PITX2 and non-canonical Wnt pathway interaction in metastatic prostate cancer

被引:0
|
作者
I. Vela
C. Morrissey
X. Zhang
S. Chen
E. Corey
G. M. Strutton
C. C. Nelson
D. L. Nicol
J. A. Clements
E. M. Gardiner
机构
[1] Princess Alexandra Hospital,Department of Urology
[2] University of Queensland,School of Medicine
[3] University of Washington,Department of Urology, School of Medicine
[4] Fred Hutchinson Cancer Research Center,Public Health Sciences
[5] Pathology Queensland Princess Alexandra Hospital,Department of Anatomical Pathology
[6] Queensland University of Technology at the Translational Research Institute,Australian Prostate Cancer Research Centre
[7] University of Queensland,QLD, Institute of Health and Biomedical Innovation
[8] Memorial Sloan-Kettering Cancer Center,Diamantina Institute for Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital
[9] Royal Marsden Hospital,Department of Surgery
[10] University of Washington,Department of Orthopaedics and Sports Medicine, Harborview Medical Center
来源
Clinical & Experimental Metastasis | 2014年 / 31卷
关键词
Prostate cancer; Metastasis; Non-canonical Wnt pathway; PITX2; Bone;
D O I
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中图分类号
学科分类号
摘要
The non-canonical Wnt pathway, a regulator of cellular motility and morphology, is increasingly implicated in cancer metastasis. In a quantitative PCR array analysis of 84 Wnt pathway associated genes, both non-canonical and canonical pathways were activated in primary and metastatic tumors relative to normal prostate. Expression of the Wnt target gene PITX2 in a prostate cancer (PCa) bone metastasis was strikingly elevated over normal prostate (over 2,000-fold) and primary prostate cancer (over 200-fold). The elevation of PITX2 protein was also evident on tissue microarrays, with strong PITX2 immunostaining in PCa skeletal and, to a lesser degree, soft tissue metastases. PITX2 is associated with cell migration during normal tissue morphogenesis. In our studies, overexpression of individual PITX2A/B/C isoforms stimulated PC-3 PCa cell motility, with the PITX2A isoform imparting a specific motility advantage in the presence of non-canonical Wnt5a stimulation. Furthermore, PITX2 specific shRNA inhibited PC-3 cell migration toward bone cell derived chemoattractant. These experimental results support a pivotal role of PITX2A and non-canonical Wnt signaling in enhancement of PCa cell motility, suggest PITX2 involvement in homing of PCa to the skeleton, and are consistent with a role for PITX2 in PCa metastasis to soft and bone tissues. Our findings, which significantly expand previous evidence that PITX2 is associated with risk of PCa biochemical recurrence, indicate that variation in PITX2 expression accompanies and may promote prostate tumor progression and metastasis.
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页码:199 / 211
页数:12
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