Inactivation of hippo pathway is significantly associated with poor prognosis in hepatocellular carcinoma

Bo Hwa Sohn, Jae Jun Shim, Sang Bae Kim, Kyu Yun Jang, Soo Mi Kim, Ji Hoon Kim, Jun Eul Hwang, Hee Jin Jang, Hyun Sung Lee, Sang Cheol Kim, Woojin Jeong, Sung Soo Kim, Eun Sung Park, Jeonghoon Heo, Yoon Jun Kim, Dae Ghon Kim, Sun Hee Leem, Ahmed Kaseb, Manal M. Hassan, Minse ChaIn Sun Chu, Randy L. Johnson, Yun Yong Park, Ju Seog Lee

Research output: Contribution to journalArticlepeer-review

82 Citations (Scopus)

Abstract

Purpose: The Hippo pathway is a tumor suppressor in the liver. However, the clinical significance of Hippo pathway inactivation in HCC is not clearly defined. We analyzed genomic data from human and mouse tissues to determine clinical relevance of Hippo pathway inactivation in HCC. Experimental Design: We analyzed gene expression data from Mst1/2-/- and Sav1-/- mice and identified a 610-gene expression signature reflecting 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 HCC patients, via univariate and multivariate 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 Fudan University cohorts (n = 242, P = 0.001 for OS). On multivariate analysis, the signature was an independent predictor of recurrence-free survival (HR, 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). Conclusions: Inactivation of the Hippo pathway in HCC is significantly associated with poor prognosis. Clin Cancer Res; 22(5); 1256-64.

Original languageEnglish
Pages (from-to)1256-1264
Number of pages9
JournalClinical Cancer Research
Volume22
Issue number5
DOIs
Publication statusPublished - 2016 Mar 1
Externally publishedYes

Bibliographical note

Funding Information:
Grant Support This research was supported in part by the 2011 and 2012 cycles of the MD Anderson Sister Institute Network Fund (J.-S. Lee), Scientific Research Center Program grant 2012R1A5A1048236 and 2014R1A2A2A01003983 (W. Jeong), Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2014R1A1A2053529) (Y.-Y. Park), and the GlaxoSmithKline Research Fund of the Korean Association for the Study of the Liver (J.H. Kim).

Publisher Copyright:
© 2015 American Association for Cancer Research.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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