studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 329A
sion rate, and malignant macroscopic classification. Conclusion:
CTGF is up-regulated through Ras/Mek/Erk pathway in
HCC. CTGF promotes the progression of HCC and related with
its malignant characteristics. CTGF could be a new therapeutic
target against HCC.
Disclosures:
Hayato Hikita - Grant/Research Support: Bristol-Myers Squibb
Tetsuo Takehara - Grant/Research Support: Chugai Pharmaceutical Co., MSD
K.K., Bristol-Meyer Squibb, Mitsubishi Tanabe Pharma Corparation, Toray Industories
Inc. ; Speaking and Teaching: MSD K.K., Bristol-Meyer Squibb, Janssen
Pharmaceutical Companies
The following authors have nothing to disclose: Yuki Makino, Takahiro Kodama,
Minoru Shigekawa, Yugo Kai, Yasutoshi Nozaki, Tasuku Nakabori, Yoshinobu
Saito, Satoshi Tanaka, Ryotaro Sakamori, Naoki Hiramatsu, Tomohide Tatsumi
232
p62 is a Key Regulator for Initiation and Development
of Hepatocellular carcinoma
Atsushi Umemura 1,2 , Yoshito Itoh 1 , Maria T. Diaz-Meco 3 , Jorge
Moscat 3 , Michael Karin 2 ; 1 Department of Molecular Gastroenterology
and Hepatology, Graduate School of Medical Science,
Kyoto Prefectural University of Medicine, Kyoto, Japan; 2 Laboratory
of Gene Regulation and Signal Transduction, Department of
Pharmacology, University of California San Diego, San Diego,
CA; 3 Sanford-Burnham Medical Research Institute, San Diego, CA
p62, a scaffold protein interacting with various
signaling pathways, accumulates and forms aggregates
frequently observed in chronic liver diseases including NASH
(non-alcoholic steatohepatitis), ASH (alcoholic steatohepatitis),
and their progressed conditions, liver cirrhosis and hepatocellular
carcinoma (HCC). p62 has also been reported as a
critical oncoprotein involved in tumorigenesis and the development
of many types of cancer including lung, breast, and
kidney, whereas the tumorigenic role of p62 in the liver still
remains unknown. It is reported that loss of p62 suppresses
adenoma development in the autophagy knockout liver, importantly,
however, this liver does not develop HCC.
To elucidate the impact of p62 on HCC initiation and development,
we decided to use two different animal models. First off,
we injected a chemical carcinogen diethylnitrosamine (DEN),
which induces multiple HCCs 7 months later, into liver-specific
p62 knockout mice (p62KO) and their control mice (CON)
to evaluate HCC development. We then established liver-specific
TSC1 (tuberous sclerosis complex1)/p62 double-knockout
mice (DKO). It is reported that liver-specific TSC1 knockout
mice (TSC1KO) develop multiple HCCs spontaneously around
10-12 months old. This means that DKO mice are useful in
analyzing the role of p62 in hepatocarcinogenesis . CON mice developed multiple HCCs 7 months
after DEN injection, but p62KO mice showed much lower incidence
and smaller size of DEN-induced HCCs. Loss of TSC1 in
the liver induced multiple HCCs as expected, but surprisingly,
DKO mice did not developed HCCs nor even small tumors. In
addition, liver injury and fibrosis observed in TSC1KO mice
were attenuated in DKO livers. Among a number of signaling
pathways, which p62 may be involved, Nrf2 was clearly activated
in the livers of both DEN-injected CON and TSC1KO
mice, and this activation was diminished in DEN-injected
p62KO and DKO mice, respectively. Here we
show that p62 plays important roles in HCC initiation as well
as its development using two different HCC models. The Nrf2
signaling pathway seems to be the most crucial in both models.
Furthermore, additional p62 ablation ameliorated liver injury
and fibrosis in TSC1KO mice. p62 is a well-known regulator of
Nrf2 via its interaction with keap1. Since Nrf2 activation was
suppressed by deletion of p62, the p62/keap1/Nrf2 signaling
axis may profoundly contribute to hepatocarcinogenesis. In
conclusion, p62 has a strong oncogenic function in the liver
and is a promising target for HCC therapy.
Disclosures:
Yoshito Itoh - Grant/Research Support: MSD KK, Bristol-Meyers Squibb, Dainippon
Sumitomo Pharm. Co., Ltd., Otsuka Pharmaceutical Co., Chugai Pharm
Co., Ltd, Mitsubish iTanabe Pharm. Co.,Ltd., Daiichi Sankyo Pharm. Co.,Ltd.,
Takeda Pharm. Co.,Ltd., AstraZeneca K.K.:, Eisai Co.,Pharm.Ltd, FUJIFILM Medical
Co.,Ltd., Gelaed Sciences Co., GlaxoSmithKline
The following authors have nothing to disclose: Atsushi Umemura, Maria T. Diaz-
Meco, Jorge Moscat, Michael Karin
233
Sitagliptin, a Dipeptidyl Peptidase 4 inhibitor, Suppressed
Tumor Progression with Down-regulation of Nrf
Nuclear Expression in a Mouse Model of Non-alcoholic
Steatohepatitis-related Hepatocellular Carcinoma
Takumi Kawaguchi, Eitaro Taniguchi, Minoru Itou, Tetsuharu Oriishi,
Takuji Torimura; Division of Gastroenterology, Department of
Medicine, Kurume University School of Medicine, Kurume, Japan
Background and Aims: Sitagliptin is an anti-diabetic agent classified
as a dipeptidyl peptidase 4 (DPP4) inhibitor. Although
sitagliptin is known to improve non-alcoholic steatohepatitis
(NASH), the effects of sitagliptin on NASH-related hepatocellular
carcinoma (HCC) remains unclear. In addition, it is still
unclear whether sitagliptin affects Nrf, a transcription factor
regulating tumor proliferation via reprogramming of glucose
metabolism. The aims of this study are to investigate effects of
sitagliptin on HCC progression and nuclear expression of Nrf
in a mouse model of NASH-related HCC. Material and Methods:
A mouse model of NASH-related HCC without genetic
modification (STAM mice) was employed in this study. Eightweek
old STAM mice were orally administrated with either
sitagliptin (30 mg/kg/day: DPP4 group; n=7) or distilled
water (CON group; n=7) for 10 weeks. Then, the incidence,
number, and volume of HCC were evaluated by contrast-enhanced
computed tomography and histopathological examination.
Nuclear expression of Nrf in HCC and non-tumor tissues
were evaluated by immunostaining and quantified by Image
J (U. S. National Institutes of Health, Bethesda, MD). Results:
All mice survived until the end of this study. No significant
difference was seen in body weight and the amount of food
intake between the DPP4 and CON groups during the course
of this study. While, liver-to-body weight ratio was significantly
lower in the DPP4 group than in the CON group (7.3±1.2% vs.
11.0±1.8%, P