This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nakau, M. Articles by Taketo, M. M. Search for Related Content PubMed PubMed Citation Articles by Nakau, M. Articles by Taketo, M. M.

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.

This article has been cited by other articles:

				M. Jansen, J. P. ten Klooster, G. J. Offerhaus, and H. Clevers LKB1 and AMPK Family Signaling: The Intimate Link Between Cell Polarity and Energy Metabolism Physiol Rev, July 1, 2009; 89(3): 777 - 798. [Abstract] [Full Text] [PDF]

				Z. Xie, Y. Dong, J. Zhang, R. Scholz, D. Neumann, and M.-H. Zou Identification of the Serine 307 of LKB1 as a Novel Phosphorylation Site Essential for Its Nucleocytoplasmic Transport and Endothelial Cell Angiogenesis Mol. Cell. Biol., July 1, 2009; 29(13): 3582 - 3596. [Abstract] [Full Text] [PDF]

				S. Rodriguez-Nieto and M. Sanchez-Cespedes BRG1 and LKB1: tales of two tumor suppressor genes on chromosome 19p and lung cancer Carcinogenesis, April 1, 2009; 30(4): 547 - 554. [Abstract] [Full Text] [PDF]

				D. Fan, C. Ma, and H. Zhang The molecular mechanisms that underlie the tumor suppressor function of LKB1 Acta Biochim Biophys Sin, February 1, 2009; 41(2): 97 - 107. [Abstract] [Full Text] [PDF]

				A. K. Rustgi The genetics of hereditary colon cancer Genes & Dev., October 15, 2007; 21(20): 2525 - 2538. [Abstract] [Full Text] [PDF]

				Y. Kojima, H. Miyoshi, H. C. Clevers, M. Oshima, M. Aoki, and M. M. Taketo Suppression of Tubulin Polymerization by the LKB1-Microtubule-associated Protein/Microtubule Affinity-regulating Kinase Signaling J. Biol. Chem., August 10, 2007; 282(32): 23532 - 23540. [Abstract] [Full Text] [PDF]

				P.-Y. Zeng and S. L. Berger LKB1 Is Recruited to the p21/WAF1 Promoter by p53 to Mediate Transcriptional Activation. Cancer Res., November 15, 2006; 66(22): 10701 - 10708. [Abstract] [Full Text] [PDF]

				S. Upadhyay, C. Liu, A. Chatterjee, M. O. Hoque, M. S. Kim, J. Engles, W. Westra, B. Trink, E. Ratovitski, and D. Sidransky LKB1/STK11 Suppresses Cyclooxygenase-2 Induction and Cellular Invasion through PEA3 in Lung Cancer Cancer Res., August 15, 2006; 66(16): 7870 - 7879. [Abstract] [Full Text] [PDF]

				C. Wilson, C. Bonnet, C. Guy, S. Idziaszczyk, J. Colley, V. Humphreys, J. Maynard, J. R. Sampson, and J. P. Cheadle Tsc1 Haploinsufficiency without Mammalian Target of Rapamycin Activation Is Sufficient for Renal Cyst Formation in Tsc1+/- Mice Cancer Res., August 15, 2006; 66(16): 7934 - 7938. [Abstract] [Full Text] [PDF]

				H Mehenni, N Resta, J-G Park, M Miyaki, G Guanti, and M C Costanza Cancer risks in LKB1 germline mutation carriers Gut, July 1, 2006; 55(7): 984 - 990. [Abstract] [Full Text] [PDF]

				A J Bauer and C A Stratakis The lentiginoses: cutaneous markers of systemic disease and a window to new aspects of tumourigenesis J. Med. Genet., November 1, 2005; 42(11): 801 - 810. [Abstract] [Full Text] [PDF]

				J.-S. Lee, J. W. Grisham, and S. S. Thorgeirsson Comparative functional genomics for identifying models of human cancer Carcinogenesis, June 1, 2005; 26(6): 1013 - 1020. [Abstract] [Full Text] [PDF]

				D. G. Hardie The AMP-activated protein kinase pathway - new players upstream and downstream J. Cell Sci., November 1, 2004; 117(23): 5479 - 5487. [Abstract] [Full Text] [PDF]

				J. M. Ward and D. E. Devor-Henneman Mouse Models of Human Familial Cancer Syndromes Toxicol Pathol, January 1, 2004; 32(1_suppl): 90 - 98. [Abstract] [PDF]

				A. I. Jimenez, P. Fernandez, O. Dominguez, A. Dopazo, and M. Sanchez-Cespedes Growth and Molecular Profile of Lung Cancer Cells Expressing Ectopic LKB1: Down-Regulation of the Phosphatidylinositol 3'-Phosphate Kinase/PTEN Pathway Cancer Res., March 15, 2003; 63(6): 1382 - 1388. [Abstract] [Full Text] [PDF]