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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.

SUBMITTER: Hu BR

PROVIDER: S-EPMC7455032 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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

Hu Brian R BR Fairey Adrian S AS Madhav Anisha A Yang Dongyun D Li Meng M Groshen Susan S Stephens Craig C Kim Philip H PH Virk Navneet N Wang Lina L Martin Sue Ellen SE Erho Nicholas N Davicioni Elai E Jenkins Robert B RB Den Robert B RB Xu Tong T Xu Yucheng Y Gill Inderbir S IS Quinn David I DI Goldkorn Amir A

The Prostate 20160115 6

<h4>Background</h4>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.<h4>Methods</h4>Radical prostatectomy (RP) specimens (±disease recurrence, N = 276) were analyzed by qRT-PCR to quantify expression of genes associated with self-renewal, drug resistance, ...[more]

PMID: 26771938

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Project description:DNA methyltransferase (DNMT) is one of the major factors mediating the methylation of cancer related genes such as TGF-? receptors (T?Rs). This in turn may result in a loss of sensitivity to physiologic levels of TGF-? in aggressive prostate cancer (CaP). The specific mechanisms of DNMT's role in CaP remain undetermined. In this study, we describe the mechanism of TGF-?-mediated DNMT in CaP and its association with clinical outcomes following radical prostatectomy.We used human CaP cell lines with varying degrees of invasive capability to describe how TGF-? mediates the expression of DNMT in CaP, and its effects on methylation status of TGF-? receptors and the invasive capability of CaP in vitro and in vivo. Furthermore, we determined the association between DNMT expression and clinical outcome after radical prostatectomy. We found that more aggressive CaP cells had significantly higher TGF-? levels, increased expression of DNMT, but reduced T?Rs when compared to benign prostate cells and less aggressive prostate cancer cells. Blockade of TGF-? signaling or ERK activation (p-ERK) was associated with a dramatic decrease in the expression of DNMT, which results in a coincident increase in the expression of T?Rs. Blockade of either TGF-? signaling or DNMT dramatically decreased the invasive capabilities of CaP. Inhibition of TGF-? in an TRAMP-C2 CaP model in C57BL/6 mice using 1D11 was associated with downregulation of DNMTs and p-ERK and impairment in tumor growth. Finally, independent of Gleason grade, increased DNMT1 expression was associated with biochemical recurrence following surgical treatment for prostate cancer.Our findings demonstrate that CaP derived TGF-? may induce the expression of DNMTs in CaP which is associated with methylation of its receptors and the aggressive potential of CaP. In addition, DNMTs is an independent predictor for disease recurrence after prostatectomy, and may have clinical implications for CaP prognostication and therapy.

Dataset Information

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

Publications

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

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