Serum microcystin levels positively linked with risk of hepatocellular carcinoma: A case‐control study in southwest China

Zheng, Chuanfen; Zeng, Hui; Lin, Hui; Jia, Wang; Feng, Xiaoshan; Qiu, Zhiqun; Chen, Jian; Luo, Jiaohua; Luo, Yang; Huang, Yujing; Wang, Lingqiao; Liu, Wenyi; Tan, Yao; Xu, Anwei; Yao, Yuan; Shu, Weiqun

doi:10.1002/hep.29310

Cited by 117 publications

(68 citation statements)

References 49 publications

(89 reference statements)

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“…While the conventional treatment technologies can eliminate intact toxic cyanobacterial cells effectively, these technologies have limited capability for removal of dissolved cyanobacterial toxins, which allows that these reach human populations via drinking water supplies in sufficiently high concentrations to cause adverse effects in the gastrointestinal system (Table 1). Chronic exposures to drinking water contaminated with cyanobacterial compounds, in some instances in combination with other confounding factors, have been associated with an increased incidence of liver cancers or chronic liver damage and diseases, as reviewed and discussed by Svirčev et al [12], and supported by recent findings [18][19][20]. Interestingly, epidemiologic studies have also linked chronic exposures to drinking water contaminated with cyanobacteria and their metabolites to the increased incidence of colorectal or small intestinal cancer in China [21], Portugal [22], and Serbia [12,23], or stomach cancer mortality in China [24].…”

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confidence: 82%

Effects of cyanobacterial toxins on the human gastrointestinal tract and the mucosal innate immune system

et al. 2019

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Background: Cyanobacterial blooms occur with increasing frequency in freshwater ecosystems, posing a hazard to human and environmental health. Exposure of human to cyanobacterial metabolites occurs mostly via accidental ingestion through contaminated drinking water or during recreational activities and, most frequently, results in gastrointestinal symptoms. Despite the clinical manifestation, cyanobacterial metabolites are rather investigated for their toxicity towards specific organs or tissues, especially hepato-, nephro-, and neurotoxicity, than for effects on the gastrointestinal tract and the associated lymphoid tissue. Main body: The aim of this review was to systematically summarize available literature on the effects on the gastrointestinal tract and the mucosal innate immune system and compile the data from both, in vitro and in vivo studies, focusing on human health-relevant models. Our systematic literature review revealed significant data gaps in the understanding on metabolites breaching the gastrointestinal barrier and the role of the immune system in the establishment of clinical symptoms. Microcystins and cylindrospermopsin were linked to gastrointestinal symptoms, immune system effects, or both. Furthermore, cyanobacterial bloom lipopolysaccharides, other less studied metabolites and their mixtures have been also implicated to have a role in gastrointestinal inflammation. Conclusion: The collected data indicate the need for a reassessment of potential enterotoxicity of microcystins and cylindrospermopsin. In addition, the carcinogenic potential of cyanotoxins, especially microcystins, has to be clarified, as an increasing amount of epidemiological studies show correlations between cyanobacterial blooms and gastrointestinal cancer incidence. Furthermore, other, often highly abundant bioactive metabolites such as aeruginosins, have to be toxicologically evaluated at distinct levels also accounting for (sub-)chronic exposure to low concentrations and in combination with naturally co-occurring metabolites, which can be expected in drinking water supplies.

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confidence: 82%

Effects of cyanobacterial toxins on the human gastrointestinal tract and the mucosal innate immune system

et al. 2019

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“…Microcystinleucine arginine (LR) displays L-leucine and L-arginine at the two positions, respectively, and is the most abundant toxicant among microcystin variants. Microcystin-LR is broadly reported to pose a threat to aquatic animals and humans 20,21 .…”

Section: Introductionmentioning

confidence: 99%

Microcystin-LR ameliorates pulmonary fibrosis via modulating CD206+ M2-like macrophage polarization

Wang

Zou

et al. 2020

Cell Death Dis

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Idiopathic pulmonary fibrosis (IPF) is a group of chronic interstitial pulmonary diseases characterized by myofibroblast proliferation and extracellular matrix deposition with limited treatment options. Based on our previous observation, we hypothesized microcystin-leucine arginine (LR), an environmental cyanobacterial toxin, could potentially suppress pulmonary fibrosis. In this study, we first demonstrated that chronic exposure of microcystin-LR by oral for weeks indeed attenuated the pulmonary fibrosis both on bleomycin-induced rat and fluorescein isothiocyanate-induced mouse models. Our data further indicated that treatment with microcystin-LR substantially reduced TGF-β1/Smad signaling in rat pulmonary tissues. The experiments in vitro found that microcystin-LR was capable of blocking epithelial-mesenchymal transition (EMT) and fibroblast-myofibroblast transition (FMT) through suppressing the differentiation of CD206 + macrophages. Mechanically, microcystin-LR was found to bind to glucose-regulated protein 78 kDa (GRP78) and suppress endoplasmic reticulum unfolded protein response (UPR ER) signaling pathways. These events led to the modulation of M2 polarization of macrophages, which eventually contributed to the alleviation of pulmonary fibrosis. Our results revealed a novel mechanism that may account for therapeutic effect of microcystin-LR on IPF.

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“…We randomly selected 96 patients with HCC from our previous case-control study [12]. Liver tumor tissues were collected following surgery on patients diagnosed with HCC from Army Medical University hospitals.…”

Section: Hcc Patient Tumor Tissues and Mc-lr Exposure Testmentioning

confidence: 99%

“…However, controversy surrounds whether MC-LR can induce tumor formation. Although chronic low-dose MC-LR exposure did not increase the risk of developing tumors or induce tumors in animals [9], some data has indicated its tumorigenicity in cell lines [10,11] and our recent population study demonstrated a significant positive correlation between serum MC-LR levels and risk of hepatocellular carcinoma (HCC) [12]. Hence, the objective of this study was to elucidate the effects and mechanisms of MC-LR in tumor inducement in vitro and in vivo.…”

mentioning

confidence: 96%

Chronic Microcystin-LR Exposure Induces Hepatocarcinogenesis via Increased Gankyrin in Vitro and in Vivo

He¹,

Huang²,

Guo³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Our recent study indicated that the serum microcystin-LR (MC-LR) level is positively linked to the risk of human hepatocellular carcinoma (HCC). Gankyrin is over-expressed in cancers and mediates oncogenesis; however, whether MC-LR induces tumor formation and the role of gankyrin in this process is unclear. Methods: We induced malignant transformation of L02 liver cells via 35 passages with exposure to 1, 10, or 100 nM MC-LR. Wound healing, plate and soft agar colony counts, and nude mice tumor formation were used to evaluate the tumorigenic phenotype of MC-LR-treated cells. Silencing gankyrin was used to confirm its function. We established a 35-week MC-LR exposure rat model by twice weekly intraperitoneal injection with 10 μg/kg body weight. In addition, 96 HCC patients were tested for tumor tissue gankyrin expression and serum MC-LR levels. Results: Chronic low-dose MC-LR exposure increased proliferation, mobility, clone and tumor formation abilities of L02 cells as a result of gankyrin activation, while silencing gankyrin inhibited the carcinogenic phenotype of MC-LR-treated cells. MC-LR also induced neoplastic liver lesions in Sprague-Dawley rats due to up-regulated gankyrin. Furthermore, a trend of increased gankyrin was observed in humans exposed to MC-LR. Conclusion: These results suggest that MC-LR induces hepatocarcinogenesis in vitro and in vivo by increasing gankyrin levels, providing new insight into MC-LR carcinogenicity studies.

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Serum microcystin levels positively linked with risk of hepatocellular carcinoma: A case‐control study in southwest China

Abstract: We provide evidence that serum MC-LR was an independent risk factor for HCC in humans, with an obvious positive interaction with hepatitis B virus and alcohol but a negative interaction with aflatoxin. (Hepatology 2017;66:1519-1528).

Cited by 117 publications

References 49 publications

Effects of cyanobacterial toxins on the human gastrointestinal tract and the mucosal innate immune system

Effects of cyanobacterial toxins on the human gastrointestinal tract and the mucosal innate immune system

Microcystin-LR ameliorates pulmonary fibrosis via modulating CD206+ M2-like macrophage polarization

Chronic Microcystin-LR Exposure Induces Hepatocarcinogenesis via Increased Gankyrin in Vitro and in Vivo

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