Inactivation of Hippo pathway is significantly associated with poor prognosis in hepatocellular
carcinoma
Bo Hwa Sohn1,2+, Sang-Bae Kim1,2+, Kyu Yun Jang3, Soo Mi Kim4, Ji Hoon Kim5, Shim Jae-Jun1,2, Hwang
Jun Eul1,2, Hee-Jin Jang1,2, Hyun-Sung Lee1,2, Sang-Cheol Kim6, Woojin Jeong7, Sung Soo Kim8, Eun
Sung Park9, Jeonghoon Heo10, Yoon Jun Kim11, Dae-Ghon Kim12, Sun-Hee Leem13, Ahmed Kaseb14, InSun Chu15, Randy L. Johnson16, Yun-Yong Park17*, and Ju-Seog Lee1,2,8*
1Department
of Systems Biology, 2Kleberg Center for Molecular Markers, 14Department of Gastrointestinal
Medical Oncology, and
16Department
of Biochemistry and Molecular Biology, Division of Cancer Medicine,
The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
3
Department of Pathology, 4Department of Physiology, and 12Division of Gastroenterology and
Hepatology, Department of Internal Medicine, Chonbuk National University Medical School and Hospital,
Jeonju, Korea.
5Division
of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College
of Medicine, Seoul, Korea.
6
Samsung Genome Institute, Samsung Medical Center, Gangnam-Gu, Seoul, Korea.
7
Department of Life Sciences, Division of Life and Pharmaceutical Sciences, Center for Cell Signaling and
Drug Discovery Research, Ewha Womans University, Seoul, Korea.
8
Department of Biochemistry and Molecular Biology, Medical Research Center and Biomedical Science
Institute, School of Medicine, Kyung Hee University, Seoul, Korea.
9
Institute for Medical Convergence, Yonsei University College of Medicine, Seoul, South Korea.
10
Departments of Molecular Biology and Immunology, Kosin University College of Medicine, Busan,
Korea.
11
Department of Internal Medicine and Liver Research Institute, Seoul National University College of
Medicine, Seoul, Korea.
13
Department of Biological Science, Dong-A University, Busan, Korea.
15
Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon,
Korea.
17ASAN
Institute for Life Sciences, ASAN Medical Center, Department of Medicine, University of Ulsan
College of Medicine, Seoul , Korea
+ These authors contributed equally to this work.
* Corresponding author. Tel: +1 713 834 6154; fax: +1 713 563 4235; e-mail address:
jlee@mdanderson.org (J-S. Lee); tel: +82 2 3010 8610; e-mail address: yypark@amc.seoul.kr (Y-Y.
Park).
Key Words: HCC, microarrays, genomics, prognosis, Hippo pathway
Abstract
Background & Aims: The Hippo pathway is a tumor suppressor in the liver, as demonstrated by the
development of hepatocellular carcinoma (HCC) after the pathway is inactivated in the livers of mice.
However, the clinical significance of Hippo pathway inactivation in HCC is currently unknown. In current
study, we aim to assess the clinical significance of inactivation of Hippo pathway in HCC.
Methods: We analyzed gene expression data from Mst1/2-/- and Sav1-/- mice and identified a 610-gene
expression signature that reflected Hippo pathway inactivation in the liver (silence of Hippo [SOH]
signature). By integrating gene expression data from mouse models with those from human HCC tissues,
we developed a prediction model that could identify HCC patients with an inactivated Hippo pathway and
used it to test its significance in four independent cohorts of HCC patients (n = 546), via univariate and
multi-variate Cox analyses.
Results: HCC patients (National Cancer Institute cohort, n = 113) with the SOH signature had a
significantly poorer prognosis than those without the SOH signature (P < 0.001 for overall survival [OS]).
The significant association of the signature with poor prognosis was further validated in the Korean
(n=100, P = 0.006 for OS) and Fundan University cohorts (n=242, P = 0.001 for OS). On multivariate
analysis, the signature was an independent predictor of recurrence-free survival (hazard ratio, 1.6; 95%
confidence interval, 1.12–2.28: P = 0.008). We also demonstrated significant concordance between the
SOH HCC subtype and the hepatic stem cell HCC subtype that had been identified in a previous study (P
< 0.001). Furthermore, the SOH signature was significantly correlated with a previously developed 65gene based recurrence risk score in HCC (P < 0.001).
Conclusions: Inactivation of the Hippo pathway in HCC is significantly associated with poor prognosis.