Reference SummarySheth SS, Oncogene 2006 Jun 15;25(25):3528-36

Title

Hepatocellular carcinoma in Txnip-deficient mice.

Authors

Sheth SS; Bodnar JS; Ghazalpour A; Thipphavong CK; Tsutsumi S; Tward AD; Demant P; Kodama T; Aburatani H; Lusis AJ

Journal

Oncogene

Volume

25

Issue

25

Year

2006

Pages

3528-36

Abstract

The molecular pathogenesis and the genetic aberrations that lead to the progression of hepatocellular carcinoma (HCC) are largely unknown. Here, we demonstrate that the thioredoxin interacting protein (Txnip) gene is a candidate tumor suppressor gene in vivo. We previously showed that the recombinant inbred congenic strain HcB-19 has a spontaneous mutation of the Txnip gene, and we now show that the strain has dramatically increased incidence of HCC, and that the HCC cosegregates with the Txnip mutation. Approximately 40% of the Txnip-deficient mice developed hepatic tumors with an increased prevalence in male mice. Visible tumors develop as early as 8 months of age. Histological analysis confirmed the morphology of HCC in the Txnip-deficient mice. Molecular markers of HCC, alpha-fetoprotein and p53, were increased in tumors of Txnip-deficient mice. The upregulation of p53 preceded tumor development; however, bromodeoxyuridine (BrdU) labeling of normal hepatic tissue of Txnip-deficient mice did not reveal increased cell proliferation. Finally, microarray analyses of tumor, non-tumor adjacent, and normal tissue of Txnip-deficient mice highlighted the genetic differences leading to the predisposition and onset of HCC. Our findings suggest that Txnip deficiency is sufficient to initiate HCC and suggest novel mechanisms in hepatocarcinogenesis.

Links

J:112292 – MGI References
16607285 – National Library of Medicine/PubMed
Visual Summary Grid

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
HcB-19/Dem-TxnipHyplip1 Liver hepatocellular carcinoma Liver

observed

HcB-19/Dem-TxnipHyplip1 Liver normal tissue (control) Liver

not applicable

HcB-19/Dem-TxnipHyplip1 Liver tumor Liver

observed - 66.09

C3H/DiSnA Liver tumor Liver

0

(HcB-19/Dem x CAST/Ei)F1 x HcB-19/Dem-TxnipHyplip1 Liver tumor Liver

28.89

(HcB-19/Dem x CAST/Ei)F1 x HcB-19/Dem-TxnipHyplip1/+ Liver tumor Liver

5.56