The change of gene expression related to DNA damage induced by aflatoxins.
Abstract
Hepatocellular carcinoma (hepatocarcinoma) is a major type of primary liver cancer and one of the most frequent human malignant neoplasms. Aflatoxins are I-type chemical carcinogen for hepatocarcinoma. Increasing evidence has shown that hepatocarcinoma induced by aflatoxins is the result of interaction between aflatoxins and hereditary factor. Aflatoxins can induce DNA damage including DNA strand break, adducts formation, oxidative DNA damage, and gene mutation and determine which susceptible individuals feature cancer. Inheritance such as alterations may result in the activation of proto-oncogenes and the inactivation of tumor suppressor genes and determine individual susceptibility to cancer. Interaction between aflatoxins and genetic susceptible factors commonly involve in almost all pathologic sequence of hepatocarcinoma: chronic liver injury, cirrhosis, atypical hyperplastic nodules, and hepatocarcinoma of early stages. In this review, we discuss the biogenesis, toxification, and epidemiology of aflatoxins and signal pathways of aflatoxin-induced hepatocarcinoma. We also discuss the roles of some important genes related to cell apoptosis, DNA repair, drug metabolism, and tumor metastasis in hepatocarcinogenesis related to aflatoxins.
Keywords
- hepatocellular carcinoma
- molecular mechanism
- aflatoxin
1. Introduction
Hepatocellular carcinoma (also called hepatocarcinoma or liver carcinoma) is a major type of primary liver cancer and one of the most frequent human malignant neoplasms. This malignancy has been proved to correlate with aflatoxins, especially aflatoxin B1 (AFB1) [1, 2, 3]. Increasing evidence has exhibited that several mechanisms, including the toxic production from metabolism, the accumulation of DNA damage and genic mutation–induced aflatoxins, the decreasing DNA repair capacity, and dysregulation of signal pathways may play a central role in the tumorigenesis of aflatoxin-induced hepatocarcinoma [4, 5, 6]. In this review, we discuss the biogenesis, metabolism, and genic toxification of aflatoxins. We also discuss the molecular mechanisms of aflatoxin-induced hepatocarcinoma, involving in aflatoxin toxification, abnormal change of tumor relative genes, the interaction of aflatoxins and genetic factors, and signal pathway for tumorigenesis. The roles of some important genes related to cell apoptosis, DNA repair, drug metabolism, and tumor metastasis in hepatocarcinogenesis related to aflatoxins are further emphasized.
2. Aflatoxin biosynthesis, metabolism, and toxification
2.1. Aflatoxin biosynthesis
The biosynthesis of aflatoxins has been fully summarized in several previous reviews [7, 8]. In brief, aflatoxins are an important type of mycotoxins, which were the most early identified in the
Toxigenic strains of
Numeral synthetical genes, such as aflatoxin regulatory protein gene (aflR), are required for aflatoxin biosynthesis and act as a huge neighbor gene cluster consisting of about 60–70 kb in original fungi (Figure 1) [8, 9, 10]. All corresponding gene-encoding enzymes and transcription factors produce aflatoxin production and regulate biosynthesis. Increasing evidence has proved that aflatoxin biosynthesis involves in at least 3 stages and 18 enzyme steps (Figures 2–4). The first stage, including the first (R01) to eighth reaction (R08) of biosynthesis, refers from acetyl CoA to hydroxyversicolorone. The primary product hydroxyversicolorone will be formed and regulated by transcription factors aflR and aflJ (Figure 2) [8, 10]. The second (biosynthesis reaction: R09–R12) (Figure 3) and third stages (biosynthesis reaction: R13–R18) (Figure 4) refer from hydroxyversicolorone to versicolorin B and from versicolorin B (VB) to the formation of ultimate products, respectively. These two stages involve in the formation of hydroxy- and non–hydroxy-versicolorone, and toxins. During the aflatoxin synthesis, more than 10 nicotinamide-adenine dinucleotide phosphate reduced form (NAPDH), one nicotinamide-adenine dinucleotide (NAD), and 2
2.2. The metabolism of aflatoxins in liver
Aflatoxins synthesized in the mycelia are finally excreted into such mediums as cereals (maize, wheat, sorghum, rice, and millet), nuts (peanuts, pistachios, walnuts, Brazil nut, and coconut), spices (chili, turmeric, paprika, black pepper, and ginger), and seeds. Epidemiological studies have exhibited that AFB1 is the most common in contaminated human foods [8, 10]. Once this aflatoxin in the mediums is taken into body, it is metabolized via two-stage reactions in the liver. The first-stage metabolisms include reduction reaction (ketoreduction to aflatoxicol), oxidative reaction (O-dealkylation to aflatoxin P1), and hydrolytic reactions (hydroxylation to aflatoxin M1, aflatoxin Q1, and aflatoxin B2). This stage reaction involves numerous enzymes such as cytochromes P450 (CYP450), monooxygenases, amino-oxidases, alcohol dehydrogenases, epoxide-hydrolases, aldehyde-reductases, and ketone-reductases. The second-stage reaction mainly comprises covalent binding reaction (toxic produces) and conjugation reaction (excretion and detoxification). Through these metabolites, aflatoxins ultimately transform into nontoxic secretions and toxic products [10, 11].
2.3. The toxification of aflatoxins in liver
Toxification of aflatoxins in liver is mainly divided into acute and chronic toxic effects. Data from epidemiological, experimental, and clinical studies have shown that above 6000 mg exposure of aflatoxin through digestion will cause acute severe liver damage and subsequent illness or death. This kind of acute effect is mainly associated with malfunction of the liver induced by toxic metabolic products. For chronic toxic effects, chronic exposure of aflatoxins can induce DNA damage and produce genotoxicity and carcinogenicity. In the past decades, increasing evidence has proved that AFB1 as aflatoxins often induce genic mutations such as TP53 and are among the most carcinogenic substances known and the major cancerous hepatocarcinoma risk factor.
3. The molecular mechanisms of aflatoxin-induced hepatocarcinoma
As described earlier, the main chronic toxification of aflatoxins is chronic liver damage and induced tumorigenesis of hepatocarcinoma. AFB1 has been proved as an I-type chemical carcinogen. Mechanisms of AFB1-induced hepatocarcinoma mainly involve in DNA damage and repair, the inactivation of tumor suppressor genes and the activation of oncogenes from genic mutations, abnormal immunoreaction, and inheritance alterations.
3.1. Aflatoxin-induced DNA damage
Increasing evidence has shown that the carcinogenicity of aflatoxins results from aflatoxin-induced DNA damage, including the formation of DNA adducts, DNA single strand breaks (SSBs) or double strand breaks (DSBs), chromosomal aberration damage (CAD), unscheduled DNA synthesis (USDS), abnormal chromatid exchange (ACE), the formation of micronuclei and macronuclei, and oxidation DNA damage. Of these DNA damages, AFB1-DNA adducts are the most common damage types and consist of 8,9-dihydro-8-(N7-guanyl)-9-hydroxy–AFB1 adduct (AFB1-GA) and ring-opened formamidopyrimidine AFB1 adduct (AFB1-FAPYA). The formation of AFB1-GA begins from AFB1 covalent binding to DNA and its product 8,9-epoxide-AFB1 (AFBE) by CYP450 [12, 13]. This adduct can automatically not only give rise to AFB1-FAYPA, which is accumulated using a time-dependence and nonenzyme pathway, but also be transferred into AFP1, AFM1, AFQ1, and other products by metabolic enzymes.
Additionally, AFB1 also induces oxidation DNA damage such as 8-oxodeoxyguanosine (8-oxyG). These damages induced by aflatoxins, if not timely repaired, can cause subsequent repair-resistant adducts and depurination or lead to error-prone DNA repair resulting in DSBs, SSBs, USDs, CAD, ACE, and frame shift mutations. Interestingly, the accumulation of DNA damages is positively associated with the time and the levels of aflatoxin exposure and modifies the risk of hepatocarcinoma through regulating the expression of some genes such as a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) [14], X-ray repair complementing 4 (XRCC4) [15], microRNA-4651 [16], and so on (Table 1). For example, Huang et al. [14] investigated the association between AFB1-DNA adducts via a hospital-based case control study and found increasing AFB1-DNA adducts negatively correlated with ADAMTS5 expression. It is known that ADAMTS5 may act as a tumor suppressor gene via decreasing vascular endothelial growth factor (VEGF) expression and inhibiting tumor angiogenesis and metastasis [17]. The downregulation of XRCC4 by increasing AFB1-DNA adducts decreases repair capacity for SSBs and DSBs and increases risk of tumor suppressor gene TP53 mutation and tumors [15, 18, 19, 20, 21, 22]. These genes progress the tumorigenesis and progression of hepatocarcinoma via regulating DNA repair capacity and angiogenesis. Although AFB1-DNA adducts are mainly produced in liver cells, they are also found in the immune cells and may regulate the immune function. Thus, DNA damage may be an important molecular event and may play a crucial role in the carcinogenesis of hepatocarcinoma caused by aflatoxins.
Gene | Expression change | Role of change in the hepatocarcinoma carcinogenesis | Ref |
---|---|---|---|
ADAMTS5 | Down | Angiogenesis, metastasis, prognosis | [14] |
XRCC4 | Down | Low DNA repair capacity, gene mutation | [15] |
MicroRNA-4651 | Up | Angiogenesis, metastasis, prognosis | [16] |
MicroRNA-24 | Up | Angiogenesis, metastasis, prognosis | [23] |
MicroRNA-429 | Up | Angiogenesis, metastasis, prognosis | [24] |
3.2. The mutagenesis of aflatoxins
Aflatoxin-induced DNA adducts can produce depurination, DSBs, the substitution of DNA bases, and frame shift mutations. In the past decades, the
3.3. The abnormality of tumor suppressor genes induced by aflatoxins
Studies
Gene | Study design | Change | Significance | Ref |
---|---|---|---|---|
TP53 | Mice model with HNP | Expression ↑ | DNA damage ↑ | [39] |
bcl2 | Mice model with HNP | Expression ↓ | DNA damage ↑ | [39] |
p27 | Hepatocytes |
Expression ↓ | DNA damage ↑ | [40] |
p21 | Hepatocytes |
Expression ↓ | DNA damage ↑ | [40] |
TP53 | HCCs (n = 223) | Expression ↑, multiplot mutation | Carcinogenesis | [41] |
TP53 | HCCs (n = 124) | Mutation at codon 249: 60% | Carcinogenesis | [42] |
H2AX | HCC cells |
Phosphorylation | Carcinogenesis | [43] |
BP1 | HCC cells |
Phosphorylation | Carcinogenesis | [43] |
TP53 | HCCs (n = 52) | Mutation at codon 249: 50% | Carcinogenesis | [44] |
p16 | HCCs (n = 40) | Methylation | Carcinogenesis | [45] |
p53 | HCCs (n = 40) | Multiplot mutation | Carcinogenesis | [45] |
p53 | AFB1-induced mutation |
Multiplot mutation at CpG | Carcinogenesis | [46] |
TP53 | HCCs (n = 64) plus a meta-analysis | Mutation at codon 249: 36%, protein accumulation: 50% | Carcinogenesis | [47] |
TP53 | Mice model with HNP | Multiplot mutation | Carcinogenesis | [48] |
TP53 | HCC cells |
AFB1-induced mutation at codon 249 promoting IGF-II expression | Carcinogenesis | [49] |
TP53 | Atcc-Ccl13 |
Mutation at codon 249 | Carcinogenesis | [50] |
TP53 | HCCs (n = 36) | Mutation at codon 249 | Carcinogenesis | [51] |
TP53 | Mice model | Mutation at codon 249 and 346, mutant protein increasing | Carcinogenesis | [52, 53, 54, 55, 56, 57] |
TP53 | HCCs (n = 60) | Mutation at codon 249: 69% | Carcinogenesis | [58, 59] |
TP53 | Hepatocytes |
Multiplot mutation | Carcinogenesis | [60] |
TP53 | HCCs (n = 110) | Mutation at codon 249: 69% | DNA damage, carcinogenesis | [61] |
TP53 | HCCs (n = 15) | Mutation at codon 249 and 254 | Carcinogenesis | [62] |
TP53 | HCC cells |
AFB1-induced Mutation at codon 249 | Carcinogenesis | [63] |
TP53 | HCCs (n = 18) | Mutation at codon 249: 53% | Carcinogenesis | [64] |
3.4. The abnormality of oncogenes induced by aflatoxins
In the past decades, the abnormality of oncogenes induced by aflatoxins has mainly been focused on c-myc and ras genes, involving in the activation, expression, and mutation of proto-oncogenes (Table 3). For example, Tashiro et al. investigated the effects of AFB1 exposure on oncogenes based on rat model with AFB1-induced hepatomas and found that the expression of both c-myc and c-Ha-ras was upregulated in all the tumors [65]. They also observed c-Ha-ras amplification and rearrangement [65]. In Fischer rat models with AFB1- and AFG1-induced liver tumors, Sinha et al. observed that aflatoxins can induce activation of N-ras and spot mutation of G to A at codon 12 of Ki-ras [66]. This type of activation and mutation will increase in the tissues with liver cancer than those with noncancers [66, 67, 68, 69]. Results from
Gene | Study design | Change | Significance | Ref |
---|---|---|---|---|
N-ras | HCCs (n = 36) | Mutation at codon 61 | Carcinogenesis | [51] |
c-myc | Mice model with HNP | Expression ↑, amplification, rearrangement | Carcinogenesis | [65] |
c-Ha-ras | Mice model with HNP | Expression ↑, amplification, rearrangement | Carcinogenesis | [65] |
Ki-ras | Mice model with HNP | Activation | Carcinogenesis | [69] |
N-ras | Mice model with HNP | Activation | Carcinogenesis | [66] |
Ki-ras | Mice model with HNP | Mutation at codon 12 | Carcinogenesis | [66] |
N-ras | Mice model with HCC | Activation | Carcinogenesis | [67] |
Ki-ras | Mice model with HCC | Activation | Carcinogenesis | [67] |
c-Ha-ras | Mice model with HNP | Mutation at codon 61: 40–60% | Carcinogenesis | [71, 72] |
3.5. The interaction of aflatoxins and hepatitis B virus promoting hepatocarcinogenesis
The interaction of aflatoxins and hepatitis B virus (HBV) has been proved in the carcinogenesis of hepatocarcinoma by molecular epidemiological and clinicopathological studies and systematically reviewed by several studies [73, 74, 75]. In brief, the first clinicopathological evidence of aflatoxins interacting with HBV was provided by Yeh et al. [76]. Through a case-control study design conducted in Guangxi Area, they found that these HBV-positive individuals with high AFB1 exposure consumption featured 10-times the mortality rate compared with those with low exposure consumption. Results from multivariable interactive analyses have further convinced that AFB1 multiplicatively interacted with HBV status for promoting hepatocarcinoma risk [77, 78, 79, 80]. For example, Williams et al. reported that the risk of developing hepatocarcinoma was 6.37 for aflatoxin exposure, 11.3 for HBV infection, and 73.0 for the combination of aflatoxin and HBV [77]. The following several molecular epidemiological studies with large-size samples from areas with high aflatoxin exposure and high HBV infection in China showed remarkably multiplicative effect for hepatocarcinoma risk (multiplicative interaction: 63.2 (both positive) > 1.9 (AFB1 positive) × 9.5 (HBV positive) [78, 79, 80].
This interaction of two hepatocarcinogenic causes has been proved in the transgenic mice models with overexpressing HBV large envelope polypeptide [81]. Results from this study exhibited that animals will produce more rapid and extensive hepatic dysplasia and hepatocarcinoma under the conditions with aflatoxin consumption [81]. Similar findings have also shown in the studies based on woodchuck and duck models [82, 83, 84].
The aflatoxins interacting with HBV infection promoting hepatocarcinoma development mechanically involve in the following aspects. First, HBV infection directly or indirectly increases the sensitivity of hepatocytes on the toxification of aflatoxins. Evidence from observation studies have displayed that HBV-positive carriers have more amount of aflatoxin adducts than those with negative HBV status, although they are from the same high aflatoxin exposure area [85, 86]. The active product of aflatoxin AFBE is found to significantly increase the risk of viral DNA integrating into damaged DNA strand [87]. This promotes malignant transformation of damaged hepatocytes by aflatoxins. Second, HBV infection increases the mutation frequency at codon 249 of TP53 gene and coordinates with aflatoxins for abrogating the normal functions of TP53 (such as the control of cell cycle, DNA damage repair, and cell apoptosis), which contributes to multisteps of hepatic carcinogenesis [64, 88]. Third, the HBV X gene–expressing protein inhibits base excision repair potential and results in an increasing accumulation of aflatoxin-DNA adducts [89]. Finally, HBV infections can cause hepatocytic necrosis, inflammatory proliferation, and oxygen/nitrogen active products, which may increase the likelihood of aflatoxin-induced mutations and the cellular clonal expansion containing mutations [90, 91, 92].
3.6. The interaction of aflatoxins and inheritance alterations promoting hepatocarcinogenesis
Increasing evidence has exhibited that the genetic alterations in DNA repair genes increase the amount of AFB1-DNA adducts and the frequency of hot-spot mutation at codon 249 of TP53 gene and may promote hepatic toxification of aflatoxins [1, 19, 20, 22, 37, 93, 94, 95, 96, 97, 98]. Joint analyses based on meta-analyses further showed this kind of toxic effects (Table 4) [1, 22]. The genetic variants in other genes, such as CYP450, glutathione
Gene | RS# | Genotype | TP53M | DNA adducts | |||
---|---|---|---|---|---|---|---|
% | Risk | Mean | |||||
XRCC1 | rs25487 | CC | 46.51 | Reference | 3.276 | ||
CT | 45.25 | 2.419 | 3.371 × 10−11 | 3.264 | 0.899 | ||
TT | 8.24 | 5.028 | 6.651 × 10−6 | 3.640 | 0.026 | ||
XRCC3 | rs861539 | GG | 32.17 | Reference | 2.990 | ||
GA | 43.55 | 1.380 | 0.018 | 3.216 | 0.025 | ||
AA | 24.28 | 1.524 | 0.011 | 3.897 | 4.962 × 10−14 | ||
XRCC7 | rs7003908 | AA | 21.24 | Reference | 2.879 | ||
AC | 46.06 | 1.883 | 1.372 × 10−5 | 3.347 | 1.663 × 10−5 | ||
CC | 32.71 | 2.089 | 4.368 × 10−6 | 3.550 | 1.751 × 10−8 | ||
XRCC4 | rs28383151 | GG | 67.03 | Reference | 3.308 | ||
GA | 21.68 | 1.688 | 0.001 | 3.405 | 0.069 | ||
AA | 11.29 | 3.829 | 7.387 × 10−6 | 3.721 | 2.867×10−4 | ||
XRCC4 | rs3734091 | GG | 72.31 | Reference | 3.229 | ||
GT | 17.56 | 2.799 | 9.191 × 10−7 | 3.439 | 0.095 | ||
TT | 10.13 | 5.104 | 3.826 × 10−6 | 3.654 | 0.005 | ||
XPD | rs13181 | TT | 34.41 | Reference | 2.926 | ||
TG | 41.85 | 1.458 | 0.005 | 3.253 | 0.011 | ||
GG | 23.75 | 1.744 | 0.001 | 4.062 | 4.265 × 10−6 | ||
XPC | rs2228001 | TT | 34.05 | Reference | 3.083 | ||
TG | 48.30 | 1.500 | 0.002 | 3.332 | 0.001 | ||
GG | 17.65 | 1.818 | 0.001 | 3.666 | 3.404 × 10−22 |
3.7. The aflatoxin-caused immunosuppression promoting hepatocarcinogenesis
Increasing evidence from
4. Limitation and further direction
In the past decades, the advance in pathological mechanisms of aflatoxin-related hepatocarcinoma held great promise. However, we are still far from a comprehensive view of this kind of potentials. First, the detailed metabolic step and corresponding enzymes, especially the first-stage reaction and toxicity mechanisms, have not been elucidated. Second, although the activation of aflatoxins is found to act as a crucial step, it is unclear how the tumorigenesis of hepatocarcinoma is triggered by aflatoxins. Third, the vast literature for aflatoxin-induced hepatocarcinoma mainly focuses on the studies on AFB1, and some important information may have been lost. Fourth, in spite of some evidence of AFB1 inducing abnormal immunoreaction and interacting with hepatitis virus and genetic factors, they are at the primary stage and still far from elucidation. Therefore, the detailed toxicity mechanisms of aflatoxins and corresponding carcinogenesis mechanism will greatly benefit our understanding of aflatoxin-related hepatocarcinoma.
5. Summary
It has been shown that increasing exposure of aflatoxins may promote the carcinogenesis of hepatocarcinoma. Molecular mechanisms of aflatoxin-induced hepatocarcinoma involve in DNA damage, gene mutations, the inactivation of such tumor suppressor gene as TP53, the activation of proto-oncogenes, abnormal immunoreaction, and the interaction between aflatoxins and other carcinogens such as HBV. However, an understanding of aflatoxin-induced hepatocarcinoma is far from complete, and further research in this field is looked forward to elucidating more detailed mechanisms responsible for hepatocarcinoma related to aflatoxins in the future.
Conflicts of interest and source of funding
The authors declare no competing financial interests. This study was supported in part by the National Natural Science Foundation of China (Nos. 81760502, 81572353, 81372639, 81472243, 81660495, and 81460423), the Innovation Program of Guangxi Municipal Education Department (Nos. 201204LX674 and 201204LX324), Innovation Program of Guangxi Health Department (No. Z2013781), the Natural Science Foundation of Guangxi (Nos. 2017GXNSFGA198002, 2017JJF10001, 2017GXNSFAA198002, 2016GXNSFDA380003, 2015GXNSFAA139223, 2013GXNSFAA019251, 2014GXNSFDA118021, and 2014GXNSFAA118144), Research Program of Guangxi “Zhouyue Scholar” (No. 2017-38), Research Program of Guangxi Specially-invited Expert (No. 2017-6th), Research Program of Guangxi Clinic Research Center of Hepatobiliary Diseases (No. AD17129025), and Open Research Program from Molecular Immunity Study Room Involving in Acute & Severe Diseases in Guangxi Colleges and Universities (Nos. kfkt20160062 and kfkt20160063).
Abbreviations
AFB1 | aflatoxin B1 |
AFB2 | aflatoxin B2 |
AFG1 | aflatoxin G1 |
AFG2 | aflatoxin G2 |
AFP | α-fetoprotein |
A. flavus | Aspergillus flavus |
A. parasiticus | Aspergillus parasiticus |
A. nidulans | Aspergillus nidulans |
A. pseudotamarii | Aspergillus pseudotamarii |
A. bombycis | Aspergillus bombycis |
HBV | hepatitis virus B |
HCV | hepatitis virus C |
Hepatocarcinoma | hepatocellular carcinoma |
NAPDH | nicotinamide-adenine dinucleotide phosphate reduced form |
NAD | one nicotinamide-adenine dinucleotide |
SAM | S-adenosylmethionine |
CYP450 | cytochromes P450 |
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