title: PITX2 and non-canonical Wnt pathway interaction in metastatic prostate cancer.
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.
authors.affiliation: Department of Urology, Princess Alexandra Hospital, Brisbane, QLD, Australia.
authors.forename: I
authors.initials: I
authors.lastname: Vela
authors.forename: C
authors.initials: C
authors.lastname: Morrissey
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: S
authors.initials: S
authors.lastname: Chen
authors.forename: E
authors.initials: E
authors.lastname: Corey
authors.forename: G M
authors.initials: GM
authors.lastname: Strutton
authors.forename: C C
authors.initials: CC
authors.lastname: Nelson
authors.forename: D L
authors.initials: DL
authors.lastname: Nicol
authors.forename: J A
authors.initials: JA
authors.lastname: Clements
authors.forename: E M
authors.initials: EM
authors.lastname: Gardiner
mesh_terms: D001483:Base Sequence; D001859:Bone Neoplasms / Q000556:secondary*; D045744:Cell Line, Tumor; D017931:DNA Primers; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D000097577:Homeobox Protein PITX2
chemical_list: D017931:DNA Primers; D018398:Homeodomain Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2