The Hippo-Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis.
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.
Lee
Kwang-Pyo
KP
Department of Biological Sciences, Graduate School of Medical Science and Engineering, National Creative Research Initiatives Center, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
Lee
Joo-Hyeon
JH
Kim
Tae-Shin
TS
Kim
Tack-Hoon
TH
Park
Hee-Dong
HD
Byun
Jin-Seok
JS
Kim
Min-Chul
MC
Jeong
Won-Il
WI
Calvisi
Diego F
DF
Kim
Jin-Man
JM
Lim
Dae-Sik
DS
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008099:Liver / Q000033:anatomy & histology / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; C485935:Sav1 protein, mouse; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D017346:Protein Serine-Threonine Kinases
Nat Cell Biol. 2003 Oct;5(10):921-7
14502295
EMBO J. 2004 Sep 15;23(18):3677-88
15343267
Nat Genet. 1999 Feb;21(2):182-6
9988269
Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1431-6
20080598
Hum Gene Ther. 2002 Mar 1;13(4):533-42
11874631
Proc Natl Acad Sci U S A. 2003 Sep 30;100 Suppl 1:11881-8
12902545
Mol Cell Biol. 2006 Jan;26(1):77-87
16354681
Hepatology. 2006 Feb;43(2 Suppl 1):S89-98
16447292
Genes Dev. 2007 Nov 1;21(21):2747-61
17974916
Mech Dev. 2003 Jan;120(1):117-30
12490302
Liver. 1998 Aug;18(4):288-93
9766827
Curr Biol. 2007 Dec 4;17(23):2054-60
17980593
Cell. 2006 Jun 30;125(7):1253-67
16814713
Hepatology. 2003 Mar;37(3):632-40
12601361
J Clin Invest. 2005 Sep;115(9):2330-40
16110324
J Gastroenterol Hepatol. 2006 Jul;21(7):1093-8
16824058
Cancer Res. 2008 Apr 15;68(8):2789-94
18413746
Lab Invest. 1999 Feb;79(2):103-9
10068199
J Biol Chem. 2008 Feb 29;283(9):5496-509
18158288
J Hepatol. 2004 Feb;40(2):298-304
14739102
Am J Pathol. 1989 Jun;134(6):1347-63
2474256
Oncogene. 2006 Jun 26;25(27):3818-22
16799623
Cancer. 2009 Oct 1;115(19):4576-85
19551889
J Biol Chem. 2008 Oct 10;283(41):27534-27546
18640976
Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1437-42
20080689
Environ Health Perspect. 1993 Dec;101 Suppl 5:15-26
7516873
Nat Rev Mol Cell Biol. 2004 Oct;5(10):836-47
15459664
Exp Toxicol Pathol. 1993 Aug;45(4):239-44
8219714
J Gastroenterol Hepatol. 2008 May;23(5):687-98
18410603
Cell. 2007 Sep 21;130(6):1120-33
17889654
Cancer Cell. 2009 Nov 6;16(5):425-38
19878874
Nature. 2004 Oct 28;431(7012):1112-7
15475948
Carcinogenesis. 2002 Mar;23(3):435-45
11895858
Genes Dev. 2008 Jul 15;22(14):1962-71
18579750
World J Gastroenterol. 2004 Sep 1;10(17):2482-7
15300889
Mol Cell Biol. 2009 Dec;29(23):6309-20
19786569
Cancer Cell. 2008 Mar;13(3):188-92
18328423
Am J Pathol. 2008 May;172(5):1238-47
18385520
Differentiation. 1993 Dec;55(1):19-26
8299877
Histopathology. 2003 Sep;43(3):263-71
12940779
Biochem J. 2008 Apr 1;411(1):1-18
18333835
Hepatology. 2005 Jun;41(6):1252-61
15880565
Cell. 2002 Aug 23;110(4):467-78
12202036
EMBO J. 2008 Apr 23;27(8):1231-42
18369314
Cell Metab. 2008 Mar;7(3):227-35
18316028