microcystin and Carcinoma--Hepatocellular

Cyanobacteria-derived toxin microcystin-LR (MCLR) has been widely investigated in its effects on normal cells, there is little information concerning its effects on cancer cells. In the present study, the SMMC-7721 human liver cancer cell line treated with MCLR was used to investigate the change of PP2A, cytoskeleton rearrangement, phosphorylation levels of PP2A substrates that related with cytoskeleton stability and explored underlying mechanisms. Here, we confirmed that MCLR entered into SMMC-7721 cells, bound to PP2A/C subunit and inhibited the activity of PP2A. The upregulation of phosphorylation of the PP2A/C subunit and PP2A regulation protein α4, as well as the change in the association of PP2A/C with α4, were responsible for the decrease in PP2A activity. Another novel finding is that the rearrangement of filamentous actin and microtubules led by MCLR may attribute to the increased phosphorylation of HSP27, VASP and cofilin due to PP2A inhibition. As a result of weakened interactions with PP2A and alterations in its subcellular localization, Rac1 may contribute to the cytoskeletal rearrangement induced by MCLR in SMMC-7721 cells. The current paper presents the first report demonstrating the characteristic of PP2A in MCLR exposed cancer cells, which were more susceptible to MCLR compared with the normal cell lines we previously found, which may be owing to the absence of some type of compensatory mechanisms. The hyperphosphorylation of cytoskeleton-associated proteins and Rac1 inactivation which were induced by inhibition of PP2A are shown to be involved in cytoskeleton rearrangement.

Topics: Bacterial Toxins; Carcinoma, Hepatocellular; Cell Line, Tumor; Cyanobacteria Toxins; Cytoskeletal Proteins; Cytoskeleton; Dose-Response Relationship, Drug; Environmental Pollutants; Enzyme Activation; Humans; Liver Neoplasms; Marine Toxins; Microcystins; Phosphorylation; Protein Phosphatase 2; rac1 GTP-Binding Protein; Up-Regulation

To explore the relationship between primary liver cancer (PLC) and MC in drinking pond-ditch water.. Epidemiological and ecological assays, Meta-analysis and risk assessment were used in this study. Cyanotoxin (Microcystin, MC) in the water of different sources was detected by ELISA. The F344 and HBVx transgenic mice were used to confirm the promotion effect on PLC and the synthetically carcinogenic effect of HBV, aflatoxin and MC.. Using Meta-analysis the results of six case-control studies showed that the pooled odds ratio (OR) was 2.46 (95% CI 1.69-2.59), population attributable rick (PAR) was 30.39% (95% CI, 23.30%-37.47%), heterogeneity test P > 0.05. Eutrophication led to cyanobacterial bloom in the pond-ditch water. Cyanotoxin released from dead cyanobacteria was hepatotactic tumor promoter. In HBVx transgenic rats, hepatocellular carcinoma was induced by the joint administration of aflatoxin B1 and cyanotoxin. Epidemiological study showed that the recombined index of HBsAg, aflatoxin-albumin adducts and drinking of pond-ditch water correlated with PLC mortalities in 13 townships.. Microcystin in the pond-ditch water is a hepatotactic toxin which can induce hepatitis and promote development of hepatocellular carcinoma. The combined effect of microcystin, HBV and aflatoxin may be responsible for the endemicity of PLC.

Topics: Aflatoxin B1; Animals; Animals, Genetically Modified; Carcinoma, Hepatocellular; Child; China; Fresh Water; Glutathione Transferase; Hepatectomy; Humans; Liver; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Microcystins; Peptides, Cyclic; Rats; Rats, Inbred F344; Trans-Activators; Viral Regulatory and Accessory Proteins