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. 2023 Mar 15:487:153470.
doi: 10.1016/j.tox.2023.153470. Epub 2023 Feb 28.

Cyanotoxin exposure and hepatocellular carcinoma

Brenda Y Hernandez  1 , Xuemei Zhu  2 , Michelle Nagata  2 , Lenora Loo  2 , O Chan  2 , Linda L Wong  2
Affiliations

Cyanotoxin exposure and hepatocellular carcinoma

Brenda Y Hernandez et al. Toxicology. .

Abstract

Cyanobacteria are ubiquitous in aquatic and terrestrial environments worldwide and include a number of species producing tumor-promoting hepatotoxins. Human exposure to cyanobacteria and cyanotoxins primarily occurs though ingestion of contaminated drinking water and food sources. In a Northeast U.S. population, we recently reported an independent association of oral cyanobacteria with risk of hepatocellular carcinoma (HCC). In a cross-sectional study of 55 HCC patients in Hawaii, U.S.A., serum microcystin/nodularin (MC/NOD), cylindrospermopsin (CYN), and anabaenopeptin (AB) were measured by ELISA. In a subset of 16 patients, cyanotoxin levels were compared by tumor expression of over 700 genes analyzed via the Nanostring nCounter Fibrosis panel. MC/NOD, CYN, and AB were detected in all HCC patients. MC/NOD and CYN levels significantly varied by etiology with the highest levels in cases attributed to metabolic risk factors, specifically, hyperlipidemia, type 2 diabetes, and non-alcoholic fatty liver disease/non-alcoholic steatohepatitis. Cyanotoxin levels were significantly positively correlated with tumor expression of genes functioning in PPAR signaling and lipid metabolism. Our study provides novel albeit limited evidence that cyanotoxins may a role in the pathogenesis of HCC through the dysregulation of lipid metabolism and progression of hepatic steatosis.

Keywords: Cancer; Cyanotoxins; Cylindrospermopsin; Liver; Microcystin; Nodularin.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1.
Figure 1.
Comparisons of mean serum cyanotoxin concentrations (ng/ml) in hepatocellular carcinoma patients across all etiologic groups: a) microcystin/nodularin (p= 0.0052) (left) and; b) cylindrospermopsin (p=0.033) (right)
Figure 2.
Figure 2.
a) Comparisons of mean serum microcystin/nodularin concentrations (ng/ml) in hepatocellular carcinoma patients with and without a history of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis, type 2 diabetes, and hyperlipidemia (p<0.05 for each comparison) (left); b) Comparisons of mean serum cylindrospermopsin concentrations (ng/ml) in hepatocellular carcinoma patients with and without a history of type 2 diabetes and hyperlipidemia (p<0.05 for each comparison) (right)
Figure 3.
Figure 3.
Tumor gene expression correlated with serum cyanotoxin levels (ng/ml): a) CD36 expression by microcystin, cylindrospermopsin, anabaenopeptin (r=0.53, p =0.0346; 0.60, p=0.0144; 0.70, p=0.002, respectively); b) LPL expression by microcystin, cylindrospermopsin, anabaenopeptin (r= 0.55, p=0.0285; r=0.68, p=0.0037; 0.58, p=0.019, respectively); c) FAPB4 expression by microcystin, cylindrospermopsin, anabaenopeptin (r=0.65, p=0.0063; r=0.64, p=0.0082; r=0.64, p=0.008. respectively).
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