, Joo-Hyeon Leea,1
, Tae-Shin Kima
, Tack-Hoon Kima
, Hee-Dong Parka
, Jin-Seok Byunb
, Min-Chul Kima
, Won-Il Jeongb
, Diego F. Calvisic
, Jin-Man Kimd
, and Dae-Sik Lima,2
National Creative Research Initiatives Center, Department of Biological Sciences and b
Graduate School of Medical Science and Engineering, Biomedical Research Center, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea; c
Institut fur Pathologie, Ernst-Moritz-Arndt-Universitat, Greifswald 17487, Germany; and d
Department of Pathology, College of Medicine, Chungnam National University, Daejeon 301-721, Korea
Edited by Tyler Jacks, Massachusetts Institute of Technology, Cambridge, MA, and approved March 31, 2010 (received for review October 23, 2009)
K.-P.L. and J.-H.L. contributed equally to this work.
Loss of Hippo signaling in Drosophila
leads to tissue overgrowth as a result of increased cell proliferation and decreased cell death. YAP (a homolog of Drosophila
Yorkie and target of the Hippo pathway) was recently implicated in control of organ size, epithelial tissue development, and tumorigenesis in mammals. However, the role of the mammalian Hippo pathway in such regulation has remained unclear. We now show that mice with liver-specific ablation of WW45 (a homolog of Drosophila
Salvador and adaptor for the Hippo kinase) manifest increased liver size and expansion of hepatic progenitor cells (oval cells) and eventually develop hepatomas. Moreover, ablation of WW45 increased the abundance of YAP and induced its localization to the nucleus in oval cells, likely accounting for their increased proliferative capacity, but not in hepatocytes. Liver tumors that developed in mice heterozygous for WW45
deletion or with liver-specific WW45 ablation showed a mixed pathology combining characteristics of hepatocellular carcinoma and cholangiocarcinoma and seemed to originate from oval cells. Together, our results suggest that the mammalian Hippo-Salvador pathway restricts the proliferation of hepatic oval cells and thereby controls liver size and prevents the development of oval cell-derived tumors.
conditional knockout mice, DDC diet, hepatoma, WW45, YAP
To whom correspondence should be addressed.
Author contributions: K.-P.L., J.-H.L., and D.-S.L. designed research; K.-P.L., J.-H.L., T.-S.K., T.-H.K., H.-D.P., J.-S.B., M.-C.K., W.-I.J., D.F.C., J.-M.K., and D.-S.L. performed research; K.-P.L., J.-H.L., T.-S.K., T.-H.K., H.-D.P., J.-S.B., M.-C.K., W.-I.J., D.F.C., J.-M.K., and D.-S.L. analyzed data; and K.-P.L., J.-H.L., and D.-S.L. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.0912203107/-/DCSupplemental