title: Transcriptome analysis of human cancer reveals a functional role of heme oxygenase-1 in tumor cell adhesion.
abstract: BACKGROUND
  Heme Oxygenase-1 (HO-1) is expressed in many cancers and promotes growth and survival of neoplastic cells. Recently, HO-1 has been implicated in tumor cell invasion and metastasis. However, the molecular mechanisms underlying these biologic effects of HO-1 remain largely unknown. To identify a common mechanism of action of HO-1 in cancer, we determined the global effect of HO-1 on the transcriptome of multiple tumor entities and identified a universal HO-1-associated gene expression signature.
  
  
  RESULTS
  Genome-wide expression profiling of Heme Oxygenase-1 expressing versus HO-1 silenced BeWo choriocarcinoma cells as well as a comparative meta-profiling of the preexisting expression database of 190 human tumors of 14 independent cancer types led to the identification of 14 genes, the expression of which correlated strongly and universally with that of HO-1 (P = 0.00002). These genes included regulators of cell plasticity and extracellular matrix (ECM) remodeling (MMP2, ADAM8, TGFB1, BGN, COL21A1, PXDN), signaling (CRIP2, MICB), amino acid transport and glycosylation (SLC7A1 and ST3GAL2), estrogen and phospholipid biosynthesis (AGPAT2 and HSD17B1), protein stabilization (IFI30), and phosphorylation (ALPPL2). We selected PXDN, an adhesion molecule involved in ECM formation, for further analysis and functional characterization. Immunofluorescence and Western blotting confirmed the positive correlation of expression of PXDN and HO-1 in BeWo cancer cells as well as co-localization of these two proteins in invasive extravillous trophoblast cells. Modulation of HO-1 expression in both loss-of and gain-of function cell models (BeWo and 607B melanoma cells, respectively) demonstrated a direct relationship of HO-1 expression with cell adhesion to Fibronectin and Laminin coated wells. The adhesion-promoting effects of HO-1 were dependent on PXDN expression, as loss of PXDN in HO-1 expressing BeWo and 607B cells led to reduced cell attachment to Laminin and Fibronectin coated wells.
  
  
  CONCLUSIONS
  Collectively, our results show that HO-1 expression determines a distinct 'molecular signature' in cancer cells, which is enriched in genes associated with tumorigenesis. The protein network downstream of HO-1 modulates adhesion, signaling, transport, and other critical cellular functions of neoplastic cells and thus promotes tumor cell growth and dissemination.
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Tauber
authors.forename: Alexander
authors.initials: A
authors.lastname: Jais
authors.forename: Markus
authors.initials: M
authors.lastname: Jeitler
authors.forename: Sandra
authors.initials: S
authors.lastname: Haider
authors.forename: Julia
authors.initials: J
authors.lastname: Husa
authors.forename: Josefine
authors.initials: J
authors.lastname: Lindroos
authors.forename: Martin
authors.initials: M
authors.lastname: Knöfler
authors.forename: Matthias
authors.initials: M
authors.lastname: Mayerhofer
authors.forename: Hubert
authors.initials: H
authors.lastname: Pehamberger
authors.forename: Oswald
authors.initials: O
authors.lastname: Wagner
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
mesh_terms: D001483:Base Sequence; D002448:Cell Adhesion; D017931:DNA Primers; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D006419:Heme Oxygenase (Decyclizing)