AXIN2 expression predicts prostate cancer recurrence and regulates invasion and tumor growth

Brian R. Hu, Adrian S. Fairey, Anisha Madhav, Dongyun Yang, Meng Li, Susan Groshen, Craig Stephens, Philip H. Kim, Navneet Virk, Lina Wang, Sue Ellen Martin, Nicholas Erho, Elai Davicioni, Robert Brian Jenkins, Robert B. Den, Tong Xu, Yucheng Xu, Inderbir S. Gill, David I. Quinn, Amir Goldkorn

Research output: Contribution to journalArticle

7 Citations (Scopus)

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. Prostate 76:597-608, 2016.

Original languageEnglish (US)
Pages (from-to)597-608
Number of pages12
JournalProstate
Volume76
Issue number6
DOIs
StatePublished - May 1 2016

Fingerprint

Prostatic Neoplasms
Recurrence
Growth
Neoplasms
Prostatectomy
Gene Expression
Computer Simulation
Small Interfering RNA
Drug Resistance
Genes
Disease Progression
Prostate
Neoplasm Metastasis
Phenotype
Polymerase Chain Reaction
Pharmaceutical Preparations
Population

Keywords

  • AXIN2
  • biomarker
  • cancer stem-like cells
  • prostate cancer
  • radical prostatectomy

ASJC Scopus subject areas

  • Urology
  • Oncology

Cite this

Hu, B. R., Fairey, A. S., Madhav, A., Yang, D., Li, M., Groshen, S., ... Goldkorn, A. (2016). AXIN2 expression predicts prostate cancer recurrence and regulates invasion and tumor growth. Prostate, 76(6), 597-608. https://doi.org/10.1002/pros.23151

AXIN2 expression predicts prostate cancer recurrence and regulates invasion and tumor growth. / Hu, Brian R.; Fairey, Adrian S.; Madhav, Anisha; Yang, Dongyun; Li, Meng; Groshen, Susan; Stephens, Craig; Kim, Philip H.; Virk, Navneet; Wang, Lina; Martin, Sue Ellen; Erho, Nicholas; Davicioni, Elai; Jenkins, Robert Brian; Den, Robert B.; Xu, Tong; Xu, Yucheng; Gill, Inderbir S.; Quinn, David I.; Goldkorn, Amir.

In: Prostate, Vol. 76, No. 6, 01.05.2016, p. 597-608.

Research output: Contribution to journalArticle

Hu, BR, Fairey, AS, Madhav, A, Yang, D, Li, M, Groshen, S, Stephens, C, Kim, PH, Virk, N, Wang, L, Martin, SE, Erho, N, Davicioni, E, Jenkins, RB, Den, RB, Xu, T, Xu, Y, Gill, IS, Quinn, DI & Goldkorn, A 2016, 'AXIN2 expression predicts prostate cancer recurrence and regulates invasion and tumor growth', Prostate, vol. 76, no. 6, pp. 597-608. https://doi.org/10.1002/pros.23151
Hu, Brian R. ; Fairey, Adrian S. ; Madhav, Anisha ; Yang, Dongyun ; Li, Meng ; Groshen, Susan ; Stephens, Craig ; Kim, Philip H. ; Virk, Navneet ; Wang, Lina ; Martin, Sue Ellen ; Erho, Nicholas ; Davicioni, Elai ; Jenkins, Robert Brian ; Den, Robert B. ; Xu, Tong ; Xu, Yucheng ; Gill, Inderbir S. ; Quinn, David I. ; Goldkorn, Amir. / AXIN2 expression predicts prostate cancer recurrence and regulates invasion and tumor growth. In: Prostate. 2016 ; Vol. 76, No. 6. pp. 597-608.
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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. Prostate 76:597-608, 2016.",
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T1 - AXIN2 expression predicts prostate cancer recurrence and regulates invasion and tumor growth

AU - Hu, Brian R.

AU - Fairey, Adrian S.

AU - Madhav, Anisha

AU - Yang, Dongyun

AU - Li, Meng

AU - Groshen, Susan

AU - Stephens, Craig

AU - Kim, Philip H.

AU - Virk, Navneet

AU - Wang, Lina

AU - Martin, Sue Ellen

AU - Erho, Nicholas

AU - Davicioni, Elai

AU - Jenkins, Robert Brian

AU - Den, Robert B.

AU - Xu, Tong

AU - Xu, Yucheng

AU - Gill, Inderbir S.

AU - Quinn, David I.

AU - Goldkorn, Amir

PY - 2016/5/1

Y1 - 2016/5/1

N2 - 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. Prostate 76:597-608, 2016.

AB - 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. Prostate 76:597-608, 2016.

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