Anja Lachenmayer 1 , 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 Show Affiliations »
Abstract
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. ©2012 AACR.
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. ©2012 AACR.
Entities: CellLine
Chemical
Disease
Gene
Mutation
Species
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Year: 2012
PMID： 22811581 PMCID： PMC3446854 DOI： 10.1158/1078-0432.CCR-11-2322
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531