DOI: 10.1101/507301Dec 28, 2018Paper

The mutational features of aristolochic acid-induced mouse and human liver cancers

BioRxiv : the Preprint Server for Biology
Zhao-Ning LuZe-Guang Han

Abstract

Aristolochic acid (AA) derived from traditional Chinese herbal remedies has recently been statistically associated with human liver cancer; however, the causal relationships between AA and liver cancer and the underlying evolutionary process of AA-mediated mutagenesis during tumorigenesis are obscure. Here, we subjected mice, including Pten -deficient ones, to aristolochic acid I (AAI) alone or a combination of AAI and carbon tetrachloride (CCl4), which may induce liver injury. Significantly, AAI promoted the development of liver cancer, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma, in a dose-dependent manner, and it increased the incidence of liver cancer, together with CCl4 or Pten deficiency. AAI could lead to DNA damage and AAI-DNA adducts that initiate liver cancer via characteristic A>T transversions, as indicated by the comprehensive genomic analysis, which revealed recurrent mutations in Hras and some genes encoding components of the Ras/Raf, PI3K, Notch, Hippo, Wnt, DNA polymerase family and the SWI/SNF complex, some of which are also often found in human liver cancer. Mutational signature analysis across human cancer types revealed that the AA-related dominant signature was especially implica...Continue Reading

Related Concepts

Malignant Neoplasms
Carbon Tetrachloride
Chemically Induced
DNA Damage
DNA-Directed DNA Polymerase
Biological Evolution
Genes
Laboratory mice
Aristolochic acid I
TP53 gene

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