Characteristics of hepatocellular carcinoma in a murine model of alpha-1-antitrypsin deficiency.
OBJECTIVE
Individuals with homozygous (ZZ) alpha-1-antitrypsin (alpha1AT) deficiency are at an increased risk for liver damage, cirrhosis and hepatocellular carcinoma (HCC). The transgenic PiZ mouse, expressing the human alpha1AT mutant Z gene, is a valuable model for this disease. We studied PiZ mice in order to identify and characterize mechanisms involved in the development of HCC.


METHODS
Tumor incidence and histology were studied, gene expression levels were surveyed with microarrays, RNA quantified with quantitative real time polymerase chain reaction and protein levels determined with immunoblots and immunohistochemistry.


RESULTS
By 16-19 months of age, approximately 69% of the PiZ mice had developed tumors. HCC was present with no evidence of benign adenomas as pre-cancerous lesions. Tumors showed abnormal mitochondria, variable levels of steatosis, globular inclusions of alpha1AT mutant Z protein and metastases. PiZ mice that subsequently developed liver tumors had higher serum levels of alpha1AT mutant Z protein than those that did not develop tumors. Cyclin D1, a cell cycle protein, was upregulated in PiZ livers without tumors compared to Wt. cFOS, a component of AP-1 that may be involved in transforming cells and MCAM, an adhesion molecule likely involved in tumorigenesis and metastases, were elevated in tumors compared with livers without tumors.


CONCLUSIONS
In the PiZ model, many of the histological characteristics of HCC recapitulated features seen in human HCC, whether from individuals with homozygous ZZ liver disease or from unrelated causes in individuals that were not homozygous ZZ. The accumulation of mutant Z protein altered the regulation of several genes driving proliferation and tumorigenesis.
Marcus
Nancy Y
NY
Department of Pediatrics, Doisy Research Center, St Louis University School of Medicine, 1100 S, Grand Avenue, St Louis, MO 63104, USA. Email: nmarcus@slu.edu.
Brunt
Elizabeth M
EM
Blomenkamp
Keith
K
Ali
Faiza
F
Rudnick
David A
DA
Ahmad
Muneeb
M
Teckman
Jeffrey H
JH