The Serum MicroRNA Expression Modified the Genic Toxicity Caused by Aflatoxin B1
The serum microRNAs have been reported as potential biomarkers for hepatocellular carcinoma (HCC); however, their role in genic toxicity related to aflatoxin B1 (AFB1), such as TP53 mutation and DNA damage, has not yet been evaluated. Here, we conducted a hospital-based case-control study, including 558 patients with pathologically diagnosed HCC and positive AFB1 and healthy controls (n = 630) without any evidence of liver diseases. Genic toxicity related to AFB1 was evaluated using the hot-spot mutation at the codon 269 of TP53 gene (TP53M) and AFB1-DNA adducts. Through serum microRNA PCR microarray screening analysis, we observed 10 differentially expressed microRNAs (including miR-7-2-3p, miR-4651, miR-127-3p, miR-192-5p, miR-382-5p, miR-10b-5p, miR-532-3p, miR-16-5p, miR-106b-5p, and miR-4688) among HCC cases with positive AFB1 and controls with positive AFB1. The miR-4651 and miR-382-5p were further identified to be significantly higher in AFB1-positive HCC cases compared to controls. This kind of increasing serum levels was significantly and positively associated with frequency of TP53M and the levels of AFB1-DNA adduct. Furthermore, these microRNAs also modified the prognosis of HCC related to AFB1. These results suggest that the serum levels of microRNAs might be able to modify AFB1-induced genic toxicity, and microRNA-4651 and miR-382-5p, are such potential candidates.
Part of the book: Aflatoxin
Genetic Single Nucleotide Polymorphisms (GSNPs) in the DNA Repair Genes and Hepatocellular Carcinoma Related to Aflatoxin B1 among Guangxiese Population
Aflatoxin B1 (AFB1) is an important environmental carcinogen for the development of hepatocellular carcinoma (HCC). HCC is a complex disease likely resulting from genetic single nucleotide polymorphisms (GSNPs) of multiple interacting genes and gene-environment interactions. Recent efforts have been made to analyze the associations between risk of this malignancy and GSNPs in genes involved in the repair of DNA damage induced by AFB1. Here, we reviewed the results of published case-control studies that have examined the effects of common alleles of all susceptible DNA repair genes, including XRCC1, XRCC3, XRCC4, XRCC7, XPC, and XPD, on risk of AFB1-related HCC among Guangxi population. Statistically significant differences in genotype frequencies found in case-control comparisons were rs25487, rs80309960, rs861539, rs7003908, rs28383151, rs3734091, rs13181, and rs2228001 polymorphism. The overall effects of these GNSPs were moderate in terms of relative risk, with ORs ranging from 2 to 10. Furthermore, some evidence of the interaction of GSNPs in DNA repair genes and AFB1 exposure modulate risk of this cancer was also found, although the results require confirmation with larger sample size studies.
Part of the book: Genetic Polymorphisms
The Diagnostic and Prognostic Potential of MicroRNAs for Hepatocellular Carcinoma
Hepatocellular carcinoma (also termed hepatocarcinoma) is the third cancer-related cause of death worldwide. To our knowledge, markers such as α-fetoprotein display poor performance in the early diagnosis and prognosis prediction of hepatocarcinoma. MicroRNAs are an evolutionarily conserved class of small noncoding single-stranded RNA typically consisting of 18–24 nucleotides. They have been reported to act as tumor suppressors or oncogenes via reversely regulating gene expression. Recent evidence has revealed that microRNAs, especially in body fluids such as the blood and urine, display important diagnostic and prognostic potential for hepatocarcinoma. Here, we reviewed currently available data on microRNAs and hepatocarcinoma, with emphasis on the biogenesis and function of microRNAs and their potential diagnostic and prognostic value for hepatocarcinoma. We also discussed the clinical utility perspectives of microRNAs in hepatocarcinoma and possible challenges.
Part of the book: Hepatocellular Carcinoma
Molecular Mechanisms of Hepatocellular Carcinoma Related to Aflatoxins: An Update
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.
Part of the book: Liver Research and Clinical Management
The Role of Deubiquitinases in DNA Double-Strand Break Repair
DNA double-strand break (DSB) is a type of the most critical DNA lesions, and if not repaired promptly, it can result in cell death or a wide variety of genetic alterations including genome instability, large- or small-scale deletions, chromosome loss, loss of heterozygosity, and translocations. DSBs are repaired by double-strand break repair (DSBR), including nonhomologous end-joining (NHEJ) and homologous recombination (HR) pathway, and defects in these pathways cause genome instability and promote tumorigenesis. Accumulating evidence has demonstrated that the superfamily of deubiquitinases (DUBs) can regulate the action and stability of DNA repair enzymes involving in DSBR via modifying ubiquitination levels, a reversible posttranslational modification pathway. In this review, we will discuss ubiquitination/deubiquitination modification involving in DSBR genes, the role of DUBs in DSBR and corresponding mechanisms, and the potential effects of this modification on human diseases.
Part of the book: Ubiquitination Governing DNA Repair
Hepatocarcinoma Angiogenesis and DNA Damage Repair Response: An Update
Hepatocarcinoma is one of the most common lethal human malignant tumors, mainly because of active angiogenesis. This kind of high angiogenesis often accounts for early metastasis, rapid recurrence, and poor survival. Growing evidence has proved that hepatocarcinoma angiogenesis is closely associated with multiple risk factors, such as DNA damages resulting from hepatitis B and C virus infection, aflatoxin B1 exposure, ethanol intake, and obesity. Genetic alterations and genomic instability, probably resulting from low DNA damage repair response (DRR) and the following unrepaired DNA lesions, are also increasingly recognized as important risk factors of hepatocarcinoma angiogenesis. Dysregulation of DRRs and signaling to cell cycle checkpoints involving in DRR pathways may accelerate the accumulation of DNA damages and trigger the dysregulation of angiogenesis-related genes and the progression of hepatocarcinoma. In this review, we discussed DNA damages/DRRs and angiogenesis during hepatocarcinogenesis and their interactive regulations. Hopefully, the review will also remind the medical researchers and clinic doctors of further understanding and validating the values of DNA damages/DRRs in hepatocarcinoma angiogenesis.
Part of the book: DNA Repair
X-Ray Repair Cross Complementing 4 (XRCC4) Genetic Single Nucleotide Polymorphisms and the Liver Toxicity of AFB1 in Hepatocellular CarcinomaView all chapters
Our previous reports have shown that the genetic single-nucleotide polymorphisms (GSNPs) in the DNA repair gene X-ray repair cross complementing 4 (XRCC4) are involved in the carcinogenesis of hepatocellular carcinoma (HCC) induced by aflatoxin B1 (AFB1). However, the effects of GSNPs in the coding regions of XRCC4 on hepatic toxicity of AFB1 have been less investigated. We conducted a hospital-based clinic tissue samples with pathologically diagnosed HCC (n = 380) in a high AFB1 exposure area to explore the possible roles of GSNPs in the coding regions of XRCC4 in AFB1-induced HCC using liver toxicity assays. A total of 143 GSNPs were included in the present study and genotyped using the SNaPshot method, whereas the liver toxicity of AFB1 was evaluated using AFB1-DNA adducts in the tissues with HCC. In the clinicopathological samples with HCC, the average adduct amount is 2.27 ± 1.09 μmol/mol DNA. Among 143 GSNPs of XRCC4, only rs1237462915, rs28383151, rs762419679, rs766287987, and rs3734091 significantly increased the levels of AFB1-DNA adducts. Furthermore, XRCC4 GSNPs (including rs28383151, rs766287987, and rs3734091) also increased cumulative hazard for patients with HCC. These results suggest that the liver toxicity of AFB1 may be modified by XRCC4 GSNPs.
Part of the book: Aflatoxin B1 Occurrence, Detection and Toxicological Effects