Abstract
Both hepatitis B virus (HBV) and aflatoxin B1 (AFB1) exposure can cause liver damage as well as increase the probability of hepatocellular carcinoma (HCC). To investigate the underlying genetic changes that may influence development of HCC associated with HBV infection and AFB1 exposure, HCC patients were subdivided into 4 groups depending upon HBV and AFB1 exposure status: (HBV(+)/AFB1(+), HBV(+)/AFB1(-), HBV(-)/AFB1(+), HBV(-)/AFB1(-)). Genetic abnormalities and protein expression profiles were analyzed by array-based comparative genomic hybridization and isobaric tagging for quantitation. A total of 573 chromosomal aberrations (CNAs) including 184 increased and 389 decreased were detected in our study population. Twenty-five recurrently altered regions (RARs; chromosomal alterations observed in ≥10 patients) in chromosomes were identified. Loss of 4q13.3-q35.2, 13q12.1-q21.2 and gain of 7q11.2-q35 were observed with a higher frequency in the HBV(+)/AFB1(+), HBV(+)/AFB1(-) and HBV(-)/AFB1(+) groups compared to the HBV(-)/AFB(-) group. Loss of 8p12-p23.2 was associated with high TNM stage tumors (P = 0.038) and was an unfavorable prognostic factor for tumor-free survival (P =0.045). A total of 133 differentially expressed proteins were identified in iTRAQ proteomics analysis, 69 (51.8%) of which mapped within identified RARs. The most common biological processes affected by HBV and AFB1 status in HCC tumorigenesis were detoxification and drug metabolism pathways, antigen processing and anti-apoptosis pathways. Expression of AKR1B10 was increased significantly in the HBV(+)/AFB1(+) and HBV(-)/AFB1(+) groups. A significant correlation between the expression of AKR1B10 mRNA and protein levels as well as AKR1B10 copy number was observered, which suggest that AKR1B10 may play a role in AFB1-related hepatocarcinogenesis. In summary, a number of genetic and gene expression alterations were found to be associated with HBV and AFB1- related HCC. The possible synergistic effects of HBV and AFB1 in hepatocarcinogenesis warrant further investigations.
Highlights
Hepatocellular carcinoma (HCC) is one of the most prevalent human cancers worldwide [1]
In Japan and the United States, more than 70% of cases are related to chronic HCV infection [4,5], while in Southern China and sub-Saharan Africa, HCC is associated with high dietary exposure to aflatoxin B1 (AFB1) and hepatitis B virus (HBV) infection and is the major causes of cancer mortality in these geographic areas [3,4,5]
We found that loss of 4q13.3-q35.2, 13q12.1-q21.2, as well as gain of 7q11.2-q35 was observed with a higher frequency in the HBV(+)/AFB1(+), HBV(+)/AFB1(-) and HBV(-)/AFB1(+) groups compared to the HBV(-)/AFB(-) group, suggesting that genes covered by these 3 recurrently altered regions (RARs) may play a role in HBV- and/or AFB1-related HCC carcinogenesis
Summary
Hepatocellular carcinoma (HCC) is one of the most prevalent human cancers worldwide [1]. Hepatocarcinogenesis is a complex process associated with the accumulation of genetic abnormalities that occur during initiation, promotion, and progression of the disease [6]. Both HBV infection and AFB1 exposure can cause liver damage, and increase the probability of HCC [2,7]. A number of studies have confirmed that more than 50% of HCC patients who have been exposed to AFB1 carry a mutation in codon 249 (AGGArg→AGTSer or AGGArg→AGCSer) of the p53 gene [9,10,11] This hotspot mutation is considered a molecular marker reflecting AFB1-induced DNA damage that eventually results in HCC [12,13,14]
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