Distinct response of the hepatic transcriptome to Aflatoxin B-1 induced hepatocellular carcinogenesis and resistance in rats

摘要

Aflatoxin is a natural potent carcinogen and a major cause of liver cancer. However, the molecular mechanisms of hepatocellular carcinogenesis remain largely unexplored. In this study, we profiled global gene expression in liver tissues of rats that developed hepatocellular carcinoma (HCC) from aflatoxin B-1 (AFB(1)) administration and those that were AFB(1)-resistant, as well as rats without AFB(1) exposure as a control. AFB(1) exposure resulted in extensive perturbation in gene expression with different functions in HCC and AFB(1) resistance (AR) samples. The differentially expressed genes (DEGs) in HCC sample were enriched for cell proliferation, cell adhesion and vasculature development that largely contribute to carcinogenesis. Anti-apoptosis genes were up-regulated in HCC sample whereas apoptosis-induction genes were up-regulated in AR sample. AFB(1) exposure also caused extensive alteration in expression level of lncRNAs. Among all the 4511 annotated lncRNAs, half of them were highly expressed only in HCC sample and up-regulated a group of protein-coding genes with cancer-related functions: apoptosis regulation, DNA repair, and cell cycle. Intriguingly, these genes were down-regulated by lncRNAs highly expressed in AR sample. Collectively, apoptosis is the critical biological process for carcinogenesis in response to AFB(1) exposure through changes in expression level of both protein-coding and lncRNA genes.