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)

The effect of fetal calf serum (FCS) on in vitro invasion by rat ascites hepatoma cells (AH130) was studied by using the in vitro invasion assay. Although the coculture of the highly invasive clone (MM1) of AH130 cells and the mesothelial cell layer or endothelial cell layer in modified minimum essential medium supplemented with 10% FCS resulted in extensive penetration of the layer by the tumor cells, the omission of FCS resulted in an almost complete elimination of the in vitro invasion. The in vitro invasiveness by human small cell lung cancer cells (OC10) was also remarkably reduced by the omission of FCS from the assay medium, suggesting a requirement of serum for the in vitro tumor cell invasion. When 10% FCS was added to the medium 2 h after the tumor cell seeding in FCS-free invasion assay system, penetration by MM1 cells was observed within an hour. This rate of penetration was almost the same as that when 10% FCS was added at the time of tumor cell seeding. FCS was also required for the penetration of a mesothelial cell monolayer by MM1 cells in a defined growth medium (SFM-101), in which MM1 cells were well maintained. The invasion-inducing activity appears to be independent of the growth-stimulating activity in serum.
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PMID:Serum requirement for in vitro invasion by tumor cells. 190 95

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

Rat ascites hepatoma cell (MM1) invade a mesothelial cell monolayer in vitro in assay medium containing serum, but not in serum-free medium. Serum could be completely replaced by 1-oleoyl lysophosphatidic acid (LPA) in inducing invasion. LPA-induced invasion was inhibited by genistein, a tyrosine-kinase inhibitor. Protein tyrosine phosphorylation in response to LPA was thus analyzed in order to determine the molecular mechanism of invasion. LPA of invasion-inducible concentrations evoked a transient increase in tyrosine phosphorylation, mainly of 110- to 130-kDa proteins in MM1 cells but not in mesothelial cells. These concentrations of LPA were over 10 times higher (10 to 25 micron) than those necessary to produce a variety of biological actions, such as tyrosine phosphorylation in fibroblasts, neurite retraction and platelet aggregation. Protein tyrosine phosphorylation and invasion by MM1 cells induced by LPA are largely regulated by rho p21, because both were inhibited by Clostridium botulinum C3 exo-enzyme, which is known to specifically inactivate rho p21. Invasion of MCL by MM1 cells induced by serum and that by B16FE7 cells induced by LPA were inhibited by genistein or C3 as well. By immunoprecipitation, we detected p 125 focal adhesion kinase (FAK) as a major protein of 110- to 130-kDa tyrosine phosphorylated in response to LPA. Tyrosine phosphorylation of paxillin by LPA was also detected.
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PMID:rho-Mediated protein tyrosine phosphorylation in lysophosphatidic-acid-induced tumor-cell invasion. 859 14

The effect of plant glycosides on tumor cell invasion was examined. Among the glycosides tested, ginsenoside Rg3 was found to be a potent inhibitor of invasion by rat ascites hepatoma cells (MM1), B16FE7 melanoma cells, human small cell lung carcinoma (OC10), and human pancreatic adenocarcinoma (PSN-1) cells, when examined in a cell monolayer invasion model. Structurally analogous ginsenosides, Rb2, 20(R)-ginsenoside Rg2 and 20(S)-ginsenoside Rg3 (a stereoisomer of Rg3), showed little inhibitory activity. Neither Rh1, Rh2, 20(R)-ginsenosides Rh1, Rb1, Rc nor Re had any effect. The effective ginsenoside, Rg3, tended to inhibit experimental pulmonary metastasis by highly metastatic mouse melanoma B16FE7 cells as well. Taking account of our previous finding that 1-oleoyl-lysophosphatidic add (LPA) induced invasion by MM1 cells in the monolayer invasion model, the effect of Rg3 on molecular events associated with the invasion induced by LPA was analyzed in order to understand the mechanism of the inhibition. Rg3, which suppressed the invasion induced by LPA, dose-dependently inhibited the LPA-triggered rise of intracellular Ca2+. Protein tyrosine phosphorylation triggered by LPA was not inhibited by Rg3.
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PMID:Inhibition of in vitro tumor cell invasion by ginsenoside Rg3. 864 66

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 transcellular migration are pivotal steps in cancer invasion and metastasis. The small GTPase Rho controls cell adhesion and motility through reorganization 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, Rho-mediated manners. Among several proteins isolated as putative target molecules of Rho, the ROCK (ROK) family of Rho-associated serine-threonine protein kinases are thought to participate in the induction of focal adhesions and stress fibers in cultured cells, and to mediate calcium sensitization of smooth muscle contraction by enhancing phosphorylation of the regulatory light chain of myosin. Transfection of MM1 cells with cDNA encoding a dominant active mutant of ROCK conferred invasive activity independently of serum and Rho. In contrast, expression of a dominant negative, kinase-defective ROCK mutant substantially attenuated the invasive phenotype. A specific ROCK inhibitor (Y-27632) blocked both Rho-mediated activation of actomyosin and invasive activity of these cells. Furthermore, continuous delivery of this inhibitor using osmotic pumps considerably reduced the dissemination of MM1 cells implanted into the peritoneal cavity of syngeneic rats. These results indicate that ROCK plays an essential part in tumor cell invasion, and demonstrate its potential as a therapeutic target for the prevention of cancer invasion and metastasis.
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PMID:An essential part for Rho-associated kinase in the transcellular invasion of tumor cells. 993 Aug 72

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

Lysophosphatidic acid (LPA) triggers the invasion of a mesothelial cell monolayer by rat ascites hepatoma (MM1) cells. LPA also induces rapid morphological changes of MM1 cells, cell surface blebbing and pseudopodia formation. Pseudopodia formation is tightly correlated with cellular invasiveness. Clostridium Botulinum C3 exoenzyme and genistein abrogated the formation of blebs and pseudopodia together with the inhibition of invasion, indicating that GTPase Rho and certain tyrosine kinases are involved in both processes. MM1 cells expressing constitutively active Rho exhibited the invasion and the formation of blebs and pseudopodia in the absence of LPA. In contrast, MM1 cells expressing constitutively active Rac were not invasive in the absence of LPA, but were invasive in the presence of LPA. Their morphological response to LPA was almost the same as that of parental MM1 cells. Expression of dominant negative Rac suppressed the invasiveness to approximately 3% of that of parental MM1 cells, together with the inhibition of pseudopodia formation. Thus, Rho and Rac are cooperatively involved in both the invasion and the related morphological changes of MM1 cells. Rho activation is sufficient both for the induction of invasion and the morphological changes leading to the invasion, whereas Rac activation is necessary but not sufficient by itself. We propose that Rho activation is not mediated by Rac but the cooperation of both GTPases is essential to trigger the invasive behavior of MM1 cells.
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PMID:Involvement of small GTPases Rho and Rac in the invasion of rat ascites hepatoma cells. 1041 Nov 6

We have previously shown that the transcellular migration of rat ascites hepatoma (AH130-MM1) cells through a cultured mesothelial cell monolayer (MCL) is triggered with lysophosphatidic acid (LPA) that stimulates actin polymerization and myosin light chain phosphorylation through the activation of Rho-ROCK (Rho-kinase) cascade. When, however, the motility of MM1 cells on a glass surface was tested by phagokinetic track motility assay, LPA failed to induce the motility. Nevertheless, when the glass had been coated with fibronectin (FN), LPA could induce phagokinetic motility which was accompanied by transformation of MM1 cells to fusiform-shape and assembly of focal adhesion. beta1 integrin, the counter receptor of FN, was expressed on MM1 cells. Anti-FN antibody, anti-beta1 integrin antibody and cyclo-GRGDSPA remarkably suppressed LPA-induced phagokinetic motility. These antibodies suppressed LPA-induced transcellular migration through MCL, as well. These results indicate that actin polymerization and phosphorylation of myosin light chain through Rho activation are insufficient for inducing motility but the cooperative FN/beta1 integrin-mediated adhesion is necessary for both the phagokinetic motility and transcellular migration of MM1 cells.
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PMID:Cooperation of fibronectin with lysophosphatidic acid induces motility and transcellular migration of rat ascites hepatoma cells. 1063 31

Migration of rat ascites hepatoma (MM1) cells, invasion and phagokinetic movement were induced by the combination of lysophosphatidic acid (LPA) and fibronectin (FN). Induction of migratory activity was tightly correlated with morphological change of MM1 cells from spherical or polygonal-shaped cells to fusiform-shaped ones with pseudopodia. MM1 cells were mobile in a fusiform shape, whereas those of a spherical or polygonal shape were not. A small GTPase Rho and one of its downstream effectors ROCK (Rho-associated coiled-coil forming protein kinase), play essential roles in these processes, as evidenced by suppression of migration and morphological change of MM1 cells by Clostridium botulinum C3 exoenzyme, an inhibitor of Rho, or by Y-27632, an inhibitor of ROCK. Y-27632 also suppressed the formation of fusiform-shaped pseudopodia-carrying MM1 cells that was induced by stimulation with the combination of LPA and FN. LPA and FN also evoked the formation of focal adhesions and actin bundles, and tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin. The inhibitory effect of Y-27632 on LPA-induced migration and morphological change of MM1 cells was considered to be mediated, at least in part, by impaired formation of focal adhesions and actin bundles. Y-27632 suppressed LPA-induced tyrosine phosphorylation of FAK and paxillin, suggesting that ROCK regulates these molecules and Y-27632 inhibits cellular migration and morphological change, at least in part, through this regulation.
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PMID:Y-27632, an inhibitor of rho-associated protein kinase, suppresses tumor cell invasion via regulation of focal adhesion and focal adhesion kinase. 1096 22


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