title: AXIN2 expression predicts prostate cancer recurrence and regulates invasion and tumor growth.
abstract: BACKGROUND
  Treatment of prostate cancer (PCa) may be improved by identifying biological mechanisms of tumor growth that directly impact clinical disease progression. We investigated whether genes associated with a highly tumorigenic, drug resistant, progenitor phenotype impact PCa biology and recurrence.
  
  
  METHODS
  Radical prostatectomy (RP) specimens (±disease recurrence, N = 276) were analyzed by qRT-PCR to quantify expression of genes associated with self-renewal, drug resistance, and tumorigenicity in prior studies. Associations between gene expression and PCa recurrence were confirmed by bootstrap internal validation and by external validation in independent cohorts (total N = 675) and in silico. siRNA knockdown and lentiviral overexpression were used to determine the effect of gene expression on PCa invasion, proliferation, and tumor growth.
  
  
  RESULTS
  Four candidate genes were differentially expressed in PCa recurrence. Of these, low AXIN2 expression was internally validated in the discovery cohort. Validation in external cohorts and in silico demonstrated that low AXIN2 was independently associated with more aggressive PCa, biochemical recurrence, and metastasis-free survival after RP. Functionally, siRNA-mediated depletion of AXIN2 significantly increased invasiveness, proliferation, and tumor growth. Conversely, ectopic overexpression of AXIN2 significantly reduced invasiveness, proliferation, and tumor growth.
  
  
  CONCLUSIONS
  Low AXIN2 expression was associated with PCa recurrence after RP in our test population as well as in external validation cohorts, and its expression levels in PCa cells significantly impacted invasiveness, proliferation, and tumor growth. Given these novel roles, further study of AXIN2 in PCa may yield promising new predictive and therapeutic strategies.
authors.affiliation: USC Institute of Urology, Keck Medical Center of USC and Translational and Clinical Science Program, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Hu
authors.affiliation: USC Institute of Urology, Keck Medical Center of USC and Translational and Clinical Science Program, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Fairey
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Southern California Keck School of Medicine and Translational and Clinical Science Program, USC Norris Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Anisha
authors.initials: A
authors.lastname: Madhav
authors.affiliation: Department of Preventive Medicine, Keck Medical Center of USC, University of Southern California, Los Angeles, California.
authors.forename: Dongyun
authors.initials: D
authors.lastname: Yang
authors.affiliation: Health Sciences Bioinformatics Core, USC Keck School of Medicine, Los Angeles, California.
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Preventive Medicine, Keck Medical Center of USC, University of Southern California, Los Angeles, California.
authors.forename: Susan
authors.initials: S
authors.lastname: Groshen
authors.affiliation: Response Genetics, Inc. Los Angeles, California.
authors.forename: Craig
authors.initials: C
authors.lastname: Stephens
authors.affiliation: USC Institute of Urology, Keck Medical Center of USC and Translational and Clinical Science Program, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Kim
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Southern California Keck School of Medicine and Translational and Clinical Science Program, USC Norris Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Navneet
authors.initials: N
authors.lastname: Virk
authors.affiliation: Department of Pathology, Keck Medical Center of USC, University of Southern California, Los Angeles, California.
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology, Keck Medical Center of USC, University of Southern California, Los Angeles, California.
authors.forename: Sue Ellen
authors.initials: SE
authors.lastname: Martin
authors.affiliation: Genome Dx, San Diego, California.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Erho
authors.affiliation: Genome Dx, San Diego, California.
authors.forename: Elai
authors.initials: E
authors.lastname: Davicioni
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jenkins
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Den
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Southern California Keck School of Medicine and Translational and Clinical Science Program, USC Norris Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Tong
authors.initials: T
authors.lastname: Xu
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Southern California Keck School of Medicine and Translational and Clinical Science Program, USC Norris Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Yucheng
authors.initials: Y
authors.lastname: Xu
authors.affiliation: USC Institute of Urology, Keck Medical Center of USC and Translational and Clinical Science Program, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Inderbir S
authors.initials: IS
authors.lastname: Gill
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Southern California Keck School of Medicine and Translational and Clinical Science Program, USC Norris Comprehensive Cancer Center, Los Angeles, California.
authors.forename: David I
authors.initials: DI
authors.lastname: Quinn
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Southern California Keck School of Medicine and Translational and Clinical Science Program, USC Norris Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Amir
authors.initials: A
authors.lastname: Goldkorn
mesh_terms: D000368:Aged; D060466:Axin Protein / Q000032:analysis / Q000235:genetics; D015415:Biomarkers; D006801:Humans; D008297:Male; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000473:pathology; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D011467:Prostate / Q000473:pathology / Q000601:surgery; D011468:Prostatectomy / Q000379:methods*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000601:surgery; D018570:Risk Assessment
chemical_list: C491761:AXIN2 protein, human; D060466:Axin Protein; D015415:Biomarkers
keywords: AXIN2; biomarker; cancer stem-like cells; prostate cancer; radical prostatectomy