studies

1156A AASLD ABSTRACTS HEPATOLOGY, October, 2015
Inhibition of autophagy could be an attractive approach for
potentiating the antitumor effect of sorafenib in HCC.
Disclosures:
The following authors have nothing to disclose: Takayuki Kogure, Yasuteru
Kondo, Jun Inoue, Yu Nakagome, Yuta Wakui, Tatsuki Morosawa, Yasuyuki
Fujisaka, Teruyuki Umetsu, Tooru Shimosegawa
1944
The relationship between hepatocellular carcinoma
development and reduced expression levels of the
major germline genotype of PROSC, which is frequently
deleted in hepatocellular carcinoma
Daiki Miki 1,2 , Hidenori Ochi 1,2 , C. Nelson Hayes 1,2 , Hiromi Abe 1,2 ,
Sakura Akamatsu 1,2 , Atsushi Ono 1,2 , Takashi Nakahara 1,2 , Yizhou
Zhang 1,2 , Keiichi Masaki 1,2 , Hatsue Fujino 1,2 , Eisuke Miyaki 1,2 ,
Hiromi Kan 1,2 , Takuro Uchida 1,2 , Nobuhiko Hiraga 1,2 , Masataka
Tsuge 1,2 , Tomokazu Kawaoka 1,2 , Michio Imamura 1,2 , Yoshiiku
Kawakami 1,2 , Hiroshi Aikata 1,2 , Kazuaki Chayama 1,2 ; 1 Laboratory
for Digestive Diseases, RIKEN Center for Integrative Medical
Sciences, Hiroshima, Japan; 2 Department of Gastroenterology and
Metabolism, Hiroshima University Hospital, Hiroshima, Japan
Background & Aims: In this study, we focused on the recurrently
amplified or deleted genes in hepatocellular carcinoma (HCC)
tissues and examined the association between their baseline
expression levels, which are regulated by single nucleotide
polymorphisms (SNPs), and development of HCC. Methods:
We searched for expression quantitative trait loci (eQTLs) for
previously reported genes with copy number alterations from
a public database of non-transformed peripheral blood samples
that includes over 5,000 individuals. We then conducted
a case-control analysis of these eQTL SNPs or SNPs linked
to them (r 2 > 0.8 in both European and Asian populations)
using our SNP typing data in HCC cases (631 HBV-related
HCC, 554 HCV-related HCC) and 5,489 controls without
any liver diseases or cancers. Results: Among 13 recurrently
amplified genes, we found 10 cis-acting eQTL SNPs (i.e., the
SNP is located near the expressed gene) and 2 trans-acting
eQTL SNPs (i.e., the SNP is located far from the expressed
gene or on another chromosome). Among 18 recurrently
deleted genes, we found 15 eQTL SNPs and 3 trans-acting
eQTL SNPs. Among these 30 eQTL SNPs, we have successfully
genotyped 22 of either the target SNP, when available, or
else a closely linked SNP. We genotyped 9 cis-acting and 1
trans-acting eQTL SNPs for amplified genes, and 9 cis-acting
and 3 trans-acting eQTL SNPs for deleted genes. In case-control
analysis, no significant association was observed between
SNP frequencies and HCC development both in HBV-related
and HCV-related HCC studies (vs. controls). Subsequently, we
compared each HCC case to chronic HBV and HCV patients
without HCC (n = 1,997 and 1,354). After adjustment for
multiple testing, we found 2 significantly associated eQTL SNPs
with HCC for PROSC in the HBV study (Odds ratio [OR] =
1.27) and for TNFAIP3 in the HCV study (OR = 1.37), suggesting
their baseline expression levels may be important for
virus-related hepatocarcinogenesis. The risk allele of the eQTL
SNP for HBV-related HCC strongly down-regulates PROSC (P
= 8.25 × 10 -149 ), whereas the risk allele of the eQTL SNP
for HCV-related HCC weakly up-regulates TNFAIP3 (P = 2.60
× 10 -4 ). Furthermore, both PROSC and TNFAIP3 are recurrently
deleted genes in HCC. Taken together, the association
of the eQTL SNP for PROSC with HBV-related HCC susceptibility
seems to be more compatible than that for TNFAIP3 with
HCV-related HCC susceptibility. Conclusions: As a result of
integrative analysis using our large-scale genome-wide SNP
genotype data and public eQTL data, we suggest that germline
variants of recurrently deleted genes may affect viral hepatocarcinogenesis
by regulating their expression levels.
Disclosures:
Kazuaki Chayama - Consulting: AbbVie; Grant/Research Support: Ajinomoto,
Astellas, Torii, Tsumura, Aska, Bayer, Zeria, Daiichi Sankyo, Dainippon Sumitomo,
Eisai, Eli Lily, Janssen, Kowa, Mitsubishi Tanabe, MSD, Nippon Kayaku,
Nippon Shinyaku, Otsuka, Roche, Takeda, Toray; Speaking and Teaching:
Ajinomoto, AbbVie, Abott, Astellas, AstraZeneca, Aska, Bayer, BMS, Chugai,
Daiichi Sankyo, Dainippon Sumitomo, Eisai, J & J, Jimro, Miyarisan, MSD, Nihon
Kayaku, Olympus
The following authors have nothing to disclose: Daiki Miki, Hidenori Ochi, C.
Nelson Hayes, Hiromi Abe, Sakura Akamatsu, Atsushi Ono, Takashi Nakahara,
Yizhou Zhang, Keiichi Masaki, Hatsue Fujino, Eisuke Miyaki, Hiromi Kan, Takuro
Uchida, Nobuhiko Hiraga, Masataka Tsuge, Tomokazu Kawaoka, Michio
Imamura, Yoshiiku Kawakami, Hiroshi Aikata
1945
Steatosis Induces Wnt/Β-Catenin Pathway To Stimulate
Proliferation Of Hepatic Tumor Initiating Cells And Promote
Liver Cancer Development
Anketse D. Kassa 1 , Ni Zeng 1 , Vivian G. Medina 1 , Lina He 1 , Kaiting
Yang 1 , Indra Mahajan 1 , Chien-Yu Chen 1 , Richa Aggarwal 1 ,
Zhechu Peng 1 , Megan Rieger 2 , Chia-Lin Chen 2 , Keigo Machida 2 ,
Zea Borok 2 , Michael Kahn 2 , Bangyan L. Stiles 1,2 ; 1 Pharmacology
and Pharmaceutical Sciences, USC School of Pharmacy, Los Angeles,
CA; 2 Keck School of Medicine, USC, Los Angeles, CA
Obesity is a major compounding factor for liver cancer where
male with a body mass index (BMI) >35 has 4.52 fold higher
incidence of liver cancer vs. those with BMI between 18.5 and
24.9. In mouse models, constitutive activation of the insulin/
PI3K signaling pathway by deletion of the negative regulator
Pten (phosphatase and tensin homologue deleted on chromosome
10) leads to hepatosteatosis and later tumor phenotypes.
In this model (Pten loxP/loxP ; Alb-Cre + ), we have shown that the
presence of the underlying fatty liver condition is required for
the development of liver cancers, which expands from a population
of tumor initiating cells (TICs). In this study, we investigated
how fatty liver disease may contribute to cancer formation.
We show here that blocking fatty liver formation by genetic
or non-genetic approaches significantly reduced the TIC population.
Concomitantly, tumor development in the Pten loxP/loxP ;
Alb-Cre + mice is inhibited despite of the tumor transformation
signals of PTEN loss. We further demonstrated that hepatic
steatosis resulting from Pten deletion or high fat diet feeding
induces the activation of Wnt/b-catenin pathway. Genomic
profiling of human liver cancer specimens has indicated a high
prevalence of b-catenin activating mutation. However, consistent
with mouse studies that genetically modify b-catenin,
such mutation is not sufficient to drive malignant transformation.
We show here that Wnt/b-catenin activation signal is the
tumor promoting factor induced by lipid accumulation and that
this signal is critical for the expansion of the transformed liver
TICs. In the Pten loxP/loxP ; Alb-Cre + mice fed low caloric diet to
inhibit hepatic steatosis, reduced expression of Wnt ligands
is observed concurrent with inhibited expansion of TICs and
complete blockage of tumor development. Blocking the signal
of Wnt/b-catenin with shRNA or a pharmacological reagent
ICG-001 inhibits the proliferation of TICs in vitro and lead to
decreased accumulation of TICs and reduction of tumor grafts
in vivo. Together, our study suggests that fatty liver activates the
niche factor Wnt/b-catenin to promote tumorigenesis using the
Pten null liver cancer model.
Disclosures:
The following authors have nothing to disclose: Anketse D. Kassa, Ni Zeng, Vivian
G. Medina, Lina He, Kai-ting Yang, Indra Mahajan, Chien-Yu Chen, Richa
Aggarwal, Zhechu Peng, Megan Rieger, Chia-Lin Chen, Keigo Machida, Zea
Borok, Michael Kahn, Bangyan L. Stiles