title: CD98hc (SLC3A2) drives integrin-dependent renal cancer cell behavior.
abstract: BACKGROUND
  Overexpression of CD98hc (SLC3A2) occurs in a variety of cancers and is suspected to contribute to tumor growth. CD98, a heterodimeric transmembrane protein, physically associates with certain integrin β subunit cytoplasmic domains via its heavy chain, CD98hc. CD98hc regulates adhesion-induced intracellular signal transduction via integrins, thereby, affecting cell proliferation and clonal expansion. Disruption of CD98hc led to embryonic lethality in mice (E 3.5 and E 9.5) and CD98hc -/- embryonic stem cell transplantation failed to form teratomas, while CD98hc over-expression in somatic cells resulted in anchorage-independent growth. However, it is unclear whether interference with CD98hc expression tumor cell behavior.
  
  
  METHODS
  Renal cell cancer cell lines have been used to determine the effect of CD98hc expression on cancer cell behavior using cell adhesion, cell trans-migration and cell spreading assays. Flow cytometric analysis was performed to study the rate of apoptosis after detachment or serum starvation. shRNA-lentiviral constructs were used to stably knockdown or reconstitute full length or mutated CD98hc. The role of CD98 as a promotor of tumorigenesis was evaluated using an in in vivo tumor transplantation animal model. Immunohistochemical analysis was performed to analyze cell proliferation and CD98 expression in tumors.
  
  
  RESULTS
  This report shows that CD98hc silencing in clear cell renal cancer cells reverts certain characteristics of tumorigenesis, including cell spreading, migration, proliferation and survival in vitro, and tumor growth in vivo. Acquisition of tumorigenic characteristics in clear cell renal cancer cells occurred through the integrin binding domain of CD98hc. A CD98hc/integrin interaction was required for adhesion-induced sustained FAK phosphorylation and activation of the major downstream signaling pathways PI3k/Akt and MEK/ERK, while overexpression of a constitutive active form of FAK rescued the CD98hc deficiency.
  
  
  CONCLUSIONS
  In this study we demonstrate that loss of CD98hc blocks tumorigenic potential in renal cell cancer.
authors.forename: Marina
authors.initials: M
authors.lastname: Poettler
authors.forename: Matthias
authors.initials: M
authors.lastname: Unseld
authors.forename: Kira
authors.initials: K
authors.lastname: Braemswig
authors.forename: Andrea
authors.initials: A
authors.lastname: Haitel
authors.forename: Christoph C
authors.initials: CC
authors.lastname: Zielinski
authors.affiliation: Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. gerald.pragergerald.prager@meduniwien.ac.at.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Prager
mesh_terms: D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000235:genetics / Q000502:physiology*; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D015398:Signal Transduction
chemical_list: D027282:Fusion Regulatory Protein 1, Heavy Chain; D016023:Integrins; C545989:SLC3A2 protein, human