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)

Inbred strains of guinea pigs, JY-1 and Hartley/F, established in this Institute, were injected subcutaneously with 3-methylcholanthrene. During 1972 to 1974, 15 solid tumors (7 fibrosarcomas, 6 liposarcomas, and 2 atheroma-like tumors) have been induced in 12 animals out of 30 employed. Among the 15 tumors, 1 fibrosarcoma induced in JY-1 and 2 liposarcomas and 1 fibrosarcoma induced in Hartley/F were transplantable and established as the syngeneic lines named J4, H10, H12, and H9A, respectively. In addition, a transplant of J4 into the Hartley/F strain animal was established as an allogeneic subline and named JH4. Pathological and biological characteristics of these tumors are described and differences between these tumors and line 10 hepatoma, established by Rapp et al. in strain-2 guinea pig, are discussed.
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PMID:Transplantable sarcomas induced by 3-methylcholanthrene in inbred guinea pigs of JY-1 and Hartley/F strains. 126 55

Rat ascites hepatoma cells (MM1 cells) penetrate through a cultured mesothelial cell monolayer (MCL) in the presence of fetal calf serum (FCS), but scarcely do so in its absence. Inactivation of rhop21 of MM1 cells by ADP-ribosyltransferase C3 resulted in the suppression of this serum effect on the penetration, suggesting that the serum effect was mediated by rhop21. To ascertain this assumption MM1 cells were transfected with an activated (Val14) human rhoA cDNA (Neo/RhoA 1-7). The transfectants penetrated MCL extensively even in the absence of FCS and became largely independent of serum for the penetration. These results suggest that serum-induced invasion by MM1 cells is mainly mediated by rhop21.
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PMID:Participation of rhop21 in serum-dependent invasion by rat ascites hepatoma cells. 755 36

Two forms of phospholipase D (PLD) have been found to be present in nuclei isolated from rat hepatocytes by measuring phosphatidylbutanol produced from exogenous radiolabeled phosphatidylcholine in the presence of butanol. In nuclear lysates from either rat liver or ascites hepatoma AH 7974 cells, the PLD activity was markedly stimulated by a recombinant ADP-ribosylation factor (rARF) in the presence of the guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) and phosphatidylinositol 4, 5-bisphosphate. ATP and phorbol-12-myristate 13-acetate had no synergistic effect on this PLD activity. On the other hand, the nuclear PLD was stimulated by unsaturated fatty acids, especially by oleic acid. The ARF-dependent nuclear PLD activity was increased in the S-phase of the regenerating rat liver after partial hepatectomy and also was much higher in AH 7974 cells than in the resting rat liver. In contrast, the levels of the oleate-dependent PLD activity remained constant throughout the cell cycle in liver regeneration. The intranuclear levels of the stimulating proteins of the nuclear PLD activity, e.g. ARF, RhoA, and protein kinase Cdelta increased in the S-phase of the regenerating liver. These results suggested that the nuclear ARF-dependent PLD activity may be associated with cell proliferation.
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PMID:Nuclear ADP-ribosylation factor (ARF)- and oleate-dependent phospholipase D (PLD) in rat liver cells. Increases of ARF-dependent PLD activity in regenerating liver cells. 903 May 90

We have shown previously that Rho plays a pivotal role in 1-oleoyl-lysophosphatidic acid (LPA)-dependent invasion of rat hepatoma cells (MM1). Herein we made stable transfectants of MM1 expressing active and Botulinum exoenzyme C3 (C3)-sensitive (Val14), or active and C3-insensitive (Val14/Ile41) forms of human RhoA. Both transfectants showed greatly promoted invasive ability in vitro in the absence of LPA as well as in vivo, adherence to the dish with scattered shape, and enhanced phosphorylation level of 20-kDa myosin light chain (MLC20). A specific MLC kinase inhibitor (KT5926) could inhibit their invasion and the phosphorylation level of MLC20. Stable active RhoA transfectants of W1 cells (low invasive counterpart of MM1) also demonstrated promoted invasive ability in vitro and in vivo, and enhanced phosphorylation level of MLC20. C3 treatment inhibited the invasiveness of the Val14 RhoA transfectant but not that of the Val14/Ile41 RhoA transfectant. LPA enhanced the invasiveness of both transfectants, and this enhancement was abolished by the C3 treatment. These results suggested that 1) the Rho signaling pathway and actomyosin system were linked in the transmigration of tumor cells, and 2) expressed active RhoA enhanced LPA-induced tumor cell invasion via the activation of endogenous RhoA pathway, indicating a positive feedback mechanism in the activation of RhoA.
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PMID:Small GTP-binding protein Rho stimulates the actomyosin system, leading to invasion of tumor cells. 947 68

Adhesion of tumor cells to host cell layers and subsequent migration are pivotal steps in cancer invasion and metastasis. The small GTP-binding protein RhoA controls cell adhesion and motility through organization of the actin cytoskeleton and regulation of actomyosin contractility. Cultured rat MM1 hepatoma cells migrate through a mesothelial cell monolayer in vitro in a serum-dependent, RhoA-mediated manner (K. Yoshioka et al., J. Biol. Chem., 273: 5146-5154, 1998). Furthermore, the ROCK family of RhoA-associated serine-threonine protein kinases is involved in this migration, and an inhibitor for these kinases effectively inhibits the invasion of MM1 cells in vitro and in vivo (K. Itoh et al., Nat. Med., 5: 221-225, 1999). Although there have been no reports of genetic alterations directly affecting RhoA in human cancer, the expression level of RhoA in tumors has been several times higher than that of surrounding normal tissue; RhoA was especially highly expressed in the metastatic region. To determine whether RhoA is activated by its overexpression, we made stable transfectants of MM1 cells expressing various levels of wild-type human RhoA. These transfectants showed promoted invasive ability in vitro in the absence and presence of 1-oleoyl-lysophosphatidic acid, marked adherence to the plastic culture dish with scattered shape, elevated phosphorylation of Mr 20,000 myosin light chain, and translocation of RhoA protein from the cytosol to the membrane. All of these phenotypes were similar to those of active RhoA transfectants, correlated with the expression level of RhoA and reversed by the treatment of the cells with Clostridium botulinum exoenzyme C3 ADP-ribosyltransferase. In addition, overexpression of wild-type RhoA in MM1 cells also conferred invasive ability in vivo after the cells were transplanted into the syngeneic rats. Thus, high expression of RhoA in the cell facilitates the translocation of this protein to the membrane, where it is activated, resulting in the stimulation of the RhoA-ROCK-actomyosin system, leading to invasion.
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PMID:Overexpression of small GTP-binding protein RhoA promotes invasion of tumor cells. 1021 13

To investigate the role of RhoA on the intracellular membrane dynamics of lysosomes in rat hepatoma cells (MM1), we analyzed the localization of lysosomal aspartic proteinase cathepsin D by confocal immunofluorescence microscopy in the dominant active RhoA-transfected cells. Here we show that the transfection of the dominant active form of human small guanosine triphosphatase (GTPase) RhoA in MMI cells, a highly invasive cell line, causes the redistribution and spreading of small punctate structures stained for cathepsin D throughout the cytoplasm. We found that the microtubule organization was markedly different in the two cell lines: uniformly developed and polymerized microtubule filaments were seen in the mock transfectants; however, the dynamic organization of microtubules was less pronounced in the active RhoA transfectants. Furthermore, we found for the first time that a selective inhibitor of Rho-associated kinase (p160ROCK), Y-27632, impeded the subcellular spreading of cathepsin D staining and promoted reclustering of cathepsin D toward the perinuclear region in the active RhoA-transfected cells. To our knowledge, this is the first indication that the RhoA/ROCK-mediated signaling pathway is involved in the intracellular membrane dynamics of lysosomes by regulating the cytoskeletal microtubule organization as well as the actin cytoskeletons.
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PMID:Small guanosine triphosphatase Rho/Rho-associated kinase as a novel regulator of intracellular redistribution of lysosomes in invasive tumor cells. 1099 80

1-Oleoyl lysophosphatidic acid (LPA) induces transmonolayer migration (in vitro invasion) of rat ascites hepatoma MM1 cells and their morphological changes leading to the migration. We have previously shown that an LPA analog, palmitoyl cyclic phosphatidic acid (Pal-cPA), suppresses transmonolayer migration of MM1 cells by rapidly increasing the intracellular cyclic AMP (cAMP) concentration. We report here that various cAMP-elevating agents, including dibutyryl cAMP, forskolin, cholera toxin and 3-isobutyl-1-methylxanthine, consistently inhibited LPA-induced transmonolayer migration of MM1 cells. Moreover, pull-down assays for GTP-bound, active RhoA demonstrated that the blockage by cAMP-elevating agents of morphological changes leading to the migration was probably mediated through inhibiting RhoA activation.
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PMID:Hepatoma cell migration through a mesothelial cell monolayer is inhibited by cyclic AMP-elevating agents via a Rho-dependent pathway. 1106 34

We demonstrated previously that rat ascites hepatoma MM1 cells require both lysophosphatidic acid (LPA) and fibronectin (FN) for phagokinetic motility and transcellular migration and that these events are regulated through the RhoA-ROCK pathway. It remains to be elucidated, however, how the signals from both LPA and FN are integrated into cell migration. To examine this, total cellular lysates after stimulation with LPA or FN were subjected to time-course immunoblot analysis with anti-phosphotyrosine antibodies (Abs). Consequently, tyrosine-phosphorylation of paxillin was obviously persistent after stimulation with FN + LPA as compared to after stimulation with either alone. Tyrosine-phosphorylated paxillin comprised 2 components; slowly and fast migrating ones. Immunoblotting of anti-paxillin immunoprecipitates with phosphorylation site-specific Abs revealed the following: tyrosine-phosphorylation was enhanced preferentially on a slowly migrating component after stimulation with FN + LPA; this component contained phosphorylation at both tyrosine residue (Y) 31 and Y118; and phosphorylation of paxillin at Y181 was constitutive and not augmented by stimulation with either FN or LPA. Amiloride, an inhibitor of the Na+/H+ antiporter downstream of ROCK, suppressed cell motility and correspondingly paxillin tyrosine-phosphorylation at both Y31 and Y118. Paxillin phosphorylation weakly induced by FN alone, insufficient for cell migration, was not inhibited by amiloride. These results demonstrate that LPA collaborates with FN for persistent tyrosine phosphorylation of paxillin at both Y31 and Y118, regulated by the Na+/H+ antiporter downstream of ROCK and that this phosphorylated paxillin is essential for MM1 cancer cell migration.
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PMID:Involvement of phosphorylation of Tyr-31 and Tyr-118 of paxillin in MM1 cancer cell migration. 1177 84

Gene expression profiling with cDNA array allows simultaneous analysis of the gene expression pattern of a large number of genes and may enhance the investigation of the molecular mechanisms involved in the treatment of hepatocellular carcinoma with cisplatin. We used cDNA array technology to assess the gene expression profiles related to cell cycle regulation and apoptosis in human hepatoma Hep3B cells in response to cisplatin treatment. In Hep3B cells, apoptosis induced by cisplatin was p53-independent, and was associated with up-regulation of cell cycle regulators, pro-apoptotic genes, growth receptors, and genes involved in signal transduction. These included p33ING1, c-Abl, Bax, insulin-like growth factor binding protein 3, Siva, cyclin D1, RhoA, and Raf-1. Down-regulation of cell cycle regulator CDC2 was observed. Semi-quantitative reverse transcription-polymerase chain reaction and/or Western blot analysis performed on seven of these genes confirmed their upregulation of gene expression. Such global analysis of the cytotoxic response to chemotherapeutic drugs may yield insight into the mechanisms of drug action and allow rational design of more effective treatment strategies.
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PMID:Gene expression profiling by cDNA array in human hepatoma cell line in response to cisplatin treatment. 1199 Dec 55

DLC-1 (deleted in liver cancer 1) is a candidate tumor suppressor gene for hepatocellular carcinoma and other cancers. It is the human homologue of rat p122, which has been shown to function as a GTPase activating protein for RhoA, and it may be involved in signal transduction pathways regulating cell proliferation and adhesion. To establish an animal model for studying the regulation and function of DLC-1, we have undertaken the characterization of the mouse DLC-1 gene. Northern blot analysis shows that the mouse DLC-1 mRNA is widely expressed, with the highest levels in heart, liver, and lung. Mouse genomic clones that contain the entire DLC-1 gene of 47 kb were isolated. The mouse gene consists of 14 exons, and the structural organization is highly similar to that of the human gene. The promoter region of the mouse gene was GC-rich and contained potential binding sites for transcription factors SP1, GCF, and AP-2. A polymorphic microsatellite marker in intron 8 was used for mapping the gene (Arhgap7) to 20 cM on mouse chromosome 8 and for allelotyping of mouse liver tumor DNAs.
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PMID:Gene structure, tissue expression, and linkage mapping of the mouse DLC-1 gene (Arhgap7). 1203 1


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