microcystin and Liver-Neoplasms

In this review we present recent studies on the effects of the protein phosphatase inhibitor microcystin on mammalian cells. Whereas high concentrations of microcystin promote liver cell death induced by ROS signalling without the involvement of typical apoptotic proteins, intermediate doses activate classic apoptotic pathways. Low concentrations however, increase liver cell survival and proliferation, and can cause primary liver cancer.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hepatocytes; Humans; Liver Neoplasms; Microcystins; Models, Chemical; Peptides, Cyclic; Phosphoric Monoester Hydrolases

Many species of cyanobacteria (blue-green algae) produce secondary metabolites with potent biotoxic or cytotoxic properties. These metabolites differ from the intermediates and cofactor compounds that are essential for cell structural synthesis and energy transduction. The mass growth of cyanobacteria which develop in fresh, brackish and, marine waters commonly contain potent toxins. Cyanobacterial toxins or cyanotoxins are responsible for or implicated in animal poisoning, human gastroenteritis, dermal contact irritations and primary liver cancer in humans. These toxins (microcystins, nodularins, saxitoxins, anatoxin-a, anatoxin-a(s), cylindrospermopsin) are structurally diverse and their effects range from liver damage, including liver cancer to neurotoxicity. Several incidents of human illness and more recently, the death of 60 haemodialysis patients in Caruaru, Brazil, have been linked to the presence of microcystins in water. In response to the growing concern about the non-lethal acute and chronic effects of microcystins, World Health Organization has recently set a new provisional guideline value for microcystin-LR of 1.0 microg/L in drinking water. Cyanobacteria including microcystin-producing strains produce a large number of peptide compounds, e.g. micropeptins, cyanopeptolins, microviridin, circinamide, aeruginosin, with varying bioactivities and potential pharmacological application. This article discusses briefly cyanobacterial toxins and their implications on human health.

Topics: Bacterial Toxins; Cyanobacteria; Eutrophication; Gastroenteritis; Humans; Liver Neoplasms; Marine Toxins; Microcystins; Peptides, Cyclic; Public Health; Renal Dialysis; Water Supply

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 study the molecular mechanism of microcystin (MC) induced liver tumorigenesis in rats.. The two-stage-medium-term tumorigenesis theory was applied to establish the animal model, and the effect of MC in liver tumor formation was evaluated by the Albert gamma-GT methods, and then, the immunohistochemical technique and image analysis were used to study the expression of the bcl-2 and bax genes during tumorigenesis.. (1) MC enhanced the formation of gamma-GT foci in liver (100%), which was significantly higher than the diethylnitrosamine (DEN) control group (22.22%) (P < 0.05). (2) MC decreased the expression of bax gene. The intensity and area of bax gene expression in the pure MC toxin group were 0.028 3 AODV and 0.007 3 ( micro m(2)/ micro m(2)) and in the DEN control group were 0.065 5 AODV and 0.024 4 ( micro m(2)/ micro m(2)), respectively. The intensity and areas of bax gene expression in the pure MC toxin group were significantly lower than those in the DEN control group (P < 0.05). (3) MC increased the expression of bcl-2 gene. The intensity and area of bcl-2 gene expression in the pure MC toxin group wee 0.097 7 AODV and 0.031 5 ( micro m(2)/ micro m(2)), respectively, and in the DEN control group were 0.046 0 AODV and 0.020 5 ( micro m(2)/ micro m(2)) respectively (P < 0.05).. (1) MC can strongly promote liver tumorigenesis. (2) The changes of bcl-2 and bax gene expression possibly play an important role in the MC induced liver tumor formation.

Topics: Animals; bcl-2-Associated X Protein; Carcinogens; Immunohistochemistry; Liver; Liver Neoplasms; Mice; Microcystins; Peptides, Cyclic; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar

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

Raw water of poor quality still causes many drinking-water associated health problems all over China, largely because of poor sanitation, inadequate disposal of sewage and excreta. Eutrophication due to excess of total nitrogen and phosphorous in some sources for drinking-water has led to massive proliferation of cyanobacteria. The dominant species of cyanophyta can produce microcystins, a potent liver cancer promotor. As in previous studies, high incidence of liver cancer coincided with high microcystin concentration in the source water, especially in pond water. A frequent consequence of heavy pollution of source water is further the high incidence of infectious intestinal diseases, which are more than 10-100 times as frequent in China than in developed countries.

Topics: Carcinogens; Cyanobacteria; Developing Countries; Humans; Liver Neoplasms; Microcystins; Peptides, Cyclic; Sewage; Water Microbiology; Water Purification; Water Supply

To understand the effects of microcystin (MC) in drinking water on health of human beings.. In Taixing, a cross-sectional study was conducted in two middle schools with different types of drinking water, from which 111 and 92 students were randomly selected and investigated. Blood samples from all individuals were collected and tested for serum HBsAg, HBeAg, anti-HBe, anti-HBs, anti-HBc with enzyme linked immunoabsorbent assay and for serum alanine aminotransferase (ALT), gamma-glutamyltransferase (gamma-GT) and alkaline phosphatase (ALP) contents by colorimetry. These levels of enzymes in sera were compared after the students were stratified according to the status of HBV infection.. With the exclusion of the effect of HBV infection, three enzymes levels in sera between two groups of students showed significant differences (P < 0.01), much higher in exposure group than those in control group.. MC was possibly harmful to human beings in drinking water and induced the contents of some enzymes from the liver of human beings to increase in sera.

Topics: Adolescent; Adult; Bacterial Toxins; Carcinogens, Environmental; Child; China; Cross-Sectional Studies; Female; Humans; Liver Neoplasms; Male; Microcystins; Middle Aged; Peptides, Cyclic; Water Pollutants, Chemical; Water Supply

An epidemiological survey for the causes of a high incidence of primary liver cancer (PLC) in Haimen city, Jian-Su province and Fusui county, Guangxi province in China, found a close correlation between the incidence of PLC and the drinking of pond and ditch water. With an aim to clarify whether microcystins (MC), a hepatotoxic peptide produced by water bloom algae, contaminate the drinking water in the endemic areas of PLC in China, a highly sensitive enzyme-linked immunosorbent assay with a detection limit of 50 pg/ml, was introduced to monitor the MC. Three trials to survey the drinking water were carried out in 1993-1994. Samples, 1135 in total, were collected from different sources such as: ponds, ditches, rivers, shallow wells and deep wells in Haimen city. The first survey in September 1993 found that three out of 14 ditch water specimens were positive for MC, with a range of 90-460 pg/ml. Several toxic algae such as Oscillatoria agardhii were present in some of the ditches. In the second trial, samples were collected from five ponds/ditches, two rivers, two shallow wells and two deep wells monthly for the whole year of 1994. These data showed that MC was highest in June to September, with a range of 62-296 pg/ml. A third trial on the 989 different water samples collected from the different types of water sources in July 1994 revealed that 17% of the pond/ditch water, 32% of the river water, and 4% of the shallow-well water were positive for MC, with averages of 101, 160 and 68 pg/ml respectively. No MC was detected in deep well water. A similar survey on 26 drinking water samples in Fusui, Guangxi province, demonstrated a high contamination frequency of MC in the water of ponds/ditches and rivers but no MC in shallow and deep wells. These data support a hypothesis that the blue-green algal toxin MC in the drinking water of ponds/ditches and rivers, or both, is one of the risk factors for the high incidence of PLC in China. Based on previous findings on the epidemiology of PLC and the present results from the mass screening of MC in the drinking water, an advisory level of MC in drinking water was proposed to below 0.01 microg/l. The combined effect of a potent hepatocarcinogen AFB1 and an intermittent intake of MC in drinking water in the summer season was discussed as an etiology of PLC.

Topics: Antibodies, Monoclonal; China; Cyanobacteria; Enzyme-Linked Immunosorbent Assay; Humans; Incidence; Liver Neoplasms; Microcystins; Peptides, Cyclic; Sensitivity and Specificity; Water Pollutants; Water Supply

In order to study the pollution with microcystin (MC), a potent liver promoter, in drinking water in highly endemic area of liver cancer, cyanobacteria and its product MC were detected in drinking water in Haimen, Jiangsu Province during 1992 to 1993. Oscillatoria was identified as the most common species of cyanobacteria in pond-ditch and river water in Haimen, Jiangsu Province, which can produce MC. MC was detected in two of 65 water samples with high performance liquid chromatography, liquid chromatography and mass spectrography. In addition, studies were conducted in 989 samples collected from drinking water in Haimen, Jiangsu Province and more sensitive ELISA was used to detect their MC contents. Results showed proportions of samples with positive MC (greater than 50 pg/ml) were 17.3%, 31.9%, 4.3% and 0 for pond-ditch, river, shallow and deep well water, respectively, with average contents of 101, 160, 68 and 0 pg/ml, respectively. Proportions of positive MC samples and average MC contents for pond-ditch water were significantly greater than those in shallow and deep well water. It suggests studies on relationship between MC and liver cancer should be conducted further.

Topics: Carcinogens; Cyanobacteria; Humans; Liver Neoplasms; Microcystins; Peptides, Cyclic; Water Pollutants; Water Supply