Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas
Yasuo Horie, Akira Suzuki, Ei Kataoka, Takehiko Sasaki, Koichi Hamada, Junko Sasaki, Katsunori Mizuno, Go Hasegawa, Hiroyuki Kishimoto, Masahiro Iizuka, Makoto Naito, Katsuhiko Enomoto, Sumio Watanabe, Tak Wah Mak, Toru Nakano
Yasuo Horie, Akira Suzuki, Ei Kataoka, Takehiko Sasaki, Koichi Hamada, Junko Sasaki, Katsunori Mizuno, Go Hasegawa, Hiroyuki Kishimoto, Masahiro Iizuka, Makoto Naito, Katsuhiko Enomoto, Sumio Watanabe, Tak Wah Mak, Toru Nakano
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Article Oncology

Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas

Abstract

PTEN is a tumor suppressor gene mutated in many human cancers, and its expression is reduced or absent in almost half of hepatoma patients. We used the Cre-loxP system to generate a hepatocyte-specific null mutation of Pten in mice (AlbCrePtenflox/flox mice). AlbCrePtenflox/flox mice showed massive hepatomegaly and steatohepatitis with triglyceride accumulation, a phenotype similar to human nonalcoholic steatohepatitis. Adipocyte-specific genes were induced in mutant hepatocytes, implying adipogenic-like transformation of these cells. Genes involved in lipogenesis and β-oxidation were also induced, possibly as a result of elevated levels of the transactivating factors PPARγ and SREBP1c. Importantly, the loss of Pten function in the liver led to tumorigenesis, with 47% of AlbCrePtenflox/flox livers developing liver cell adenomas by 44 weeks of age. By 74–78 weeks of age, 100% of AlbCrePtenflox/flox livers showed adenomas and 66% had hepatocellular carcinomas. AlbCrePtenflox/flox mice also showed insulin hypersensitivity. In vitro, AlbCrePtenflox/flox hepatocytes were hyperproliferative and showed increased hyperoxidation with abnormal activation of protein kinase B and MAPK. Pten is thus an important regulator of lipogenesis, glucose metabolism, hepatocyte homeostasis, and tumorigenesis in the liver.

Authors

Yasuo Horie, Akira Suzuki, Ei Kataoka, Takehiko Sasaki, Koichi Hamada, Junko Sasaki, Katsunori Mizuno, Go Hasegawa, Hiroyuki Kishimoto, Masahiro Iizuka, Makoto Naito, Katsuhiko Enomoto, Sumio Watanabe, Tak Wah Mak, Toru Nakano

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Figure 5

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Liver tumors observed in AlbCrePtenflox/flox mice. (A) Macroscopic view ...
Liver tumors observed in AlbCrePtenflox/flox mice. (A) Macroscopic view of representative liver adenomas (arrows) observed in 9/19 flox/flox mice of 40_44 weeks of age. (B) H&E-stained section of a liver cell adenoma (T) in (A) flox/flox male mouse, showing its distinct demarcation from the surrounding nontumorous liver tissue. The adenoma hepatocytes contain large quantities of lipid. (C) H&E-stained section of a flox/+ liver (male, 42 weeks). (D) Macroscopic view of a representative mutant liver (male) showing the HCCs observed in 8/12 flox/flox mice at 74_78 weeks of age. (E) H&E-stained section of the flox/flox (male) liver in (D), showing an HCC with a trabecular-like arrangement that disrupts normal liver architecture. (F) Lung of the mouse in D, showing a metastasis (T). Magnifications are ∞40 (B), ∞400 (C), ∞400 (E), and ∞400 (F).