Expression of the TPα and TPβ isoforms of the thromboxane prostanoid receptor (TP) in prostate cancer: clinical significance and diagnostic potential.
The prostanoid thromboxane (TX)A2 plays a central role in haemostasis and is increasingly implicated in cancer progression. TXA2 signals through two T Prostanoid receptor (TP) isoforms termed TPα and TPβ, with both encoded by the TBXA2R gene. Despite exhibiting several functional and regulatory differences, the role of the individual TP isoforms in neoplastic diseases is largely unknown.This study evaluated expression of the TPα and TPβ isoforms in tumour microarrays of the benign prostate and different pathological (Gleason) grades of prostate cancer (PCa). Expression of TPβ was significantly increased in PCa relative to benign tissue and strongly correlated with increasing Gleason grade. Furthermore, higher TPβ expression was associated with increased risk of biochemical recurrence (BCR) and significantly shorter disease-free survival time in patients post-surgery. While TPα was more variably expressed than TPβ in PCa, increased/high TPα expression within the tumour also trended toward increased BCR and shorter disease-free survival time. Comparative genomic CpG DNA methylation analysis revealed substantial differences in the extent of methylation of the promoter regions of the TBXA2R that specifically regulate expression of TPα and TPβ, respectively, both in benign prostate and in clinically-derived tissue representative of precursor lesions and progressive stages of PCa. Collectively, TPα and TPβ expression is differentially regulated both in the benign and tumourigenic prostate, and coincides with clinical pathology and altered CpG methylation of the TBXA2R gene. Analysis of TPβ, or a combination of TPα/TPβ, expression levels may have significant clinical potential as a diagnostic biomarker and predictor of PCa disease recurrence.
UCD School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin, Ireland.
Eamon P
EP
Mulvaney
Department of Pathology, Beaumont Hospital and Royal College of Surgeons, Dublin, Ireland.
Christine
C
Shilling
UCD School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin, Ireland.
Sarah B
SB
Eivers
UCD School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin, Ireland.
Antoinette S
AS
Perry
Department of Translational Medicine, Division of Urological Cancers, Skåne University Hospital Malmö, Lund University, Lund, Sweden.
Anders
A
Bjartell
Department of Pathology, Beaumont Hospital and Royal College of Surgeons, Dublin, Ireland.
Elaine W
EW
Kay
UCD School of Medicine, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland.
R William
RW
Watson
UCD School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin, Ireland.
B Therese
BT
Kinsella
D019175:DNA Methylation; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D060787:Neoplasm Grading; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D020033:Protein Isoforms; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000737:chemistry / Q000235:genetics*; D014158:Transcription, Genetic
D020033:Protein Isoforms; D044244:Receptors, Thromboxane A2, Prostaglandin H2
cancer; prostanoid; prostate; receptor; thromboxane
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