Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas

Horie, Yasuo; Suzuki, Akira; Kataoka, Ei; Sasaki, Takehiko; Hamada, Koichi; Sasaki, Junichi; Mizuno, Katsunori; Hasegawa, Go; Kishimoto, Hiroyuki; Iizuka, Masahiro; Naito, Makio; Enomoto, Katsuhiko; Watanabe, Sumio; Mak, Tak W.; Nakano, Toru

doi:10.1172/jci200420513

Cited by 198 publications

(279 citation statements)

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“…The TNAP-AID mouse model exhibits several characteristics of human HCC, in that the mice develop HCC spontaneously and the HCC tissue expresses a-fetoprotein and that it has the p53 gene mutations, some of which cause the same amino acid replacements as those seen in human tumours. Earlier HCC mouse models include mice with genetic modifications of Lkb1, Mdr2, Aox and Pten genes (Fan et al, 1998;Nakau et al, 2002;Horie et al, 2004;Katzenellenbogen et al, 2006), transgenic mice overexpressing c-myc, transforming growth factor-a, transforming growth factor-b1, HBx of hepatitis B virus and HCV core (Sandgren et al, 1989;Kim et al, 1991;Murakami et al, 1993;Koike et al, 1994Koike et al, , 2002Factor et al, 1997;Riehle et al, 2008) and chemical-or diet-induced HCC (Sell, 2001;Maeda et al, 2005;Ma et al, 2006;Sakurai et al, 2006). In contrast to these models, our TNAP-AID model is unique because it does not arbitrarily target specific oncogenes, tumour suppressors or stability genes.…”

Section: Discussionmentioning

confidence: 99%

A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations

et al. 2008

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Activation-induced cytidine deaminase (AID), the only enzyme that is known to be able to induce mutations in the human genome, is required for somatic hypermutation and class-switch recombination in B lymphocytes. Recently, we showed that AID is implicated in the pathogenesis of human cancers including hepatitis C virus (HCV)-induced human hepatocellular carcinoma (HCC). In this study, we established a new AID transgenic mouse model (TNAP-AID) in which AID is expressed in cells producing tissue-nonspecific alkaline phosphatase (TNAP), which is a marker of primordial germ cells and immature stem cells, including ES cells. High expression of TNAP was found in the liver of the embryos and adults of TNAP-AID mice. HCC developed in 27% of these mice at the age of approximately 90 weeks. The HCC that developed in TNAP-AID mice expressed a-fetoprotein and had deleterious mutations in the tumour suppressor gene Trp53, some of which corresponded to those found in human cancer. In conclusion, TNAP-AID is a mouse model that spontaneously develops HCC, sharing genetic and phenotypic features with human HCC, which develops in the inflamed liver as a result of the accumulation of genetic changes.

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Section: Discussionmentioning

confidence: 99%

A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations

et al. 2008

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“…20 Although loss of PTEN can occur as a result of mutations, these are rare in HCC. Changes in PTEN expression potentially may reflect aberrant expression of miR-21.…”

Section: Pten Is Involved In Mir-21-dependent Effects In Hcc Invasionmentioning

confidence: 99%

MicroRNA-21 Regulates Expression of the PTEN Tumor Suppressor Gene in Human Hepatocellular Cancer

et al. 2007

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“…Antoniades et al 1 are to be congratulated on their extensive study of intrahepatic and circulating macrophage populations in patients with acetaminophen-induced acute liver failure (ALF). However, their important findings deserve clarification.…”

Section: Functional Characteristics Of Macrophages In Patients With Amentioning

confidence: 99%

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2013

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Reply:We thank Dr. Anna Alisi and her colleagues for their interest in our recent study. We agree that the mechanism underlying the antisteatotic effects of all-trans-retinoic acid (ATRA) is not simple and may involve several pathways.Previous studies have demonstrated that the constitutive activation of AKT in pten knockout or pik3ca transgenic mice resulted in better glucose tolerance than their wildtype counterparts, despite severe steatosis, 1,2 while akt2 knockout induced hyperglycemia, but alleviated steatosis in ob/ob mice. 3 Because ATRA increased (although not significantly) AKT phosphorylation ( Fig. 1) and decreased the hepatic lipid content in mice that were fed a high-fat, high-fructose (HFHFr) diet, 4 the involvement of phosphatase and tensin homolog (PTEN) in the mode of action of ATRA remains to be clarified.We did not investigate PTEN expression but AKT phosphorylation was significantly higher in the HFHFr group and these results are consistent with the findings of Dr. Anna Alisi indicating that a high fructose-enriched diet could have inhibited PTEN activity. However, ATRA induced more intense AKT phosphorylation than that caused by the HFHFr diet, which suggests a mechanism different from that proposed by Dr. Anna Alisi. In fact, it has been reported that AKT phosphorylation is regulated by many molecules other than PTEN. 5 At the moment, we lack sufficient data to determine whether PTEN activity regulation by ATRA affects the anti-insulin action in these models.

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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

Cited by 198 publications

References 63 publications

A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations

A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations

MicroRNA-21 Regulates Expression of the PTEN Tumor Suppressor Gene in Human Hepatocellular Cancer

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