chronic viral hepatitis (CVH), 16 of primary biliary cirrhosis (PBC), two of primary sclerosing cholangitis, and six normal livers], using the reverse transcription-polymerase chain reaction (RT-PCR), nested PCR, and in situ hybridization (ISH). Six hepatocellular carcinoma (HCC) cases and one colonic cancer were used as positive controls. Telomeric repeat amplification protocol (TRAP) assay disclosed distinct telomerase activity in all positive controls and weak telomerase activity in non-neoplastic livers in 4 of 13 CVH cases and 5 of 16 PBC cases. By RT- and nested PCR, both hTERC and hTEP1 mRNA were detectable in all non-neoplastic liver tissues; ISH revealed hTERC and hTEP1 mRNA in the periportal and periseptal hepatocytes and inflammatory mononuclear cells in those cases examined. ISH revealed hTERT mRNA only in a few infiltrating mononuclear cells in 3 of 13 CVH and 2 of 16 PBC livers and these five cases were also positive by TRAP assay. In four of these five cases, hTERT mRNA was also detectable by nested PCR, suggesting that hTERT mRNA in the non-neoplastic liver is expressed by infiltrating mononuclear cells. Biliary epithelial cells were totally negative for these human telomerase subunits. Three subunits were constantly detected in all positive controls by ISH as well as by RT- and nested PCR. The finding that hTERC and hTEP1 mRNA, but not hTERT mRNA, were detectable in the non-neoplastic hepatocytes suggests that telomerase is present but not activated and that additional factor(s) are necessary for the expression of hTERT mRNA in the hepatocytes, along with immortalization and neoplastic transformation.
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PMID:PCR and in situ hybridization studies of telomerase subunits in human non-neoplastic livers. 1118 Jan 68

Human telomeres are several kilobases of repeated (TTAGGG)(n) sequences at the ends of chromosomes, a short fragment of which is lost with each cell division. This shortening serves as a "mitotic clock" which limits the number of divisions that a normal somatic cell can undergo. Cells undergoing continuous division need some method of bypassing this clock. One such method is the expression of telomerase. This ribonucleoprotein is an enzyme that rebuilds the lost portion of the telomeres. Between 80-95% of tumors are telomerase-positive, including ovarian carcinoma, hepatocellular carcinoma, neuroblastoma, leukemia/lymphoma, and cancers of the breast, prostate, lung, kidneys and bladder, as well as many immortalized cell lines. While absent in most normal tissues, this enzyme is expressed at higher levels in germline tissues, bone marrow, and lymphocytes. Due to the expression of telomerase in most tumor cells and its absence in most normal tissues, telomerase inhibitors are being investigated as possible anticancer agents. This review focuses on non-reverse transcriptase inhibitor, non-oligonucleotide and non-G-quartet interactive agent telomerase inhibitors. These agents include: differentiating agents, kinases and phosphatases, cell cycle and apoptosis regulating agents, immunotherapeutic agents, antibiotics, steroids, bisindole derivatives, and a variety of other compounds. These agents hold much promise for the future treatment of malignancies.
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PMID:The 'other' telomerase inhibitors: non-G-quadruplex interactive agent, non-antisense, non-reverse transcriptase telomerase inhibitors. 1267 26

Prominent nucleoprotein sedimentation boundaries were demonstrable in cytoplasmic extracts of Novikoff hepatoma. Fractionation of the homogenates by differential centrifugation or a density gradient method revealed that 65 to 75 per cent of the cytoplasmic ribonucleic acid was present in the form of free ribonucleoprotein particles. After purification by differential centrifugation in dilute buffer, the particles contained 37 per cent RNA, very little lipid, and no demonstrable membrane material. Ultracentrifugal boundaries corresponding to those seen in the original extracts were present, the main component having an s20, (w) of 81 S. Upon exposure to chelating agents, the particles dissociated through an intermediate component with sedimentation rate of 56 S to a final stage in which 46 and 28 S subunits were present in a weight ratio of 2:1. ATP and pyrophosphate were equally effective in causing dissociation. ADP was considerably less effective. Treatment of the purified particles with deoxycholate removed one-third of the protein and significantly altered the ultracentrifugal pattern. The particles now dissociated directly to the 46 and 28 S subunit when exposed to chelating agents. Upon electron microscopy, the 81 S particle appeared as an oblate spheroid 24 mmicro in diameter. The 46 and 28 S subunits also appeared spheroidal.
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PMID:Cytoplasmic ribonucleoprotein components of the Novikoff hepatoma. 1441 46


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