| Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib. | |
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MedLine Citation:
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PMID: 22811581 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-07-18 |
Journal Detail:
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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:
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Created Date: 2012-09-18 Completed Date: 2013-03-22 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 9502500 Medline TA: Clin Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 4997-5007 Citation Subset: IM |
Copyright Information:
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©2012 AACR. |
Affiliation:
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Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York, NY 10029, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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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:
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1R01DK076986-01/DK/NIDDK NIH HHS; 1R01DK37340/DK/NIDDK NIH HHS; 1R01DK56621/DK/NIDDK NIH HHS; R01 DK076986/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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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 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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