title: EFEMP1 suppresses malignant glioma growth and exerts its action within the tumor extracellular compartment.
abstract: OBJECTIVE
  There are conflicting reports regarding the function of EFEMP1 in different cancer types. In this study, we sought to evaluate the role of EFEMP1 in malignant glioma biology.
  
  
  METHODS
  Real-time qRT-PCR was used to quantify EFEMP1 expression in 95 glioblastoma multiforme (GBM). Human high-grade glioma cell lines and primary cultures were engineered to express ectopic EFEMP1, a small hairpin RNA of EFEMP1, or treated with exogenous recombinant EFEMP1 protein. Following treatment, growth was assayed both in vitro and in vivo (subcutaneous (s.c.) and intracranial (i.c.) xenograft model systems).
  
  
  RESULTS
  Cox regression revealed that EFEMP1 is a favorable prognostic marker for patients with GBM. Over-expression of EFEMP1 eliminated tumor development and suppressed angiogenesis, cell proliferation, and VEGFA expression, while the converse was true with knock-down of endogenous EFEMP1 expression. The EFEMP1 suppression of tumor onset time was nearly restored by ectopic VEGFA expression; however, overall tumor growth rate remained suppressed. This suggested that inhibition of angiogenesis was only partly responsible for EFEMP1's impact on glioma development. In glioma cells that were treated by exogenous EFEMP1 protein or over-expressed endogenous EFEMP1, the EGFR level was reduced and AKT signaling activity attenuated. Mixing of EFEMP1 protein with cells prior to s.c. and i.c. implantations or injection of the protein around the established s.c. xenografts, both significantly suppressed tumorigenicity.
  
  
  CONCLUSIONS
  Overall, our data reveals that EEFEMP1 suppresses glioma growth in vivo, both by modulating the tumor extracellular microenvironment and by altering critical intracellular oncogenic signaling pathways.
authors.affiliation: Department of Biological Chemistry, University of California Irvine, 5171 California Ave,, Suite 150, Irvine, CA 92697, USA.
authors.forename: Yuanjie
authors.initials: Y
authors.lastname: Hu
authors.forename: Peter Dion
authors.initials: PD
authors.lastname: Pioli
authors.forename: Eric
authors.initials: E
authors.lastname: Siegel
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Zhang
authors.forename: Jodi
authors.initials: J
authors.lastname: Nelson
authors.forename: Abhishek
authors.initials: A
authors.lastname: Chaturbedi
authors.forename: Marlon S
authors.initials: MS
authors.lastname: Mathews
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Ro
authors.forename: Selma
authors.initials: S
authors.lastname: Alkafeef
authors.forename: Nelson
authors.initials: N
authors.lastname: Hsu
authors.forename: Mark
authors.initials: M
authors.lastname: Hamamura
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Hess
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Tromberg
authors.forename: Mark E
authors.initials: ME
authors.lastname: Linskey
authors.forename: Yi-Hong
authors.initials: YH
authors.lastname: Zhou
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D001932:Brain Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D047368:Tumor Burden
chemical_list: D014408:Biomarkers, Tumor; C119630:EFEMP1 protein, human; D016326:Extracellular Matrix Proteins; D011994:Recombinant Proteins; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt