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GATA3 in the urinary bladder: suppression of neoplastic transformation and down-regulation by androgens
Yi Li1, Hitoshi Ishiguro2, Takashi Kawahara2
1Department of Pathology and Laboratory Medicine, University of Rochester Medical Center Rochester, NY, USA ; Department of Urology, 2nd Affiliated Hospital, Zhejiang University School of Medicine Hangzhou, China.
Abstract:
Recent evidence suggests the involvement of sex hormone receptors in bladder cancer initiation, while precise functions of androgens and estrogens in the carcinogenesis step remain poorly understood. We recently found down-regulation of GATA3, a zinc-finger transcription factor and a new urothelial marker, in bladder cancer, which also correlated with expression status of androgen receptor (AR) and estrogen receptors (ERs). We here assessed whether GATA3 acted as a suppressor of bladder tumorigenesis and sex hormones exerted an influence on GATA3 in non-neoplastic urothelial cells. Androgen (R1881, dihydrotestosterone) treatment in SVHUC immortalized normal urothelial cells stably expressing AR (SVHUC-AR) decreased GATA3 expression at both mRNA and protein levels, which was abolished by anti-androgens. Conversely, 17β-estradiol treatment increased it in SVHUC-control endogenously expressing ERβ. GATA3 levels were also found to be higher in intact female mouse bladders compared with intact males, and orchiectomy/ovariectomy augmented/reduced GATA3 expression, respectively, which was at least partially restored by dihydrotestosterone/17β-estradiol supplement. Additionally, GATA3 silencing via short hairpin RNA (shRNA) promoted cell proliferation of SVHUC with exposure to a chemical carcinogen 3-methylcholanthrene. In vitro transformation assay with 3-methylcholanthrene then showed a significantly higher number of colonies in SVHUC-AR/GATA3-shRNA, compared with control SVHUC, and R1881 further induced colony formation. GATA3 knockdown also resulted in down-regulation of the molecules that play a protective role in bladder tumorigenesis (i.e. UGT1A, PTEN, p53, p21) and up-regulation of oncogenic genes (i.e. c-myc, cyclin D1, cyclin D3, cyclin E, FGFR3). Thus, GATA3 likely prevented neoplastic transformation of urothelial cells. Furthermore, sex hormone signals contrary regulated GATA3 in the bladder. These findings may offer not only a molecular basis for the gender-specific difference in bladder cancer incidence but also great potential for androgen deprivation as a chemopreventive option for tumor recurrence.
Insights
GATA3 acts as a tumor suppressor in bladder cancer, with androgens decreasing its expression and estrogens increasing it. This suggests a role for sex hormones in bladder cancer development and potential androgen deprivation therapies.
Area of Science:
- Urothelial Carcinogenesis
- Endocrinology
- Molecular Biology
Background:
- Sex hormone receptors are implicated in bladder cancer initiation.
- The precise roles of androgens and estrogens in bladder cancer development are unclear.
- GATA3, a transcription factor and urothelial marker, is downregulated in bladder cancer.
Purpose of the Study:
- To investigate if GATA3 suppresses bladder tumorigenesis.
- To determine how androgens and estrogens influence GATA3 expression in normal urothelial cells.
Main Methods:
- Treated immortalized normal urothelial cells (SVHUC) with androgens (R1881, dihydrotestosterone) and estrogens (17β-estradiol).
- Assessed GATA3 expression at mRNA and protein levels.
- Utilized short hairpin RNA (shRNA) for GATA3 silencing and performed in vitro transformation assays with a chemical carcinogen (3-methylcholanthrene).
Main Results:
- Androgen treatment decreased GATA3 expression, while estrogen treatment increased it.
- GATA3 silencing promoted cell proliferation and in vitro tumor transformation, especially with androgen exposure.
- GATA3 knockdown altered the expression of tumor suppressors (e.g., PTEN, p53) and oncogenes (e.g., c-myc, cyclins).
Conclusions:
- GATA3 functions as a suppressor of urothelial cell neoplastic transformation.
- Sex hormones oppositely regulate GATA3 expression in the bladder.
- Findings provide insights into gender-specific bladder cancer incidence and suggest androgen deprivation as a chemopreventive strategy.
