الفهرس 
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Abstract
Prostate cancer is the most common cancer in males worldwide and has become a significant health issue in developed and developing countries. It has a growing concern in Egypt as it is the 4th most common cancer in the country. Prostate cancer diagnosis depends mainly on transrectal ultrasound-guided biopsies (TRUSbx) of the prostate, then by increased serum levels of PSA and/or any suspicions on DRE. However, this way of diagnosis is inaccurate, resulting in up to 75% of all TRUS-biopsies being negative. Localized prostate cancer (LPC) is generally curable either by interventional or radiotherapy with a 5-year survival rate approaching 100%, while metastatic prostate cancer (MPC) is generally not curable and has a 5-year survival rate under 40%. However, many LPCs will not progress to an aggressive form, and even if left untreated would not give rise to any symptoms in the patient’s normal lifespan. So, an early and accurate diagnosis is essential for increasing a patient’s lifespan and for preventing unnecessary treatment. In recent years, liquid biopsies (e.g., blood, urine, and other bodily fluids) have great attention for analysis of circulating tumor DNA, RNA, or miRNAs in more accurate noninvasive tests for diagnosis, prognosis, recurrence, and disease monitoring with high sensitivity and specificity than the usually used diagnostic markers now. MiRNAs are a class of non-coding single-stranded RNA molecules containing between 18 and 24 nucleotides that regulate gene expression and both at the transcriptional and post-transcriptional level. MiRNAs are counted to regulate up to 60% of all human genomes by either direct interaction with complementary recognition target sites of targeted mRNAs so inhibiting the synthesis of a specific protein or causing RNA degradation. MiRNAs participate in various processes, including cell proliferation, differentiation, and maturation and there are a lot of studies that proved the dysregulation of miRNAs level in many cancers. Dysregulation of miRNAs expression in PC has previously been demonstrated in both tissue samples and liquid biopsies that was facilitated by the high stability of miRNAs in different body fluids, so this makes them specifically appealing targets as minimally invasive biomarkers. It was demonstrated that miRNAs differential expression profiles in prostate cancer can be firmly correlated with its clinical expression. Finally, A lot of data suggested that microRNAs (miRNAs) are promising potential biomarkers and can be used in the detection of PC. MiR‐375 is characterized as a pancreatic islet‐specific miRNA and regulates glucose‐induced insulin secretion, First, identified from murine pancreatic β‐cell line MIN 6. Genome‐wide miRNA expression profiling studies revealed that miR‐375 was widely present in various tissues or organs and was significantly reduced in the malignant cells, for instance, HCC, HNC, GC, melanoma, and glioma. MiR‐375 expression was significantly upregulated in tumor tissue when comparing BPH with PC patients and some studies proved its correlation with the histopathological classification of PC. Some studies have shown a significant increase in the miR‐375 levels either in serum or plasma when comparing healthy control individuals with low‐risk PC patients. this has not yet been well demonstrated in different types of blood‐based fluids. This work was carried out is to estimate the miRNA-375 level in plasma to determine its role as a novel noninvasive biomarker to distinguish between PC patients, BPH patients, and healthy population with the possibility that it can be used in the future as a more accurate diagnostic noninvasive tool for PC and to access its correlation with histopathological classification as an indicator of the severity of PC. This Comprehensive Case-Control study was conducted over a period of 21 months from September 2019 to June 2021 on prostate enlargement patients who were admitted at Urology and Nephrology Center, Mansoura University, and at the outpatient prostate clinic during this period. This study was conducted on 136 individuals subdivided into 3 groups (forty-eight PC patients, forty-eight BPH patients, and forty healthy age-matched males as control who live in the same area as the patients). The study was conducted over a period of 21 months from September 2019 to June 2021 on prostate enlargement patients who were admitted at Urology and Nephrology Center, Mansoura University, and at Outpatient prostate Clinic during this period. All patients & controls gave informed consent to their participation in this study, and the local ethics committee gave their prior approval to the study. About five cm of blood was collected from individuals prior to any diagnostic tools or medical or surgical intervention, Two cm was collected on (EDTA) tubes under complete aseptic conditions for miRNA-375 detection then centrifuged at 3000g for 4 minutes to obtain enough plasma then the collected plasma was stored at -80˚c as MiRNAs are highly unstable and three cm was collected in plain tubes (for creatinine and total PSA measurement) then centrifuged at 3000g for 4 minutes to obtain enough plasma and handled within 1-2 hours. MiR-375 is extracted from plasma using miRNeasy Mini Kit (Qiagen) then miRCURY LNA RT Kit (Qiagen) was used for conversion of MiR-375 to DNA templet and after that miRCURY LNA SYBR® Green PCR Kit (Qiagen) and miRCURY LNA miR-375 (primer) and miR-16-5p (internal reference) were used to detect the MiR-375 using step one real- time PCR. The initial data analysis was performed using the software supplied with a real-time PCR instrument to obtain raw Cq values. This study showed the following results : 1. No statistically significant differences were found between age and the three study groups, also there were no statistically significant differences found regarding smoking between the three study groups. 2. As regard creatinine, there was no statistical significance found between the PC group and the BPH group or between the BPH group and control group. There was a statistical significance between the PC group and control group but there was no statistically significant association between the three groups. 3. Total PSA plasma level is compared between the three groups, and it showed that there was no statistical significance between the PC group and the BPH group or between the BPH group and the control group. There was highly statistical significance between the PC group and the control group. There was statistical significance found between the three groups. 4. As regards miR-375 there was highly statistical significance between the PC group and the BPH group (p<0.001). There was also highly statistically significance between the PC group and the control group. A statistical significance was found between the BPH group and control group and there was highly statistical significance found between the three groups (p<0.001). 5. Clinicopathological data were collected for PC patients and the following was found: • As regards the Gleason score, score 8 was the most common, and a high statistical significance was found between severity of PC resembled in Gleason score and miR-375 level in plasma. • Grade 4 was the most common and a high statistical significance was found between grading of disease and miR-375 level in plasma. • According to TNM staging T2b was the most common. LN metastasis was found in (39.6%) of patients while distant metastasis was found in (27.1%). The study showed that there was a highly statistically significant correlation between T-staging and miR-375 levels in plasma as the higher the T stage the higher the miR-375 level in plasma. A highly statistical significance was found between the presence of LN metastasis and miR-375 level in plasma. There was a statistically significant association between the presence of metastasis and miR-375 level in plasma.