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Hepatocellular Carcinoma Caused by Loss of Heterozygosity in Lkb1 Gene Knockout Mice¹

Departments of Pharmacology [M N., H. M., M. O., M. M. T.] and Surgery [M. N., M. I.], Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; The Institute of Experimental Animal Sciences, Osaka University Medical School, Osaka 565-0871, Japan [H. M.]; and Rowe Program in Genetics, Department of Biological Chemistry, University of California, Davis, California 95616 [M.F.S.]

Germline mutations of the LKB1 gene are associated with Peutz-Jeghers syndrome, which is characterized by mucocutaneous pigmentation and gastrointestinal hamartoma with an increased risk of cancer development. To investigate the role of LKB1 in vivo, we have recently constructed Lkb1 gene knockout mice. Because of Lkb1 gene haploinsufficiency, the heterozygous Lkb1 mice develop gastrointestinal polyps of which the histological characteristics resemble those of the Peutz-Jeghers syndrome hamartomas. Here we demonstrate that the Lkb1 (+/-) mice develop hepatocellular carcinomas (HCCs). In Lkb1 (+/-) mice >50 weeks of age, >70% of the male mice developed HCCs, whereas only 20% of the females had HCCs, showing a sex difference in the susceptibility. Histological examinations revealed various types of HCCs, such as "trabecular," "clear cell," "pseudoglandular," and "sarcomatous" types, which were strikingly similar to those found in human HCCs. Western blotting and PCR analyses showed loss of Lkb1 heterozygosity in all of the HCC tissues examined, indicating a tumor suppressor role of LKB1 in the mouse liver. These results suggest that lack of LKB1 is a novel mechanism for HCC development. Thus, the Lkb1 (+/-) knockout mutant should be an important and useful model for human HCC.

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