Hepatocellular carcinoma caused by loss of heterozygosity in Lkb1 gene knockout mice

Masayuki Nakau, Hiroyuki Miyoshi, Michael F Seldin, Masayuki Imamura, Masanobu Oshima, Makoto M. Taketo

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

Germline mutations of the LKB1 gene are associated with PeutzJeghers 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.

Original languageEnglish (US)
Pages (from-to)4549-4553
Number of pages5
JournalCancer Research
Volume62
Issue number16
StatePublished - Aug 15 2002

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Gene Knockout Techniques
Loss of Heterozygosity
Knockout Mice
Hepatocellular Carcinoma
Hamartoma
Peutz-Jeghers Syndrome
Haploinsufficiency
Germ-Line Mutation
Pigmentation
Polyps
Sex Characteristics
Genes
Neoplasms
Western Blotting
Polymerase Chain Reaction
Liver

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Nakau, M., Miyoshi, H., Seldin, M. F., Imamura, M., Oshima, M., & Taketo, M. M. (2002). Hepatocellular carcinoma caused by loss of heterozygosity in Lkb1 gene knockout mice. Cancer Research, 62(16), 4549-4553.

Hepatocellular carcinoma caused by loss of heterozygosity in Lkb1 gene knockout mice. / Nakau, Masayuki; Miyoshi, Hiroyuki; Seldin, Michael F; Imamura, Masayuki; Oshima, Masanobu; Taketo, Makoto M.

In: Cancer Research, Vol. 62, No. 16, 15.08.2002, p. 4549-4553.

Research output: Contribution to journalArticle

Nakau, M, Miyoshi, H, Seldin, MF, Imamura, M, Oshima, M & Taketo, MM 2002, 'Hepatocellular carcinoma caused by loss of heterozygosity in Lkb1 gene knockout mice', Cancer Research, vol. 62, no. 16, pp. 4549-4553.
Nakau M, Miyoshi H, Seldin MF, Imamura M, Oshima M, Taketo MM. Hepatocellular carcinoma caused by loss of heterozygosity in Lkb1 gene knockout mice. Cancer Research. 2002 Aug 15;62(16):4549-4553.
Nakau, Masayuki ; Miyoshi, Hiroyuki ; Seldin, Michael F ; Imamura, Masayuki ; Oshima, Masanobu ; Taketo, Makoto M. / Hepatocellular carcinoma caused by loss of heterozygosity in Lkb1 gene knockout mice. In: Cancer Research. 2002 ; Vol. 62, No. 16. pp. 4549-4553.
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