Abstract

The cyanobacterial blooms produced by eutrophic water bodies have become a serious environmental issue around the world. After cellular lysing or algaecide treatment, microcystins (MCs), which are regarded as the most frequently encountered cyanobacterial toxins in fresh water, are released into water. Among all of the variants of MCs, MC-LR has been widely studied due to its severe hepatotoxicity. Since 1992, various studies have discovered the important role of MC-LR in the origin and progression of primary liver cancers (PLCs), while few reviews have focused on it. Therefore, this review aims to summarize the major achievements and shortcomings observed in the past few years. Based on the available literature, the mechanisms of how MC-LR induces or promotes PLCs are elucidated in this review. This review aims to enhance our understanding of the role that MC-LR plays in PLCs and provides a rational approach for future applications.

Key Contribution

Since 1992, various studies have discussed the important role of MC-LR in the origin and progression of primary liver cancers (PLCs), while few reviews have focused on it. Therefore, this review aims to summarize the major achievements and shortcomings of the research conducted in the past few years

Introduction

Contamination with harmful cyanobacterial blooms has become a serious environmental issue around the world [1]. Cyantoxins are essentially endotoxins that are released in water following cellular lysing or treatment with algaecides [2,3]. All major orders of Cyanobacteria can produce a family of hepatotoxins called microcystins (MCs), which are the most frequently encountered cyanotoxins in fresh water [4,5]. More than 279 congeners of MCs have been identified with molecular weights in the range of 882–1101 Da [6,7]. MC-LR – MCs combined with leucine (L) and arginine (R) at positions 2 and 4 (Figure 1) – is the most studied congener due to its ubiquity and toxicity [8,9]. The unique cyclic structure of MC-LR protects it from oxidation, heat, and hydrolysis, enhancing its stability in the environment and its resistance to biodegradation [10-12]. MC-LR can pose a threat to animals and humans through drinking contaminated water or through the food chain (Figure 2).

MC-LR can easily enter cells via organic anion-transporting polypeptides (OATPs) and accumulate in the target organs through blood circulation. As such, MC-LR can damage almost every system in the body, including the digestive system (liver [13,14], stomach [15], intestines [16], and pancreas [15]), nervous system (brain [17,18]), respiratory system (lung [19-21]), circulatory system (heart [22]), dermal system (skin [22,23]), genital system (testicles [24], prostate [25], ovaries [26]), etc. In addition, experimental studies have indicated that MC-LR exposure may play an important role in the origin and progression of various cancers [27-29]. Thus, MC-LR was classified as a Group 2B carcinogen by the International Agency for Research on Cancer in 2010.

Primary liver cancer (PLC) ranks as the sixth most common cancer and the third leading cause of cancer-related death in the world, accounting for more than 800 thousand deaths in 2020 [30]. The main types of PLC include hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and other rare types [31]. HCC and ICC are both malignant tumors originating from hepatocytes and the biliary epithelium, respectively [32]. The biological behaviors of HCC and ICC are completely different. MC-LR was first reported as a potent liver cancer promoter in 1992, and a range of related studies have been published in last 30 years [14]. However, there are few reviews focusing on the role of MC-LR in PLC. Previous studies mainly focused on the relationship between HCC and MC-LR, while recent research has discussed the role of MC-LR in ICC [33]. For the deeper understanding of the effects of MC-LR in PLCs, data on the function and mechanism of MC-LR in PLC was collected in this paper to review these findings. 

Summary

Microcystin-LR (MC-LR) has been shown to participate in the origin and progression of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). MC-LR was found to be able to inhibit the activity of phosphatase 2A (PP2A) activity and to be able to activate the Akt and MAPK signaling pathways, resulting in abnormal cell proliferation in hepatocytes. The inhibition of PP2A in hepatic stellate cells induced by MC-LR was also found to promote liver fibrosis and to result in the development of HCC. MC-LR can induce the accumulation of reactive oxygen species and damage the DNA in hepatocytes, which have been confirmed to be related to the formation of HCC. In addition, MC-LR can regulate expression of the proteins associated with hepatocarcinogenesis by influencing non-coding RNAs, including microRNAs, circular RNAs, long ncRNAs, as well as by influencing DNA methylation. Furthermore, some studies have demonstrated persistent carcinogenic changes and impaired hepatic recovery after MC-LR toxicity in nonalcoholic steatohepatitis-a risk factor for liver cirrhosis and HCC. Moreover, serum MC-LR levels have been confirmed to be involved in the onset and prognosis of HCC. Moreover, we have also proposed for the first time that MC-LR can induce abnormal cell proliferation in human intrahepatic biliary epithelial cells in vivo and in vitro via the direct inhibition of PP2A in biliary epithelial cells and that it has an indirect influence on the surrounding macrophages. Clinical studies have also been conducted to investigate the role of MC-LR in the poor prognosis of ICC patients, and MC-LR was identified as the independent prognostic factor for over-survival and recurrence-free survival.

Future Directions

The role of microcystin-LR (MC-LR) in primary liver cancers (PLCs) has been studied extensively, but there are still many problems to be solved. Firstly, the effects of MC-LR on the prognosis of hepatocellular carcinoma (HCC) have not been entirely confirmed. Though Lei et al. discovered that MC-LR can worsen the prognosis of HCC patients, patients who were not positive for chronic hepatitis B virus infection were not included, and those who were heavy drinkers were also not included in the study, severely reducing the reliability of the research. The molecular mechanism of MC-LR that participates in the prognosis of HCC has not yet been explained with clarity and carefulness. Secondly, the scope of future studies should be expanded to include an in-depth focus on the role of MC-LR in intrahepatic cholangiocarcinoma (ICC), with the second incidence in PLCs. Previous studies have identified that MC-LR is associated with the origin and prognosis of ICC. However, the influence of MC-LR on the incidence of ICC in human has not been confirmed. Past clinical studies have mainly focused on the relationship between MC-LR and HCC. In addition, how the mechanism of MC-LR induces pathological alteration in intrahepatic bile ducts and causes physiopathology changes still requires further study. A better understanding of MC-LR in PLCs may accelerate the progress of novel therapeutics to prevent liver cancer and may improve patient prognosis.

This entry is adapted from the peer-reviewed paper 10.3390/toxins14100715