Open AccessLack of Matrilin-2 Favors Liver Tumor Development via Erk1/2 and GSK-3β Pathways In Vivo
Author(s) -
Alexandra Fullár,
Kornélia Baghy,
F. Deák,
Bálint Péterfia,
Yvonne Zsák,
Péter Tátrai,
Zsuzsa Schaff,
József Dudás,
Ibolya Kiss,
Ilona Kovalszky
Publication year - 2014
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0093469
Subject(s) - western blot , liver regeneration , cancer research , phosphorylation , in vivo , liver tumor , extracellular matrix , retinoblastoma protein , biology , proliferating cell nuclear antigen , pathology , immunohistochemistry , chemistry , hepatocellular carcinoma , cell cycle , microbiology and biotechnology , cell , medicine , regeneration (biology) , biochemistry , gene
Matrilin-2 (Matn2) is a multidomain adaptor protein which plays a role in the assembly of extracellular matrix (ECM). It is produced by oval cells during stem cell-driven liver regeneration. In our study, the impact of Matn2 on hepatocarcinogenesis was investigated in Matn2 -/- mice comparing them with wild-type (WT) mice in a diethylnitrosamine (DEN) model. The liver tissue was analyzed macroscopically, histologically and immunohistochemically, at protein level by Proteome Profiler Arrays and Western blot analysis. Matn2 -/- mice exhibited higher susceptibility to hepatocarcinogenesis compared to wild-type mice. In the liver of Matn2 -/- mice, spontaneous microscopic tumor foci were detected without DEN treatment. After 15 μg/g body weight DEN treatment, the liver of Matn2 -/- mice contained macroscopic tumors of both larger number and size than the WT liver. In contrast with the WT liver, spontaneous phosphorylation of EGFR, Erk1/2 GSK-3α/β and retinoblastoma protein (p-Rb), decrease in p21/CIP1 level, and increase in β-Catenin protein expression were detected in Matn2 -/- livers. Focal Ki-67 positivity of these samples provided additional support to our presumption that the lack of Matn2 drives the liver into a pro-proliferatory state, making it prone to tumor development. This enhanced proliferative capacity was further increased in the tumor nodules of DEN-treated Matn2 -/- livers. Our study suggests that Matn2 functions as a tumor suppressor in hepatocarcinogenesis, and in this process activation of EGFR together with that of Erk1/2, as well as inactivation of GSK-3β, play strategic roles.