Study On The Pathogenesis Mechanisms Of Sex Steroid Hormone Receptors In Benign Prostatic Hyperplasia

Background:Benign prostatic hyperplasia(BPH)is common in elderly men,characterized by nonmalignant enlargement of both epithelial and stromal tissues within the prostate gland pathologically,which causes bladder outlet obstruction and contributes to series of urinary voiding problems commonly known as lower urinary tract symptoms.At present,China is about to enter an aging society,which may make the health economics pressures brought by BPH even more serious.Currently,it is well accepted that the pathogenesis of BPH is complicated and multi-factor involved.And so far,the exact mechanism and etiology of BPH is still to be elucidated.Therefore,it is required to identify the exact pathogenesis of BPH in order to find more effective prevention and treatment program,to improve the quality of life of older men and to reduce the burden of social health insurance.Purpose:The present study aimed to reveal the possible pathogenesis of sex steroid hormone receptors,including androgen receptor(AR),estrogen receptor ?(ER?),estrogen receptor ?(ER?)and progesterone receptor(PGR),in BPH exploringly,hoping to make a breakthrough to elucidate them.The first step was to identify the differential expression of these receptors between BPH and normal prostate tissues.Then,reseaches on the role of microRNAs,cytokines and growth factors possiblly regulated by one of these receptors and related to proliferation or apoptosis in BPH were followed.Still,the correlation between metabolic syndrome(MetS)and these receptors in BPH was identified.Methods1.Totally 40 cases of BPH and 5 cases of normal prostate were enrolled at Southwest Hospital,Third Military Medical University from February to June 2015.2.The rat model of BPH was induced by combination of exogenous testosterone propionate and estradiol benzoate on castrated male SD rats.3.The combination of IHC,qRT-PCR,and WB assay was used to identify the distribution and differential expression of AR,ER?,ER?,and PGR at the immunoactive biomarker,transcriptional,and protein levels between normal and BPH tissues.The results were then validated in the rat model of BPH.4.The present study enrolled 3 normal prostate tissues and 3 BPH tissues for miRNA microarray analysis using Agilent mi RNA array.And then the method of qRT-PCR was used to validate the aberrantly expressed mi RNAs with enlarged samples.5.The preliminary screening aberrantly expressed cytokines and growth factors,possibly regulated by sex steroid and related to the pathogenesis of BPH,were conducted by the method of qRT-PCR.6.The cases of BPH were divided into two groups,BPH with MetS and BPH without MetS,according to the diagnostic criteria of metabolic syndrome.The clinical data of the two groups were analyzed comparatively to identify the correlation between MetS and BPH.Then the methods of qRT-PCR,and WB assay were used to identify the differential expression of AR,ER?,ER?,and PGR between groups.Results:1.In both human and rat prostate tissues,AR was localized mainly to epithelial and stromal cell nuclei;ER? was distributed mainly to stromal cells,but not exclusively;ER? was interspersed in the basal layer of epithelium,but sporadically in epithelial and st romal cells;PGR was expressed abundantly in cytoplasm of epithelial and stromal cells.There were decreased expression of ER? and increased expression of PGR,but no difference in the expression of ER? in the BPH compared to the normal prostate of both human and rat.Increased expression of AR in the BPH compared to the normal prostate of human was observed,however,the expression of AR in the rat prostate tissue was decreased.2.The mi RNAs microarray analysis revealed that only mi R-126-3p and mi R-4672 had fold>1.5 and P<0.05 simultaneously and were down-regulated in BPH tissues,while the differential expression of mi R-143-3p and mi R-145-3p did not reach statistical significance.The results of qRT-PCR analysis demonstrated the dysregulation of these 4 mi RNAs was inconspicuous and the different expression levels of them were not statistically significant(P>0.1).3.Compared to normal prostate tissues,the transcriptional expression levels of ETV1 and TLR1 were significantly increased in BPH tissues(P<0.05),while those of TGF?1-SMAD2/3,IL6R-JAK2-STAT3,KRAS-ERK,TLR2 were not(P>0.05).4.The mean ages in BPH with MetS and BPH without MetS were similar,while the diagnostic factors of MetS such as BMI,fasting blood glucose,triglyceride,high density lipoprotein,blood pressure differed significantly between the two groups(P<0.05).The total PSA level and prostate volume in BPH with MetS were significantly increased compared to those in BPH without MetS(P < 0.05),while the IPSS and maximum urinary flow rate between the two groups were not(P>0.05).The prevalence of histological inflammation in BPH with MetS was 76.2%(16/21),while that in BPH with MetS was 46.7%(7/15).But the difference was not statistically significant(P>0.05).The expression levels of AR,ER? and PGR in BPH with MetS were significantly elevated compared to that in BPH without MetS at transcriptional and protein levels,while that of ER ? between the two groups was not significant different(P>0.05).Conclusion:1.The present study identified the activation of AR and PGR and the repression of ER? in BPH,which were further validated in the rat model.These results indicate that AR and PGR may play a promoting role in the pathogenesis of BPH while ER? may play an inhibitory role.There may be a different mechanism in the activation of AR pathway in human BPH than in hormone-induced rat model of BPH.2.Based on the available data,it could not conclude that mi R-126-3p,mi R-4672,mi R-143-3p and miR-145-3p are related to the pathogenesis of BPH.Further studies with larger samples,especially larger normal prostate samples,are required to certify the relationship between mi RNAs and BPH.3.This study revealed the transcriptional expression levels of ETV1 and TLR1 were significantly increased in BPH tissues,while the others were not.However,the following conclusion could not be presented based on the available data.Further study is needed to clarify the dysregulation of the protein levels and the phosphorylation levels of these factors.AR-ETV1 pathway was speculated to play a role in the pathogenesis of BPH.4.This study identified the correlation between MetS and BPH,which revealed that the patients of BPH with MetS had a greater prostate volume,higher total serum PSA level and more significant histological inflammation,while the impact of MetS on the symptom of BPH is still to be elucidated.The expression levels of AR,ER? and PGR in BPH with MetS were significantly elevated compared to that in BPH without MetS,which indicated MetS might have a role in the upregulation of AR,ER?,PGR and in the initiation,progression of BPH.