Details

Autor(en) / Beteiligte

• LACHENMAYER, Anja
• ALSINET, Clara
• BARRETINA, Jordi
• THUNG, Swan
• WARD, Stephen C
• BRUIX, Jordi
• MAZZAFERRO, Vincenzo
• SCHWARTZ, Myron
• FRIEDMAN, Scott L
• LLOVET, Josep M
• SAVIC, Radoslav
• CABETLOS, Laia
• TOFFANIN, Sara
• HOSHIDA, Yujin
• VILLANUEVA, Augusto
• MINGUEZ, Beatriz
• NEWELL, Philippa
• TSAI, Hung-Wen

Titel

Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib

Ist Teil von

• Clinical cancer research, 2012-09, Vol.18 (18), p.4997-5007

Ort / Verlag

Philadelphia, PA: American Association for Cancer Research

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. 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. 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. 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.