Increased chemosensitivity via targeting testicular nuclear receptor 4 (TR4)-Oct4-interleukin 1 receptor antagonist (IL1Ra) axis in prostate cancer CD133+ stem/progenitor cells to battle prostate cancer.

Prostate cancer (PCa) stem/progenitor cells are known to have higher chemoresistance than non-stem/progenitor cells, but the underlying molecular mechanism remains unclear. We found the expression of testicular nuclear receptor 4 (TR4) is significantly higher in PCa CD133(+) stem/progenitor cells compared with CD133(-) non-stem/progenitor cells. Knockdown of TR4 levels in the established PCa stem/progenitor cells and the CD133(+) population of the C4-2 PCa cell line with lentiviral TR4 siRNA led to increased drug sensitivity to the two commonly used chemotherapeutic drugs, docetaxel and etoposide, judging from significantly reduced IC50 values and increased apoptosis in the TR4 knockdown cells. Mechanism dissection studies found that suppression of TR4 in these stem/progenitor cells led to down-regulation of Oct4 expression, which, in turn, down-regulated the IL-1 receptor antagonist (IL1Ra) expression. Neutralization experiments via adding these molecules into the TR4 knockdown PCa stem/progenitor cells reversed the chemoresistance, suggesting that the TR4-Oct4-IL1Ra axis may play a critical role in the development of chemoresistance in the PCa stem/progenitor cells. Together, these studies suggest that targeting TR4 may alter chemoresistance of PCa stem/progenitor cells, and this finding provides the possibility of targeting TR4 as a new and better approach to overcome the chemoresistance problem in PCa therapeutics.

Recent advances in the study of testicular nuclear receptor 4.

Testicular nuclear receptor 4 (TR4), also known as NR2C2 (nuclear receptor subfamily 2, group C, member 2), is a transcriptional factor and a member of the nuclear receptor family. TR4 was initially cloned from human and rat hypothalamus, prostate, and testes libraries. For almost two decades, its specific tissue distribution, genomic organization, and chromosomal assignment have been well investigated in humans and animals. However, it has been very difficult to study TR4's physiological functions due to a lack of specific ligands. Gene knock-out animal techniques provide an alternative approach for defining the biological functions of TR4. In vivo studies of TR4 gene knockout mice (TR4(-/-)) found that they display severe spinal curvature, subfertility, premature aging, and prostate prostatic intraepithelial neoplasia (PIN) development. Upstream modulators, downstream target gene regulation, feedback mechanisms, and differential modulation mediated by the recruitment of other nuclear receptors and coregulators have been identified in studies using the TR4(-/-) phenotype. With the establishment of a tissue-specific TR4(-/-) mouse model, research on TR4 will be more convenient in the future.

Higher expression of peroxisome proliferator-activated receptor γ or its activation by agonist thiazolidinedione-rosiglitazone promotes bladder cancer cell migration and invasion.

OBJECTIVE: To investigate the role of peroxisome proliferator-activated receptor γ (PPARγ) in bladder cancer (BCa) progression. MATERIALS AND METHODS: The gene copy number of PPARγ in human BCa tissue samples was analyzed by fluorescence in situ hybridization. The migration and invasive ability of human BCa cell lines with different PPARγ expression levels or treated with thiazolidinedione-rosiglitazone, a PPARγ agonist and an antidiabetic drug, were investigated. RESULTS: PPARγ amplification was increased dramatically in BCa tissue compared with normal urothelium (38.1% vs 4.3%, P = .0082) and in tumors with lymph node metastasis compared with those without metastasis (75.0% vs 15.4%, P = .0176). The human BCa cell line 5637 with strong PPARγ expression demonstrated a greater ability for cell migration and invasion than the UMUC-3 cell line with weak PPARγ expression. Knocking down PPARγ in BCa 5637 cells led to decreased cell migration, and activation of PPARγ with thiazolidinedione-rosiglitazone promoted their migration and invasive ability. CONCLUSION: PPARγ amplification in BCa could play an important role in BCa cell migration and invasion. Alteration of PPARγ expression by PPARγ-small interfering ribonucleic acid or activation by its agonist rosiglitazone, a diabetic thiazolidinedione drug, could lead to alternation of BCa cell migration and invasion.

A new plastic surgical technique for adult congenital webbed penis.

OBJECTIVE: To introduce a novel surgical technique for correction of adult congenital webbed penis. METHODS: From March 2010 to December 2011, 12 patients (age range: 14-23 years old) were diagnosed as having a webbed penis and underwent a new surgical procedure designed by us. RESULTS: All cases were treated successfully without severe complication. The operation time ranged from 20 min to 1 h. The average bleeding volume was less than 50 ml. All patients achieved satisfactory cosmetic results after surgery. The penile curvature disappeared in all cases and all patients remained well after 1 to 3 months of follow-up. CONCLUSIONS: Adult webbed penis with complaints of discomfort or psychological pressure due to a poor profile should be indicators for surgery. Good corrective surgery should expose the glans and coronal sulcus, match the penile skin length to the penile shaft length dorsally and ventrally, and provide a normal penoscrotal junction. Our new technique is a safe and effective method for the correction of adult webbed penis, which produces satisfactory results.

Marital status and fertility of 185 male renal transplant recipients in China.

A questionnaire was designed to assess the effects of renal transplantation in men of reproductive age on marital status and fertility. The study sought to correlate recipients' marital status and fertility with the health of the recipients after the transplantation, the health of children they fathered after the procedure, and the functioning of the transplanted kidney. Male recipients (n = 243) who were single and of reproductive age before renal transplantation were selected from 2007 recipients of a renal transplant recorded in the authors' hospitals in China. Of the 243 surveyed, 185 completed the questionnaire and participated in follow-up in the clinic or by telephone. Their marital status and fertility were investigated. Of the 185 recipients, 69 got married 12-88 months (mean, 32.19 +/- 14.30 months) after renal transplantation, and 62 of 69 couples were actively attempting to become pregnant. Fifty-three patients fathered 54 children, including 1 pair of twins, 9-72 months (mean, 25.81 +/- 15.33 months) after marriage. The birth weights of the newborns ranged from 2500 to 4600 g (mean, 3395 +/- 456.80 g). These children developed well. Nine patients did not father any children, and 3 of these 9 cases were attributable to infertility in the wife. Seven patients were using contraceptives. Three recipients suffered from chronic graft rejection and resumed hemodialysis 2-11 years after they fathered children. In addition, 2 patients died after fathering 1 child: 1 from dysfunction of the transplanted kidney 9 years after birth of his child, and another in an accident 1 year after his child's birth. Our findings suggest that, like men without renal transplants, male recipients of renal transplants can get married and father children, and the transplantation procedure appears to have no significant effect on the children fathered afterwards, on the recipients' health, or on the functioning of the transplanted kidney. It is very important to indicate that, in addition to needing contraception if they do not conceive, male renal transplant recipients should expect fertility rates that are similar to those of the general population.