Research progress of miRNA and chronic nonbacterial prostatitis

GONG Ao-lei, CHEN Dong✉, WANG Jia-hui✉, ZHENG Xiao-ting, WANG Na-qin

1.Hainan Medical University, Haikou 571199, China

2.Affiliated Hospital of Nanchang Medical Research Institute/Nanchang Reproductive Hospital, Nanchang 330001, China

3.Hainan Hospital of Traditional Chinese Medicine, Haikou 570203, China

Keywords:

ABSTRACT Chronic nonbacterial prostatitis (CNP) ,also the type Ⅲ prostatitis account for more than 90% of all patients with prostatitis.It has a long course of disease, easy to repeat, unknown pathogenesis and poor clinical efficacy.At present, some scholars at home and abroad have found that there is differential expression of microRNA(miRNA) in prostatic fluid of CNP patients or prostate tissue of CNP rat model.Intervention of miRNA expression can alleviate the symptoms and pharmacodynamics of CNP to a certain extent, which opens up a new way and direction for the pathogenesis and diagnosis and treatment of CNP.Therefore, this paper reviews the research progress of miRNA and CNP in recent years.

1.Introduction

miRNA is a class of non-coded single chain RNA, of about 19-24nt which is highly conservative in the evolution of higher euaryotic organisms, Studies have shown that miRNAs, which account for 3% of the human genome, are involved in the regulation of about 90% of gene expression,miRNA pairs with the 3′-UTR region of its target gene mRNA (incomplete pairing in animals),and silences gene expression mainly by regulating the translation of target mRNA, is closely related to metabolism, immunity,inflammation, tumor and other[1-2].Research shows that miRNA is a hot topic to clarify the pathogenesis, diagnosis and treatment of various diseases[3-4].Modern medicine believes that the pathogenesis of CNP is complex and diverse and has not yet been reached.Each hypothesis tries to explain the pathogenesis of CNP at a certain level, which can not be fully summarized, and the pathogenesis of CNP may be the result of various mechanisms or a certain factor plays a leading role[5-8].Because we have not yet reached a unified understanding of the pathogenesis of CNP,in the clinical, diagnosis and treatment are mainly based on symptoms, signs and prostate fluid examination[9-12],It is difficult to receive satisfactory curative effect.At present, research has shown that there is a different expression of miRNA in the prostate fluid in CNP patients and healthy men, and the significantly different expression of miRNA has a certain regulatory effect on the immune, inflammation and oxidative stress processes related to CNP pathogenesis.Therefore,miRNA may play an important role in the pathogenesis of CNP[13].In recent years, transcriptome miRNA as a breakthrough point to explore the pathogenesis of CNP or as a diagnostic marker and drug target has been paid more and more attention[14].This paper reviews the recent developments of miRNA and CNP.

2.CNP and miRNA expression spectrum

miRNA expression is spatio-temporal specific and changes significantly in different tissues, cells, interventions, or the same interventions[2].Domestic and foreign studies show that miRNA expression spectrum in the pathogenesis of CNP may have some correlation with the pathogenesis of CNP.

2.1 miRNA expression spectrum in prostate fluid in CNP patients

Current classification and diagnostic criteria for prostatitis are determined by NIH ( National Institutes of Health), where CNP represents more than 90% of clinical prostatitis[15].There are some limitations in the diagnosis and treatment of prostatitis according to the presence or absence of bacterial infection and white blood cell count in prostatic fluid.In clinical practice, CNP is mainly diagnosed and treated according to the symptoms, signs and Anal examination of the patients,at present, there is no specific and sensitive biochemical index.

MiRNA expression has spatio-temporal specificity, and its expression spectrum will be different under different pathological conditions.These specific miRNA expression may be the typing diagnosis indicator of CNP[16].Chen et al used NGS (new generation sequencing )to identify the characteristic expression profile of miRNA in EPS (expressed prostatic secret),41 and 43 major EPS miRNA were found in 40 healthy men and 39 CNP patients,respectively.Compared with 20 healthy men, 22 rich EPS miRNAs in 20 patients were up-regulated by more than 2 times, and miR-21-5p had high diagnostic accuracy in patients with type IIIA prostatitis,and found that miR-141-3p、miR-21-5p、miR-103a-3p was closely associated with pain scores in patients with type IIIA prostatitis[17].In this study, the expression profile of miRNA secreted in EPS of CNP patients was analyzed by NGS technology, and it was found that the secreted miRNA could exist in a large number and stably in prostatic fluid.This study provides evidence that the abnormal expression of secreted miRNA in EPS is associated with prostatitis.

2.2 miRNA expression spectrum in semen in patients with CNP

Prostate fluid is an important part of semen, accounting for about 1/4 of semen, which is closely related to semen quality and sperm vitality[18].The change of prostatic fluid will inevitably lead to the change of semen, and it will have a certain impact on semen when inflammation occurs in the prostate.The change of semen in patients with CNP can indirectly reflect the situation of prostatic fluid.There is differential expression of miRNA in semen of patients with CNP,detection of miRNA in semen of patients with CNP may have reference value for diagnosis and treatment of CNP.

Guo et al found that some miRNAs in semen ncRNA (non coding RNA) of Type IIIA CNP patients have high concentration, which can be used as a detection index for the study of CNP patients;The researchers conducted differential screening of miRNA expression profiles in semen of CNP patients, A total of 486 miRNAs were included in the analytical system.Through the difference analysis between the experimental group and the control group, it was found that 52 miRNAs were up-regulated, 156 miRNAs were down regulated, and the remaining 278 miRNAs were not significantly changed[19].The results showed high miRNA in semen ncRNA in IIIA CNP, it can be used as a detection index for studying patients with type IIIA CNP.

2.3 Serum miRNA expression spectrum

Through literature search, it was found that some researchers tried to make differential diagnosis of prostate related diseases through the changes of some miRNAs in serum.Yakup et al found that in the experiment of differential diagnosis between prostate cancer and benign prostatic disease, 5 miRNAs were screened from 11 miRNAs including miR-375, miR-125b-5p, miR-30c-5p as candidate biomarkers, and found that these miRNAs alone or in combination can be used to distinguish prostate cancer and benign prostatic disease.The serum levels of miR-26b-5p and let-7c-5p in CNP group were significantly different from those in BPH group[20].The researchers believe that these specific miRNAs may be used as biomarkers for the diagnosis and differentiation of prostate diseases.

2.4 miRNA expression spectrum of prostate tissue in CNP rat model

Zhang et al used NGS sequencing technology to quantitatively and qualitatively study the miRNA expression profile in prostate tissue of carrageenan induced CNP rat model, and via GO (gene ontology)and KEGG (Kyoto Encyclopedia of Gene and Genomics) and other databases for bioinformatics analysis, determine the specific role of specific miRNA and immune factors in the occurrence, development and diagnosis of CNP, The differential expression spectrum of miRNA in normal and inflammatory prostate tissue and the potential regulatory network of its target genes were initially obtained[21].

The above studies show that miRNA expression profiles in prostatic fluid, semen, serum and animal models of CNP patients are significantly different from those in normal prostate.There are some specific miRNAs up-regulated or down regulated in the pathogenesis of CNP, which may be closely related to the pathogenesis of CNP.With the development of biotechnology, some miRNAs may become new markers of CNP, it provides a new possibility for CNP diagnosis[22].

3.Effect of miRNA on CNP patients or model inflammatory factors

Recent studies have shown that some specific miRNAs are abnormally expressed in different autoimmune inflammatory diseases MiRNA can regulate autoimmunity and inflammatory response by affecting the differentiation, maturation and function of immune cells, and thus participate in the pathogenesis of a variety of inflammatory related diseases.MiRNA is involved in regulating the functions of various immune cells, such as B cells et al and T cells and Regulation of secretion of various cytokines and chemokines et al[23-25].At present,the common hypothesis about the pathogenesis of CNP is that pathological or physiological products invade the prostate and cause local autoimmune inflammation in prostate tissue.At present, there are some reports about miRNA in this field.

Huang et al found that reduced miR-150 expression in prostate fluid in CNP patients could cause TGF-1 (transforming growth factor-β1)levels, While TGF-1 and IL-6 (Interleukin-6)、IL-10 (Interleukin-10) and TNF-α (tumor necrosis factor-α), there is a significant positive correlation between the factors of isoinflammatory factors,which can promote the progress of prostatitis[26].Zheng et al found that tamsulosin can up regulate the expression of miR-141 in rat prostate tissue, and inhibit diffuse inflammation, collagen aggregation and TNF-α,TGF-β1 and α-SMA(α-smooth muscle actin)and then to improve the symptom of prostatitis[27].

The above experiments indicate that the up-regulation or downregulation of some specific miRNAs is closely related to various inflammatory factors related to CNP, which may promote or inhibit the inflammatory response of prostate tissue.

4.CNP-associated miRNA signaling pathway

Current studies have shown that miRNA family is a key link in the regulation of gene expression in many diseases, which is involved in the influence of multiple signaling pathways or as a key link in the process of signaling pathway [28-29].In recent years, more and more attention has been paid to the relationship between miRNA and CNP signaling pathway.Wang et al found that NAC (N-acetyl-L-cysteine) can promote the expression of miR-141 in prostate tissue of carrageenan induced rat CNP model, and miR-141 can activate Keap1/Nrf2 signaling pathway, thereby improving the symptoms of carrageenan induced prostatitis in rats[30].Current research have shown that human tissues[31].Park et al found that recombinant IL-10 can inhibit the expression of miR-155 in primary bone marrow-derived macrophages and human peripheral blood monocytes through STAT3 signal, and reduce the inflammatory response of CNP[32].Fu et al found that miR-155 is upregulated with the activation of TLR4 / NF-kB signaling pathway in prostate tissue of CNP model rats.When miR-155 is reduced by intervention, TLR4 / NF-kB signaling pathway in prostate tissue is inhibited, thereby reducing inflammation and oxidative stress in prostate tissue[33].

Chen et al found several signaling pathways associated with CNP pathogenesis in KEGG pathway analysis of CNP rats, such as“MAPK signaling pathway”、“cAMP signaling pathway”、“endocytosis pathway”、“mTOR signaling pathway”、“FOXO signaling pathway”, and some specific miRNAs were significantly associated with one or more of them, Or directly involved in the signal transduction process[17].The above experiments show that miRNA may play an important role in regulating the relevant signaling pathway in the development of CNP, and is an important regulator in inflammation, immunity,and oxidative stress.

5.Effect of Chinese medicine intervention on Model miRNA in CNP rat

At present, there are few research reports between miRNA and CNP in traditional Chinese medicine.Zhang et al found that in the experiment of studying the effect of Jiedu Huoxue Decoction on CNP rat model based on miRNA expression profile, 495 mRNA expressions in prostate tissue of CNP rat model were significantly changed in the experimental group compared with the control group,among which 211 were significantly different, and 37 were related to prostate;There were 181 differentially expressed miRNAs in model group and high-dose Jiedu Huoxue Decoction group, 23 of which were the same as those in control group and model group;Compared with the control group, the expressions of miR-146a、miR-423 and miR-205 in the model group were significantly increased[34].Experimental studies show that effective Chinese medicine intervention can regulate the concentration of some specific miRNA in CNP rat model, and the changes of these specific miRNA concentrations are closely related to the changes of CNP symptoms.The effective intervention of traditional Chinese medicine may affect the concentration of some specific miRNA in prostate tissue of CNP rats, and achieve the purpose of treatment of CNP, which may provide a new direction for exploring the mechanism of Chinese medicine in the treatment of CNP.

6.Study on miRNA and prostatitis complications

Current studies have shown that prostatitis can cause a variety of male urogenital complications, such as infertility, urethritis, erectile dysfunction (ED),etc.At present, there are some reports about miRNA and prostatitis complications.

Ding et al found that NOS1 (neural nitric oxide synthase) was confirmed to be the target gene of miR-146a by luciferase assay,Reverse transcription polymerase chain reaction and Western blot analysis showed that CNP patients with miR-146a rs2910164 C allele had a lower risk of ED.It may be related to its ability to destroy the expression of miR-146a and increase the expression of its target gene NOS1[35].Xiong et al found that the researchers analyzed the expression levels of elastase and mir-551b in EPS of infertile patients induced by prostatitis and their diagnostic significance for the disease.The experiment showed that the expression levels of elastase and mir-551b had significant changes in EPS of infertile patients with prostatitis, The combined detection has high specificity and sensitivity in the diagnosis of prostatitis with infertility, which is expected to become a molecular marker for the diagnosis of prostatitis with infertility[36].

The above studies show that some specific miRNAs have certain biological significance in patients with CNP or other types of prostatitis combined with other reproductive and urinary diseases.

7.Summary and Outlook

At present, the research on the relationship between miRNA and various diseases is a hot topic, involving the etiology, pathogenesis,diagnosis, treatment and other aspects of the disease.The relationship between miRNA and CNP involves pathogenesis,diagnosis and treatment, however, there are few reports on the relationship between CNP and miRNA, and there is no systematic study.The specific mechanism of miRNA in the pathogenesis of CNP is still unclear.At present, it is mainly reported that miRNA expression profiles are significantly different in prostate fluid of healthy men and CNP patients or prostate tissue of male rats in different treatment groups, which can be used as biomarkers for diagnosis or differential diagnosis of CNP;Effective drug intervention can regulate the concentration of a specific miRNA in prostate fluid of CNP patients or prostate tissue of male rats, so as to improve the symptoms of CNP; The abnormal expression of miRNA is accompanied by the pathogenesis of CNP.The up-regulation or down-regulation of some specific miRNA is closely related to inflammatory factors or inflammatory, immune, oxidative stress and other signaling pathways related to the pathogenesis of CNP.

The pathogenesis of CNP should be the result of various pathogenic factors.It is difficult to fully explain the pathogenesis of CNP by a single factor or hypothesis.At present, the research on the relationship between miRNA and the pathogenesis of CNP is not deep enough, and the exact function, target and mechanism of miRNA on CNP have not been clearly stated.With the continuous in-depth study of the mechanism of miRNA, and the use of modern biological technology such as ngs to explore the correlation between the pathogenesis of CNP and miRNA, our understanding of the regulatory network of gene expression in the pathogenesis of CNP will be improved to a new level.Of course, miRNA is only one part of the regulation of gene expression.From the perspective of transcriptome, the final target is the mRNA related to CNP, because the mRNA determines the final protein output.To explore the relationship between miRNA -mRNA-target gene-gene function is helpful to explore the essence of CNP from the micro level, and contribute to the diagnosis and treatment of CNP.MiRNA plays an important role in the occurrence and development of human physiology and pathology.In the future, miRNA may become a new biological marker for the diagnosis of CNP.It may also make this molecule a potential drug target, or simulate this molecule for the development of new drugs, which may provide a new means for the diagnosis and treatment of CNP diseases[37-39].

To sum up, The level of miRNA in prostate tissue may reflect the condition and prognosis to a certain extent.Through the detection of miRNA expression profile in prostate tissue and the in-depth study of the relationship between miRNA and CNP, it is possible to realize the early detection and treatment of CNP, and then reduce the probability of CNP occurrence and development through corresponding intervention measures, It is helpful for the prevention,diagnosis and treatment of diseases.