Urinary thromboxane B2 and thromboxane receptors in bladder cancer: Opportunity for detection and monitoring

Abstract

We have previously found increased expression of thromboxane synthase (TXAS) and thromboxane receptor (TP) beta isoform in the tissues of patients with bladder cancer. Studies in cell lines and mice have indicated a potential significant role of the thromboxane signaling pathway in the pathogenesis of human bladder cancer. This study was designed to determine if the changes observed in the tissues of patients with bladder cancer were mirrored by changes in the urine of these patients. We found increased levels of thromboxane B2, (TXB2) the major metabolite of TXAS and increased levels of the TPβ receptor. These results raised the possibility that patients with bladder cancer may be followed for progression or remission of their disease by quantitation of these substances in their urine.

Transcriptional regulation of the human thromboxane A2 receptor gene by Wilms' tumor (WT)1 and hypermethylated in cancer (HIC) 1 in prostate and breast cancers

“…Furthermore, the studies may also provide a mechanistic basis accounting, at least in part, for the prophylactic benefits of Aspirin in reducing certain cancer risks by lowering overall TXA 2 levels. As an additional point, bearing in mind that the TP and TP isoforms display a number of important functional similarities but also differences in terms of their signaling [5] and regulation including in certain cancers [91,92], coupled with the fact that they may be regulated by distinct promoters, in magakaryoblastic HEL cells at least [6], it will be of substantial interest to investigate the expression and transcriptional regulation of TPin human cancers, in particular in prostate and breast cancers. Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.bbagrm.2014.04.010.…”

“…Genome-association studies indicate that certain single-nucleotide polymorphisms (SNPs) identified within the TXS gene may predispose individuals to the development of breast cancer [28]. Increased levels of TXA 2 and expression of TXS and of the TP/TP isoforms have been strongly correlated with bladder cancer [29] and non-small cell lung cancer [30]. In addition, over-expression of TP in lung A549 cells greatly promotes adenocarcinoma tumor growth and neovascularization/angiogenesis in athymic nude mice [31], while inhibition of TXS activity enhances apoptosis of A549 cells in vitro, implicating a role for TXA 2 also in tumor cell survival [30].…”

Transcriptional Regulation of the Human Thromboxane A2 Receptor Gene by Wilms’ Tumour (WT)

“…However, with only limited exceptions (20,31), few of those studies investigated the roles of the individual TPα or TPβ isoforms or examined their transcriptional regulation in cancer. To address this and focussing on TPα, the predominant isoform expressed in most cell/tissue types (10), we recently examined its expression in prostate and breast cancer and identified a key role for the tumour suppressor gene product Wilms' tumour (WT)1 in its transcriptional regulation (58).…”

“…TPα and TPβ are encoded by the same gene, the TBXA2R, but are differentially expressed being regulated by distinct promoters where Prm1 regulates TPα expression, mainly involving NF-E2, Sp1, GATA-1, Ets-1, WT-1/Egr1, and Prm3 regulates TPβ, involving cFos/cJun and Oct-1/-2 (7-9, 59, 60). While the clinical evidence for the role of the TXA 2 -TP axis in neoplastic progression is increasing, few studies to date have investigated the role of the individual TPα/TPβ isoforms in human cancer or indeed in most other diseases in which TXA 2 is implicated (20,31). Focussing on TPα, we investigated its expression and transcriptional regulation through Prm1 in prostate and breast cancer and established that the tumour suppressor protein WT1 plays a key role in regulating its expression in both tissue types.…”

“…As the TXA 2 -TP axis has been implicated in the development of prostate and breast cancer (20,33,47,94,95), the findings herein suggest that aberrant WT1 regulation of TPα expression may contribute to such cancers and potentially to WT itself. In addition, bearing in mind that the TPα and TPβ isoforms display a number of important functional similarities but also differences in terms of their signalling (6) and regulation including in certain cancers (96,97), coupled with the fact that they are regulated by distinct promoters within the TBXA2R gene, it will be of considerable interest to investigate the expression and transcriptional regulation of TPβ in human cancers, in particular in prostate and breast cancer.…”