4F2hc-silencing impairs tumorigenicity of HeLa cells via modulation of galectin-3 and β-catenin signaling, and MMP-2 expression

Biochim Biophys Acta. 2013 Sep;1833(9):2045-56. doi: 10.1016/j.bbamcr.2013.04.017. Epub 2013 May 4.

Abstract

4F2hc is a type-II glycoprotein whose covalent-bound association with one of several described light chains yields a heterodimer mainly involved in large neutral amino acid transport. Likewise, it is well known that the heavy chain interacts with β-integrins mediating integrin-dependent events such as survival, proliferation, migration and even transformation. 4F2hc is a ubiquitous protein whose overexpression has been related to tumor development and progression. Stable silencing of 4F2hc in HeLa cells using an artificial miRNA impairs in vivo tumorigenicity and leads to an ineffective proliferation response to mitogens. 4F2hc colocalizes with β1-integrins and CD147, but this interaction does not occur in lipid rafts in HeLa cells. Moreover, silenced cells present defects in integrin- (FAK, Akt and ERK1/2) and hypoxia-dependent signaling, and reduced expression/activity of MMP-2. These alterations seem to be dependent on the inappropriate formation of CD147/4F2hc/β1-integrin heterocomplexes on the cell surface, arising when CD147 cannot interact with 4F2hc. Although extracellular galectin-3 accumulates due to the decrease in MMP-2 activity, galectin-3 signaling events are blocked due to an impaired interaction with 4F2hc, inducing an increased degradation of β-catenin. Furthermore, cell motility is compromised after protein silencing, suggesting that 4F2hc is related to tumor invasion by facilitating cell motility. Therefore, here we propose a molecular mechanism by which 4F2hc participates in tumor progression, favoring first steps of epithelial-mesenchymal transition by inhibition of β-catenin proteasomal degradation through Akt/GSK-3β signaling and enabling cell motility.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basigin / genetics
  • Basigin / metabolism
  • Cell Movement / genetics
  • Epithelial-Mesenchymal Transition / genetics
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fusion Regulatory Protein 1, Heavy Chain / biosynthesis*
  • Fusion Regulatory Protein 1, Heavy Chain / genetics
  • Galectin 3 / genetics
  • Galectin 3 / metabolism*
  • Gene Expression Regulation, Enzymologic*
  • Gene Expression Regulation, Neoplastic*
  • Gene Silencing*
  • HeLa Cells
  • Humans
  • Integrin beta1 / genetics
  • Integrin beta1 / metabolism
  • MAP Kinase Signaling System*
  • Matrix Metalloproteinase 2 / biosynthesis*
  • Matrix Metalloproteinase 2 / genetics
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Invasiveness
  • Neoplasm Transplantation
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / metabolism*
  • Neoplasms, Experimental / pathology
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Transplantation, Heterologous
  • beta Catenin / genetics
  • beta Catenin / metabolism*

Substances

  • BSG protein, human
  • Fusion Regulatory Protein 1, Heavy Chain
  • Galectin 3
  • Integrin beta1
  • SLC3A2 protein, human
  • beta Catenin
  • Basigin
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • MMP2 protein, human
  • Matrix Metalloproteinase 2
  • Proteasome Endopeptidase Complex