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UROSCAN
Year : 2010  |  Volume : 26  |  Issue : 4  |  Page : 603-604
 

Androgen receptor: A novel molecular tool for control of bladder cancer


Department of Urology, C.S.M. Medical University, Upgraded king George's Medical College, Lucknow, India

Date of Web Publication31-Dec-2010

Correspondence Address:
Apul Goel
Department of Urology, C.S.M. Medical University, Upgraded king George's Medical College, Lucknow
India
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Source of Support: None, Conflict of Interest: None


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How to cite this article:
Sengottayan VK, Goel A, Sankhwar S N. Androgen receptor: A novel molecular tool for control of bladder cancer. Indian J Urol 2010;26:603-4

How to cite this URL:
Sengottayan VK, Goel A, Sankhwar S N. Androgen receptor: A novel molecular tool for control of bladder cancer. Indian J Urol [serial online] 2010 [cited 2019 Oct 15];26:603-4. Available from: http://www.indianjurol.com/text.asp?2010/26/4/603/74481

Wu JT, Han BM, Yu SQ, Wang HP, Xia SJ. Androgen receptor is a potential therapeutic target for bladder cancer. Urology 2010; 75: 820-7.



   Summary Top


Two transitional carcinoma cell lines T24 and 253-J were derived from a grade III Transitional cell carcinoma (TCC) and from a retroperitoneal lymph node metastasis of TCC, respectively, and were found to express androgen receptor (AR). These cells were cultured. They were transfected with AR small interference ribonucleic acid (siRNA) which was used to knock down AR expression and nonspecific siRNA duplex which were used as control. The effects of these manipulations were assessed by various tests. Results were analyzed using Student t test to assess statistical significance, with values of P < .05 considered statistically significant.

After siRNA transfection, the AR knockdown efficiency in T24 and 253-J cells was detected using reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot, which showed that AR-siRNA treatment resulted in a significant reduction in AR-mRNA and protein expression in these cell lines as compared with the controls. In the assay to measure the quantity of cell growth, AR silencing resulted in significant cell proliferation inhibition. With AR-siRNA treatment, the percentage of early apoptotic cells increased significantly. The migration capability of cells transfected with AR-siRNA was significantly lower than the controls suggesting a decreased chance for metastases in the cell lines in which AR expression was knocked off.

The second part of this study was on male, athymic mice which were injected with T24 cells and resulting tumors exceeding 5-mm diameter were used for further study. AR-siRNA was injected into the tumor region. Electroporation process to integrate the siRNA with the tumor cells was accomplished by pressing electrodes onto each side of the tumor's long diameter and pulsing it using an electric pulse generator. After 48 hours these mice were sacrificed and the AR knockdown efficiency assessed by RT- PCR which showed significant AR-mRNA destruction.

Subsequently, fresh tumor-carrying mice were randomly divided into three groups of six mice each. They were either treated with AR-siRNA, nonspecific siRNA, or were untreated, respectively. Tumor volumes were calculated weekly and observations were terminated after 4 weeks from the beginning of siRNA transfection. AR-siRNA treatment resulted in significant tumor growth inhibition, decreased cell proliferation and increased apoptosis of tumor cells. [1]

The knockdown of AR expression in the cell lines by siRNA transfection suppressed the migration capability of these cells in mice. This was associated with decreased matrix metalloproteinase-9 (MMP-9) concentrations, which resulted from silencing the AR gene. MMPs have been shown to promote cancer progression and metastasis by boosting cancer cell growth, migration with invasion and angiogenesis.


   Comments Top


Urothelial carcinoma of the bladder is approximately three times more common in men than in women and the gender-related risk of bladder cancer (BC) persisted even after controlling for factors such as excessive exposure to cigarette smoke and industrial chemicals. [2]

ARs have been detected in adult normal and malignant bladder epithelium from both male and female patients and the androgen-AR signaling has been reported to play important roles in the development and progression of BC. [3],[4],[5] This is evidenced by the fact that levels of cytochrome P450 CYP4B1 which activates amines to genotoxic substances, are reduced by castration but recover following androgen supplementation. [5] Miyamoto et al , [5] found that more than 92% of male mice and 42% of female mice treated with carcinogen eventually developed BC, whereas the male or female mice whose AR were knocked off did not develop cancer at all. They also found that recurrence-free survival (RFS) rate tended to be lower in patients with high AR-expressing tumors. These results suggested that targeting AR and androgens may provide novel chemopreventive and therapeutic approaches for management of BC.

With RNA interference recognized as a powerful tool for silencing specific gene expression and having even been used for treatment of a variety of human diseases including cancer, viral infection and eye diseases, [6] the authors have used the siRNA strategy to knock down AR expression in experimental models in vitro and in vivo in this landmark study.

The authors have been successful in suppressing BC progression significantly in in vitro and in vivo situations by targeting AR. But when Can Tuygun et al . [7] evaluated the clinical data and tumor specimens of 139 humans with BC comparing it with normal urothelium of 72 controls surprising results emerged. It was seen that none of the 58 male control cases showed any AR expression. Of the 139 patients with BC, only 71 (51%) expressed AR and expression was significantly lower in T2-tumors (21%) than in Ta-tumors (60%) and T1-tumors (60%) (P < 0.001). AR expression level also did not influence RFS and progression-free survival in this study. These results highlight the fact that when results from experiments in basic science laboratories are attempted to be replicated in humans various confounding factors are encountered and translation of experimental results to clinical practice is always difficult to achieve.

Hence, even though results of the study by Wu et al , show great promise for further research the probability of these spectacular results being replicated in human studies is not known because though it has been possible to nullify the effect of AR on BC cells the role of AR on bladder cancer growth in humans has been put in question.

 
   References Top

1.Wu JT, Han BM, Yu SQ, Wang HP, Xia SJ. Androgen receptor is a potential therapeutic target for bladder cancer. Urology 2010;75:820-7.  Back to cited text no. 1
[PUBMED]  [FULLTEXT]  
2.Hartge P, Harvey EB, Linehan WM, Silverman DT, Sullivan JW, Hoover RN, et al. Unexplained excess risk of bladder cancer in men. J Natl Cancer Inst 1990;82:1636-40.  Back to cited text no. 2
[PUBMED]  [FULLTEXT]  
3.Wilson CM, McPhaul MJ. A and B forms of the androgen receptor are expressed in a variety of human tissues. Mol Cell Endocrinol 1996;120:51-7.  Back to cited text no. 3
[PUBMED]  [FULLTEXT]  
4.Boorjian S, Ugras S, Mongan NP, Gudas LJ, You X, Tickoo SK, et al. Androgen receptor expression is inversely correlated with pathologic tumor stage in bladder cancer. Urology 2004;64:383-8.  Back to cited text no. 4
[PUBMED]  [FULLTEXT]  
5.Miyamoto H, Yang Z, Chen YT, Ishiguro H, Uemura H, Kubota Y, et al. Promotion of bladder cancer development and progression by androgen receptor signals. J Natl Cancer Inst 2007;99:558-68.  Back to cited text no. 5
[PUBMED]  [FULLTEXT]  
6.Moazed D. Small RNAs in transcriptional gene silencing and genome defence. Nature 2009;457:413-20.  Back to cited text no. 6
[PUBMED]  [FULLTEXT]  
7.Tuygun C, Kankaya D, Imamoglu A, Sertcelik A, Zengin K, Oktay M, et al. Sex-specific hormone receptors in urothelial carcinomas of the human urinary bladder: A comparative analysis of clinicopathological features and survival outcomes according to receptor expression. Urol Oncol 2009.  Back to cited text no. 7
    




 

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