g(m2)-ganglioside and Carcinoma--Hepatocellular

Ganglioside GM3 plays a well-documented and important role in the regulation of tumor cell proliferation, invasion, and metastasis by modulating tyrosine kinase growth factor receptors. However, the effect of GM3 on the hepatocyte growth factor receptor (HGFR, cMet) has not been fully delineated. In the current study, we investigated how GM3 affects cMet signaling and HGF-stimulated cell motility and migration using three hepatic cancer cell lines of mouse (Hca/A2, Hca/16A3, and Hepa1-6). Decreasing GM3 expression with the use of P4, a specific inhibitor for ganglioside synthesis inhibited the HGF-stimulated phosphorylation of cMet and activity of PI3K/Akt signaling pathway. In contrast, the increased expression of GM3 as a result of adding exogenous GM3 enhanced the HGF-stimulated phosphorylation of cMet and activity of PI3K/Akt signaling pathway. Furthermore, HGF-stimulated cell motility and migration in vitro were inhibited by reduced expression of GM3 and enhanced by increased expression of GM3. All the observations indicate that ganglioside GM3 promotes HGF-stimulated motility of murine hepatoma cell through enhanced phosphorylation of cMet at specific tyrosine sites and PI3K/Akt-mediated migration signaling.

Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Down-Regulation; G(M2) Ganglioside; G(M3) Ganglioside; Hepatocyte Growth Factor; Humans; Liver Neoplasms; Mice; Phosphatidylinositol 3-Kinases; Phosphorylation; Phosphotyrosine; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; Signal Transduction; Up-Regulation

GM2 ganglioside was detected in all five sera of hepatoma patients analyzed by thin-layer chromatography in conjunction with enzyme-immunostaining with rabbit anti-GM2 antibody and horseradish peroxidase-conjugated anti-rabbit IgG, and was quantitated by densitometry. The GM2 contents of these sera were 20 to 100 times higher than those of sera from normal adults. By the method used, an increased GM2 level could be detected with samples of less than 0.1 ml of sera from hepatoma patients. The elevated levels of serum GM2 in hepatoma patients were suggested to be due to elevated GM2 levels in the liver lesions, because the GM2 contents of the liver of five patients with liver cancer, including three with hepatoma, were higher than those of normal liver tissues.

Topics: Carcinoma, Hepatocellular; Chromatography, Thin Layer; G(M2) Ganglioside; Gangliosides; Immunoenzyme Techniques; Liver Neoplasms

Hyperplastic nodules and hepatocellular carcinomas were induced in livers of rats by a low-protein diet containing 0.05% of the carcinogen N-2-fluorenylacetamide. Ganglioside amounts and composition were determined for histologically different hepatocellular carcinomas and compared with those for control livers, hyperplastic nodules, and liver tissue surrounding hepatomas and nodules as well as those for livers of fetal, newborn, 1-week-old, weanling, and adult Sprague-Dawley rats. Ganglioside sialic acid levels were elevated above those of normal adult liver in all liver tissues following the carcinogen treatment regimen. Livers of fetal and newborn rats contained nearly twice the amount of ganglioside sialic acid on a protein or DNA basis as did livers of adult rats. Analyses of individual nodules and hepatomas revealed two populations of tumors in which the levels of ganglioside sialic acid were 2.3 and 3.8 times normal. Ganglioside sialic acid content was at hepatoma levels in small nodules. Individual gangliosides were evenly distributed between products of the monosialoganglioside and disialoganglioside pathways in normal liver with a ratio of [N-acetylneuraminic acid (sialic acid)] (NAN)-galactose (Gal)-N-acetylgalactosamine (GalNAc)-(NAN)-Gal-glucose (Glc)-ceramide (Cer) (GD1a) to Gal-GalNAc-(NAN)2-Gal-Glc-Cer (GD1b) of about one. In contrast, the monosialogangliosides predominated in liver tissues following administration of the carcinogen. Increased levels of specific monosialogangliosides were present in nodules, in liver of carcinogen-treated animals prior to the appearance of tumors, and in the liver tissues surrounding nodules and hepatomas. In single hepatomas, ganglioside patterns correlated with tumorigenicity. A well-differentiated hepatoma had a normal complement of most gangliosides but was deficient in trisialogangliosides. In a poorly diferentiated but well-circumscribed hepatoma, the relative levels of all higher gangliosides were reduced. The monosialoganglioside Gal-GalNAc-(NAN)-Gal-Glc-Cer (GM1) accounted for 80% of the total ganglioside in a poorly circumscribed and poorly differentiated hepatoma. The ganglioside pattern of fetal livers most closely resembled that of a poorly differentiated hepatoma. During the first week post natum, levels of all higher monosialogangliosides and disialogangliosides declined, but the decline was most pronounced for gangliosides GM1 and GD1a. The ratio of GM1 + GD1a to GD1b + NAN-Gal-GalNAc-(NAN)

Topics: 2-Acetylaminofluorene; Animals; Animals, Newborn; Carcinoma, Hepatocellular; Fluorenes; G(M1) Ganglioside; G(M2) Ganglioside; G(M3) Ganglioside; Gangliosides; Hyperplasia; Liver; Liver Neoplasms; Neoplasms, Experimental; Precancerous Conditions; Rats; Sialic Acids