Lack of Matrilin-2 favors liver tumor development via Erk1/2 and GSK-3β pathways in vivo

Alexandra Fullár, Kornélia Baghy, Ferenc Deák, Bálint Péterfia, Yvonne Zsák, Péter Tátrai, Zsuzsa Schaff, József Dudás, Ibolya Kiss, Ilona Kovalszky

Research output: Contribution to journalArticle

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Abstract

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-3a/b 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.

Original languageEnglish
Article numbere93469
JournalPLoS One
Volume9
Issue number4
DOIs
Publication statusPublished - Apr 1 2014

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Matrilin Proteins
Glycogen Synthase Kinase 3
liver neoplasms
Liver
Tumors
liver
Diethylnitrosamine
Neoplasms
mice
neoplasms
liver regeneration
proteins
Catenins
proteome
Retinoblastoma Protein
extracellular matrix
Phosphorylation
Liver Regeneration
stem cells
Proteome

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Lack of Matrilin-2 favors liver tumor development via Erk1/2 and GSK-3β pathways in vivo. / Fullár, Alexandra; Baghy, Kornélia; Deák, Ferenc; Péterfia, Bálint; Zsák, Yvonne; Tátrai, Péter; Schaff, Zsuzsa; Dudás, József; Kiss, Ibolya; Kovalszky, Ilona.

In: PLoS One, Vol. 9, No. 4, e93469, 01.04.2014.

Research output: Contribution to journalArticle

Fullár, Alexandra ; Baghy, Kornélia ; Deák, Ferenc ; Péterfia, Bálint ; Zsák, Yvonne ; Tátrai, Péter ; Schaff, Zsuzsa ; Dudás, József ; Kiss, Ibolya ; Kovalszky, Ilona. / Lack of Matrilin-2 favors liver tumor development via Erk1/2 and GSK-3β pathways in vivo. In: PLoS One. 2014 ; Vol. 9, No. 4.
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