Document Detail


Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib.
MedLine Citation:
PMID:  22811581     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: Hepatocellular carcinoma (HCC) is a heterogeneous cancer with active Wnt signaling. Underlying biologic mechanisms remain unclear and no drug targeting this pathway has been approved to date. We aimed to characterize Wnt-pathway aberrations in HCC patients, and to investigate sorafenib as a potential Wnt modulator in experimental models of liver cancer.
EXPERIMENTAL DESIGN: The Wnt-pathway was assessed using mRNA (642 HCCs and 21 liver cancer cell lines) and miRNA expression data (89 HCCs), immunohistochemistry (108 HCCs), and CTNNB1-mutation data (91 HCCs). Effects of sorafenib on Wnt signaling were evaluated in four liver cancer cell lines with active Wnt signaling and a tumor xenograft model.
RESULTS: Evidence for Wnt activation was observed for 315 (49.1%) cases, and was further classified as CTNNB1 class (138 cases [21.5%]) or Wnt-TGFβ class (177 cases [27.6%]). CTNNB1 class was characterized by upregulation of liver-specific Wnt-targets, nuclear β-catenin and glutamine-synthetase immunostaining, and enrichment of CTNNB1-mutation-signature, whereas Wnt-TGFβ class was characterized by dysregulation of classical Wnt-targets and the absence of nuclear β-catenin. Sorafenib decreased Wnt signaling and β-catenin protein in HepG2 (CTNNB1 class), SNU387 (Wnt-TGFβ class), SNU398 (CTNNB1-mutation), and Huh7 (lithium-chloride-pathway activation) cell lines. In addition, sorafenib attenuated expression of liver-related Wnt-targets GLUL, LGR5, and TBX3. The suppressive effect on CTNNB1 class-specific Wnt-pathway activation was validated in vivo using HepG2 xenografts in nude mice, accompanied by decreased tumor volume and increased survival of treated animals.
CONCLUSIONS: Distinct dysregulation of Wnt-pathway constituents characterize two different Wnt-related molecular classes (CTNNB1 and Wnt-TGFβ), accounting for half of all HCC patients. Sorafenib modulates β-catenin/Wnt signaling in experimental models that harbor the CTNNB1 class signature.
Authors:
Anja Lachenmayer; Clara Alsinet; Radoslav Savic; Laia Cabellos; Sara Toffanin; Yujin Hoshida; Augusto Villanueva; Beatriz Minguez; Philippa Newell; Hung-Wen Tsai; Jordi Barretina; Swan Thung; Stephen C Ward; Jordi Bruix; Vincenzo Mazzaferro; Myron Schwartz; Scott L Friedman; Josep M Llovet
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-07-18
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  18     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-09-18     Completed Date:  2013-03-22     Revised Date:  2013-09-18    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4997-5007     Citation Subset:  IM    
Copyright Information:
©2012 AACR.
Affiliation:
Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York, NY 10029, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / pharmacology*
Carcinoma, Hepatocellular / genetics,  metabolism*
Cell Line, Tumor
Cluster Analysis
Female
Gene Expression Profiling
Genomics
Hep G2 Cells
Humans
Liver Neoplasms / genetics,  metabolism*
Mice
Niacinamide / analogs & derivatives*,  pharmacology
Phenylurea Compounds / pharmacology*
Protein Kinase Inhibitors / pharmacology*
Reproducibility of Results
Transforming Growth Factor beta / genetics,  metabolism
Tumor Markers, Biological / genetics,  metabolism
Wnt Proteins / metabolism*
Wnt Signaling Pathway / drug effects*
beta Catenin / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
1R01DK076986-01/DK/NIDDK NIH HHS; 1R01DK37340/DK/NIDDK NIH HHS; 1R01DK56621/DK/NIDDK NIH HHS; R01 DK037340/DK/NIDDK NIH HHS; R01 DK056621/DK/NIDDK NIH HHS; R01 DK076986/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/CTNNB1 protein, human; 0/Phenylurea Compounds; 0/Protein Kinase Inhibitors; 0/Transforming Growth Factor beta; 0/Tumor Markers, Biological; 0/Wnt Proteins; 0/beta Catenin; 0/sorafenib; 98-92-0/Niacinamide
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