Expression of AhR-regulated miRNAs in non-small cell lung cancer in smokers and never smokers.

Smoking is a risk factor for non-small cell lung cancer (NSCLC). The most common subtypes of NSCLC are lung adenocarcinoma (LAC) and squamous cell carcinoma (SCC). The cigarette smoke contains aryl hydrocarbon receptor (AhR) ligands, such as benzo(a)pyrene (BaP). By activating the AhR, BaP can change the expression of many genes, including miRNA-encoding genes. In this study, we have evaluated the expression of few miRNAs potentially regulated by AhR (miR-21, -342, -93, -181a, -146a), as well as CYP1A1, a known AhR target gene, in lung tumor samples from smoking (n=40) and non-smoking (n=30) patients with LAC and from smoking patients with SCC (n=40). We have also collected macroscopically normal lung tissue >5 cm from the tumor margin. We compared the obtained data on the miRNA expression in tumors with data from The Cancer Genome Atlas (TCGA). We found that in 76.7% of non-smoking LAC patients, CYP1A1 mRNA was not detected in tumor and normal lung tissues, while in smoking patients, CYP1A1 expression was detected in tumors in almost half of the cases (47.5% for SCC and 42.5% for LAC). The expression profile of AhR-regulated miRNAs differed between LAC and SCC and depended on the smoking status. In LAC patients, the expression of oncogenic miRNA-21 and miRNA-93 in tumors was higher than in normal lung tissue from the same patients. However, in SCC patients from our sample, the levels of these miRNAs in tumor and non-transformed lung tissue did not differ significantly. The results of our studies and TCGA data indicate that the expression levels of miRNA-181a and miRNA-146a in LAC are associated with smoking: expression of these miRNAs was significantly lower in tumors of smokers. It is possible that their expression is regulated by AhR and AhRR (AhR repressor), and inhibition of AhR by AhRR leads to a decrease in miRNA expression in tumors of smoking patients. Overall, these results confirm that smoking has an effect on the miRNA expression profile. This should be taken into account when searching for new diagnostic and therapeutic targets for NSCLC.

Effect of Photodynamic Therapy on the microRNA Level in Breast Cancer Tissues of Female Wistar Rats.

The expression of microRNA (miR-21, miR-221, miR-27a, and miR-429) was studied normal and tumor breast tissues of female Wistar rats before and after photodynamic therapy. In breast cancer, the levels of oncogenic microRNA (miR-21, miR-221, and miR-27a) were increased, while the level of tumor-suppressing miR-429 was reduced in comparison with the intact group. After photodynamic therapy, suppression of the expression levels of oncogenic microRNAs (miR-21, miR-221, and miR-27a) was noted. The level of tumor-suppressing miR-429 in breast tumor tissues remained reduced, as in the untreated breast cancer group.

Search for New Target Genes of MicroRNA for Differential Diagnosis of Benign and Malignant Neoplasms of the Thyroid Gland by In Silico Methods.

Differential diagnosis of thyroid gland neoplasms is an urgent problem in modern oncothyroidology. This is especially true for the diagnosis of follicular thyroid cancer and follicular thyroid adenoma at the preoperative stage. In this study, in silico methods were used to search for potential markers that are microRNA target genes. A list of 19 microRNAs was compiled, the expression of which varies depending on the type of thyroid neoplasms. For these microRNAs, the target genes were selected considering tissue specificity and association with thyroid diseases. We selected 9 target genes (MCM2, RASSF2, SPAG9, SSTR2, TP53BP1, INPP4B, CCDC80, GNAS, and PLK1), which can be considered as promising markers according to published data. Also, 6 new potential markers (CDK4, FGFR1, ERBB3, EGR1, MYLK, and SRC) were found, which make it possible to distinguish between follicular thyroid cancer and follicular thyroid adenoma. The proposed algorithm using various bioinformatics tools allows us to identify potential markers for the differential diagnosis of thyroid neoplasms.

Correlation between Structural Transformations in Mesenteric Lymph Nodes and the Levels MicroRNA during Polychemotherapy of Breast Cancer.

We studied interrelationships between the cytoarchitectonics of the mesenteric lymph node and the levels of microRNA-21, microRNA-221/222, and microRNA-429 in the lymph, blood serum, and breast tissues in female Wistar rats with chemically induced breast cancer. After polychemotherapy, significant correlations were found between miRNA-221 and the number of lymphoblasts in the germinal centers and between miRNA-222 and the number of lymphoblasts in the germinal centers and macrophages in the medullary cords of the mesenteric lymph nodes.

[Oxytocin receptor expression is associated with estrogen receptor status in breast tumors]. / Ékspressiia oksitotsinovogo retseptora assotsiirovana so statusom éstrogenovogo retseptora v opukholiakh molochnoi zhelezy.

The oxytocin receptor (OXTR) plays an important role in childbirth, breastfeeding, and social interactions. There is emerging evidence that OXTR is associated with the breast cancer (BC) initiation and progression. However, the mechanisms leading to a change in its expression, the diagnostic or prognostic value of the receptor in BC are currently poorly understood. Here, we have evaluated the relative level of OXTR expression in BC samples (n=107), and also investigated the effect of estradiol on its expression in MCF-7 and MDA-MB-231 cells. The level of OXTR expression was significantly lower in breast tumor tissue than in normal tissue obtained from the same patient. The expression of OXTR was dependent on the status and expression of the estrogen receptor (ER): the level of OXTR mRNA was significantly lower in ER-negative BC samples compared to ER-positive BC samples. Moreover, OXTR expression was also lower in samples from patients with luminal subtype with a low value of ER expression (0-5 score according to the IHC assay, Allred scoring) compared with samples with high ER expression (6-8 score). In luminal BC, OXTR expression was associated with the HER2 expression level: the OXTR mRNA level was higher in tumors with a HER2 IHC score of 1+ as compared to cases with the HER2 expression score of 2+, 3+. We also showed that estradiol increased the level of OXTR mRNA in MCF-7 cells, but not in ER-negative MDA-MB-231 cells. These data indicate that changes in OXTR expression in BC tissues can be caused by increased ER expression. We found no association between OXTR and T or N stages and progesterone receptor expression.

Influence of Surgical Treatment and Neoadjuvant Therapy of Chemically Induced Breast Cancer on Correlation of Cytokine Concentrations in the Lymph with Structural Transformations in the Mesenteric Lymph Nodes.

We performed a correlation analysis of the morphometry of mesenteric lymph nodes and cytokines of the thoracic duct lymph in chemically induced breast cancer (BC) and after surgical treatment of BC and neoadjuvant chemotherapy for BC according to the CMF scheme. After surgical treatment, correlations were found between the level of cytokines in the thoracic duct lymph and morphological changes in the mesenteric lymph nodes. The observed correlations can be a result of total resection of the tumor and increased immunomodulatory and antitumor action of cytokines. Comparison of the effect of chemotherapy and surgical treatment revealed correlations between cytokine concentrations in the lymph and structural changes in the lymph nodes, which can be related to weakening of local immunity and antitumor effect of cytokines.

Spectrum of TP53 Mutations in BRCA1/2 Associated High-Grade Serous Ovarian Cancer.

Objective: Mutations in TP53 lead to loss of function (LOF) or gain of function (GOF) of the corresponding protein p53 and produce a different effect on the tumor. Our goal was to determine the spectrum of somatic TP53 variants in BRCA1/2 associated high-grade serous ovarian cancer (HGSOC). Methods: The population under study comprised of HGSOCs with pathogenic variants in BRCA1 (n = 78) or BRCA2 (n = 21). Only chemo-naive and platinum-sensitive patients were included in this study. The case group of the IARC database (n = 1249) with HGSOC not stratified by BRCA status was used as a reference. A custom NGS panel was used for sequencing TP53 and mutational hot-spots of other genes, and p53 expression was evaluated by immunohistochemistry for 68 cases of HGSOCs. Results: Somatic TP53 variants (95) or inhibition of wild-type p53 expression (3) were observed in 98 cases. The sample with normal p53 had CDKNA1 variants. The frequency of truncating variants was significantly higher than in the reference cohort (30.3 vs. 21.0%, p = 0.01). Most of the samples (41/68) demonstrated low (or absent) expression of p53, and 17 samples overexpressed p53. LOH was typical for TP53 nonsense variants (14/15). In total, 68/95 samples were LOH positive and showed LOH in all tumorous cells, thus indicating the driver effect of TP53 mutations. Three specimens had KRAS, BAX, APC, and CTNNB1 subclones variants. Conclusion: High frequency of TP53 truncating variants, the low expression of mutant p53, and low incidence of oncogene mutations show potential GOF properties of p53 to be poorly represented in BRCA1/2 associated HGSOC.

[Effect of benzo(a)pyrene on the expression of AhR-regulated microRNA in female and male rat lungs]. / Vliianie benz[a]pirena na ékspressiiu AhR-reguliruemykh mikroRNK v legkikh samok i samtsov krys.

Smoking is the main risk factor for lung cancer, mainly due to presence of nitrosamines and polycyclic aromatic hydrocarbons, including benzo[a]pyrene (BP) in tobacco smoke composition. The genotoxic effect of BP is based on the high DNA-binding ability of its metabolites, while the epigenetic effects are mediated by a change in the expression of cancer related genes or regulatory RNAs. It has been shown that women have a higher risk to develop lung cancer upon smoking rather than men. We hypothesized that crosstalk between signaling pathways activated by BP and estrogens could underlie the sex-dependent differences in miRNAs expression. To test this hypothesis, male and female rats were subjected to short-term or long-term BP exposure. Using in silico analysis, miRNAs containing the ER- and AhR-binding sites in the promoters of the genes (or host genes) were selected. During chronic exposure of BP the expression of miR-22-3p, -29a-3p, -126a-3p, -193b-5p in the lungs of male rats were significantly increased, while the level of miRNA-483-3p were decreased. Expression of miRNA-483-3p was up-regulated during chronic BP exposure in the lungs of female rats and the levels of other studied miRNAs were unchanged. In turn, changes in the expression of miRNAs were followed by changes in the expression of their target genes, including PTEN, EMP2, IGF1, ITGA6, SLC34A2, and the observed changes in female and male rat lungs were varied. Thus, our results suggest that sex-dependent epigenetic effects of BP may be based on different expression of AhR- and ER- regulated miRNAs.

[Analysis of prolactin receptor expression in breast cancer subtypes]. / Analiz ékspressii retseptora prolaktina v podtipakh raka molochnoi zhelezy.

Breast cancer (BC) is the most common cancer among women. It is known that the prolactin receptor (PRLR) may play a role in breast carcinogenesis, but the available data are often contradictory. To get a more complete picture of the relationship between the receptor and mammary gland carcinogenesis, we examined the association between changes in PRLR expression level and tumor subtype (and its main characteristics). To do this, using real-time PCR, we evaluated the level of PRLR mRNA in BC tissue samples and untransformed adjoining tissue samples (89 pairs). Since the androgen receptor (AR) has begun to be seen as a prognostic marker in breast cancer, we also evaluated the association between mRNA levels of AR and PRLR. We found a significant increase in PRLR expression in luminal subtypes; the highest level of PRLR mRNA was detected in luminal A subtype. In HER2-positive ER-, PR-negative BC, the PRLR mRNA level decreases in tumor tissues compared with untransformed tissues. High PRLR expression is also associated with smaller tumor size in luminal B HER2-negative subtype. In ER-, PR-negative tumors, PRLR expression is associated with AR expression: PRLR mRNA level is increased when AR mRNA level is reduced by more than 8 times in triple-negative tumors; in contrast, in HER2-positive subtype it decreases more significantly when AR expression is reduced by more than 3 times. A tendency towards an increase in PRLR expression with an increase in the AR mRNA level was also discovered in luminal subtypes. The level of PRLR expression depends on the age of patients. In luminal A, PRLR expression is higher in patients under 65 years. In contrast, in luminal B HER2-negative and triple-negative BC, reduced PRLR expression was observed in patients under the age of 40 years and under the age of 50 years, respectively. In this group of patients under the age of 40 years with luminal B HER2-negative BC, ER expression was also reduced (0-4 score according to the IHC assay). Thus, PRLR probably plays a different role in the development and progression of BC: in luminal A and luminal B HER2-positive subtypes PRLR may act as an oncogen, and in luminal B HER2-negative and ER-, PR-negative subtypes can play a tumor suppressor role.

Effect of Benzo(a)pyrene on the Expression of miR-483-3p in Hepatocyte Primary Culture and Rat Liver.

Here, we suggested that the epigenetic mechanism of benzo(a)pyrene (BP) action might be based on the aryl hydrocarbon receptor (AhR)-mediated transcription of the target genes, including miRNAs, that have the dioxin response element (DRE) in their promoters. The effect of BP on the expression of the oncogenic miR-483-3p, its host gene IGF2, and target gene IGF1 in primary hepatocytes and in the liver of Wistar female rats was investigated. The activation of AhR was confirmed using selective AhR inhibitor CH-223191 and by evaluating expression of the target CYP1A1 gene. The lack of coordination between the expression of miR-483-3p and its host gene IGF2 was revealed, which may be due to the presence of the binding site for the estrogen receptor alpha (ERα), which is a negative expression regulator. Our results confirm the existence of the AhR-mediated pathway in the regulation of expression of miR-483-3p, IGF1, and IGF2 under BP exposure, which is of considerable interest for understanding the epigenetic mechanisms of the carcinogenic effect of BP.

Effect of benzo[a]pyrene on the expression of miR-126, miR-190a and their target genes EGFL7, TP53INP1 and PHLPP1 in primary endometrial cells.

The main topic of this study was to investigate the effect of benzo[a]pyrene (BP) on microRNAs and their target genes expression levels in primary cell cultures from normal and malignant endometrial tissue. MicroRNA-126 (miR-126) and miR-190a were most sensitive to BP treatment. The treatment of both cultures with BP was accompanied by a decrease of miR-126 level and an increase of EGFL7 gene expression level. BP-induced upregulation of miR-190a was detected only in normal cells and it was accompanied with decrease of mRNA levels of TP53INP1 and PHLPP1 genes. Taking into account that BP promoted the proliferation of normal cells and amplified apoptosis of cancer cells, it is possible that miR-190a is involved in general cellular response to BP. The findings of this study indicate that miR-190a and its target genes may be involved in the regulation of cell fate under BP treatment.

Expression of microRNA Potentially Regulated by AhR and CAR in Malignant Tumors of the Endometrium.

We studied microRNA whose expression can be regulated by carcinogenic compounds. Bioinformatic analysis has detected microRNA potentially regulated by xenosensor receptors AhR (miR-28, miR-30c, miR-30e, miR-139, and miR-153) and CAR (miR-29c, miR-31, miR-185, miR-625, and miR-652). Published data indicate that these microRNAs are oncosuppressors, except miR-31 that can act as an oncogene. The expression of these microRNAs in malignant tumors of the endometrium was studied. The expression of the majority of the studied microRNAs, except miR-652, was 2-3-fold below the normal, which confirms their oncosuppressor function and indicates their involvement in the endometrial carcinogenesis and hence, allows considering them as potential markers of the disease.

MiR-21 regulates the ACAT1 gene in MCF-7 cells.

AIMS: The purpose of the present study was to determine whether miR-21 regulates the human ACAT1 gene. We also assessed whether transfection of MCF-7 cells with miR-21 mimic/inhibitor leads to changes in ACAT1 mRNA/protein levels, cell proliferation rate, or apoptosis. MAIN METHODS: Regulation of ACAT1 3'UTR by miR-21 was evaluated using a dual-luciferase reporter assay. The effect of miR-21 on mRNA/protein levels of ACAT1 and PTEN (confirmed as an important target of miR-21 for comparison) was measured by qPCR/western blot analysis and immunostaining. Proliferation rate was determined by cell counting. Percentage of cells undergoing late apoptosis was determined by staining with Hoechst 33342/propidium iodide. KEY FINDINGS: Dual-luciferase reporter assay confirmed the regulation of ACAT1 3'UTR by miR-21. Furthermore, transfection of MCF-7 cells with miR-21 mimic decreased mRNA and protein levels of ACAT1 and PTEN genes. In contrast, miR-21 inhibition increased the mRNA and protein levels of both genes studied. Finally, we observed an increase in cell proliferation and decrease in the percentage of cells in late apoptosis in MCF-7 cells transfected with miR-21 mimic, whereas transfection with miR-21 inhibitor led to the opposite effect. SIGNIFICANCE: Our data confirm the hypothesis that miR-21 regulates the human ACAT1 gene. As the expression of this microRNA is altered in many types of cancers, the discovery of novel targets for miR-21 is of particular interest for diagnosis and treatment.

Expression of Hormonal Carcinogenesis Genes and Related Regulatory microRNAs in Uterus and Ovaries of DDT-Treated Female Rats.

The insecticide dichlorodiphenyltrichloroethane (DDT) is a nonmutagenic xenobiotic compound able to exert estrogen-like effects resulting in activation of estrogen receptor-α (ERα) followed by changed expression of its downstream target genes. In addition, studies performed over recent years suggest that DDT may also influence expression of microRNAs. However, an impact of DDT on expression of ER, microRNAs, and related target genes has not been fully elucidated. Here, using real-time PCR, we assessed changes in expression of key genes involved in hormonal carcinogenesis as well as potentially related regulatory oncogenic/tumor suppressor microRNAs and their target genes in the uterus and ovaries of female Wistar rats during single and chronic multiple-dose DDT exposure. We found that applying DDT results in altered expression of microRNAs-221, -222, -205, -126a, and -429, their target genes (Pten, Dicer1), as well as genes involved in hormonal carcinogenesis (Esr1, Pgr, Ccnd1, Cyp19a1). Notably, Cyp19a1 expression seems to be also regulated by microRNAs-221, -222, and -205. The data suggest that epigenetic effects induced by DDT as a potential carcinogen may be based on at least two mechanisms: (i) activation of ERα followed by altered expression of the target genes encoding receptor Pgr and Ccnd1 as well as impaired expression of Cyp19a1, affecting, thereby, cell hormone balance; and (ii) changed expression of microRNAs resulting in impaired expression of related target genes including reduced level of Cyp19a1 mRNA.

[Expression of miR-21 and Its Acat1, Armcx1, and Pten Target Genes in Liver of Female Rats Treated with DDT and Benzo[a]pyrene].

MiR-21 is the most studied cancer-promoting oncomiR, which target numerous tumor suppressor genes associated with proliferation, apoptosis, and invasion. Here we have studied the synthesis of miR-21 and quantified the mRNA and protein levels for miR-21 potential target genes, i.e., Acat1, Armcx1, and Pten, in the livers of female Wistar rats after their treatment with either 1,1-trichloro-2,2-di(4-chlorophenyl)ethane (DDT) or benzo[a]pyrene (BP). The most important finding appears to be the significant decrease in the miR-21 level the day after treatment with DDT with subsequent rebound. These changes are accompanied by an increase and subsequent drop in the levels of mRNAs and proteins of the Acat1, Armcx1, and Pten genes. These observations indicate the involvement of miR-21 in the posttranscriptional regulation of the Acat1, Armcx1, and Pten genes in response to xenobiotics. We hypothesize that the toxic effects of xenobiotics may be indirect and may manifest by inducing epigenetic changes, particularly through the regulation of miRNAs and their target genes.

Search of MicroRNAs Regulating the Receptor Status of Breast Cancer In Silico and Experimental Confirmation of Their Expression in Tumors.

MicroRNA whose expression depends on the receptor status of breast cancer were selected using bioinformatic analysis. The expression of 9 microRNAs (16, 17, 21, 27, 125, 146, 155, 200a, and 221) was analyzed in 76 samples of breast cancer with various receptor phenotypes. The expression of microRNAs 155, 27, and 200a did not differ in various types of breast cancer. The data on positive correlation between the expression of microRNA-21 and microRNA-221 and negative receptor status of the tumor were confirmed. The expression of the tumor suppressing microRNA-125b decreased in samples of breast cancer expressing HER2 and ER and in triple negative breast cancer, which characterizes it as a universal marker of breast cancer. An increase in the expression of microRNA-16 was shown in samples of breast cancer expressing HER2 and ER. The expression of microRNA-17 decreased in triple negative breast cancer and increased in ER+, PR+, and HER+ types of breast cancer. MicroRNAs 16, 17, 21, 125b, 146b, and 221 can be promising markers for differential diagnostics of various phenotypes of breast cancer.

[The genetic markers and targets of target therapy of melanoma.]

Melanoma is the most dangerous malignant disease of skin with high risk of relapsing and metastasis dissemination. The molecular biological studies implemented during last decade drastically altered our concepts about mechanisms of carcinogenesis of melanocytes. The review considers both hereditary factors of predisposition to melanoma (rare alleles of genes CDKN2A и CDK4, mutations MITF and BAP1) and somatic genetic disorders involved into carcinogenesis of melanoma. These mutations in genes causing hyper-activation of RAS-MAPK (BRAF, NRAS, MEK, NF1) и PI3K- (PTEN, AKT) of signaling pathways and also genes of tyrosine-kinase receptors KIT, ERBB4 activating transfer of signal in cell. Also, the role of сAMP and NF-κB in melanomagenesis is considered. The detection of activating mutations of key signaling pathways in oncogenes permitted to apply medications of target action many of which demonstrated a good therapeutic effect. The combined treatment of melanoma in aggregate with immune therapy is especially perspective.

[Effect of xenobiotics on microRNA expression in rat liver].

Using bioinformatics analysis we selected microRNAs which could bind 3'-UTR-region of cytochrome P450 (CYP) genes. Three microRNA miR-21, -221, -222, their potential targets might be mRNA for CYP1A1, and two microRNA miR-143, miR-152 for CYP2B1 accordingly were selected for experimental verification. Expression level of these microRNAs in rat liver upon benzo(a)pyrene (BP), phenobarbital (PB), and DDT induction was determined using RT-qPCR method. In rats treated by both BP, and DDT the hepatic content of miR-21, -221, -222 significantly demonstrated a 2-3-fold decrease. The decrease in miR expression was accompanied by a considerable (5.5-8.7-fold) increase in the CYP1A1-mediated EROD activity. The expression of miR-143 remained unchanged after the PB treatment, while the expression of miR-152 increased by 2 times, however, the (10.5-fold) increase in PROD activity of CYP2B was much higher. In the DDT-treated liver PROD activity increased by 20 times, the expression of miR-152 didn't change, and the expression of miR-143 increased by 2 times. The bioinformatics analysis of interactions between microRNAs and targets showed that the studied miRs can potentially bind 3'-end of AhR, ESR1, GR, CCND1, PTEN mRNA. Thus, the expression profile of miR-21, -221, -222, -143, -152 might change under the xenobiotics exposure. In silico analysis confirmed, that microRNAs target not only cytochrome P450 mRNA but also other genes, including those involved in hormonal carcinogenesis, they also can be regulated with studied miRs.

Associativity of microRnA levels in blood serum to quantity and functional activity of haemo - and lymphopoiesis cells in experimental breast cancer.

The work purpose was to reveal an existence of an associativity of the microRNA levels in blood serum to quantitative and functional indices of cells haemo - and lymphopoiesis at the experimental breast cancer induced by N -methyl - N- nitrosourea in the remote period after surgery and carrying out neoadjuvant polychemotherapy. At animals there were investigated levels of microRNA-21, microRNA-221, microRNA-222 and microRNA-429 in serum, also investigated quantitative and functional parameters of cells from bone marrow, from lymph of a chest channel and from spleen. Statistically significant distinctions on the microRNA level in blood serum and an existence of interrelations of microRNA levels with quantitative and functional indices of haemo- and lymphopoiesis cells were revealed.

Gene expression of androgen metabolising enzymes in benign and malignant prostatic tissues.

Benign prostatic hyperplasia (BPH) as well as prostate cancer (CaP) are prevalent in the aging male population, and both the diseases display androgen-dependence when the circulating testosterone from the gonads decreases. This suggests that the local or intracrine production of androgens may drive these diseases. Both diseases are dependent on the conversion of androgen by the epithelial compartment to the ligand with higher affinity and can be treated by blocking synthesis of this androgen metabolite. For this approach to be effective, a detailed knowledge of androgen biosynthesis in both disease states is required. The aim of the present study was to investigate the gene expression levels of androgen metabolising enzymes in BPH compared to normal adjacent prostate tissues and CaP. Expression of the genes HSD3B1, HSD17B3, and SRD5A2 was significantly increased in BPH tissues compared to normal adjacent prostate tissues. In contrast to BPH, CaP demonstrated significant decrease in the expression of HSD17B3, AKR1C2, and SRD5A2 compared to normal adjacent prostate tissues. HSD17B2 expression was significantly decreased in all samples. Moreover, HSD3B1 and SRD5A2 mRNA levels were upregulated in BPH compared with CaP. These results suggest that a change in androgen metabolism may be an important step in the pathogenesis of BPH, leading to increased cell proliferation due to in situ androgen synthesis. These features can be used to develop differential treatment strategies for BPH. HSD3B1 and SRD5A2 could be used as therapeutic target for BPH.