Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib

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

Research output: Contribution to journalArticle

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.Weaimed to characterize Wnt-pathway aberrations inHCCpatients, 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-TGFb 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 Wntpathway 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.

Original languageEnglish
Pages (from-to)4997-5007
Number of pages11
JournalClinical Cancer Research
Volume18
Issue number18
DOIs
Publication statusPublished - Sep 15 2012

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Lachenmayer, A., Alsinet, C., Savic, R., Cabellos, L., Toffanin, S., Hoshida, Y., Villanueva, A., Minguez, B., Newell, P., Tsai, H. W., Barretina, J., Thung, S., Ward, S. C., Bruix, J., Mazzaferro, V., Schwartz, M., Friedman, S. L., & Llovet, J. M. (2012). Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib. Clinical Cancer Research, 18(18), 4997-5007. https://doi.org/10.1158/1078-0432.CCR-11-2322