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

Vela, Ian, Morrissey, Colm M., Zhang, X., Chen, S., Corey, Eva, Strutton, Geoffrey M., Nelson, Colleen C., Nicol, David Leslie, Clements, Judith A., & Gardiner, Edith M. (2014) PITX2 and non-canonical Wnt pathway interaction in metastatic prostate cancer. Clinical and Experimental Metastasis, 31(2), pp. 199-211.

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Abstract

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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ID Code: 66533
Item Type: Journal Article
Refereed: Yes
Keywords: Bone, Metastasis, Non-canonical Wnt pathway, PITX2, Prostate cancer
DOI: 10.1007/s10585-013-9620-7
ISSN: 02620898
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200)
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2013 Springer Science+Business Media Dordrecht
Copyright Statement: The final publication is available at Springer via http://dx.doi.org/10.1007/s10585-013-9620-7
Deposited On: 29 Jan 2014 02:15
Last Modified: 09 Mar 2015 09:21

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