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AXIN2 expression predicts prostate cancer recurrence and regulates invasion and tumor growth
Author(s) -
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 B.,
Den Robert B.,
Xu Tong,
Xu Yucheng,
Gill Inderbir S.,
Quinn David I.,
Goldkorn Amir
Publication year - 2016
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.23151
Subject(s) - axin2 , prostate cancer , cancer research , biochemical recurrence , biology , gene knockdown , cancer , in silico , prostate , oncology , medicine , wnt signaling pathway , pathology , prostatectomy , gene , genetics
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 . © 2016 Wiley Periodicals, Inc.