Introduction
Prostate cancer is the second leading cause of death in men worldwide. According to the statistics in 2012, it had the highest prevalence (28%) among the known cancers, and was the second cause of death (11%) after lung cancer (29%). The main problem in prostate cancer treatment currently is the lack of sensitive and specific biomarkers, but according to the role and function of microRNAs, one of the biomarkers in cancer diagnosis and treatment is miR-21. The miR-21 and miR-155 are known as two oncogenic protein activators. The miR-155 dysregulation has been reported in many malignant tumors including leukemia, breast and lung cancers. Recent studies have shown that miR-155 can be significantly expressed in prostate cancer cells. 
Studies on the effect of physical activity on prostate cancer have shown different results. Physical activity and exercise can play a significant role in accelerating recovery and delaying its development. Considering that so far no study has been conducted in this field in Iran and other countries, this study aims to assess the effect of eight weeks of aerobic exercise and consumption of pomegranate juice on some miR-155, miR-21 and P53 in men with prostate cancer.
Methods
This is a quasi-experimental study with a pre-test/post-test design. Participants were men with prostate cancer referred to treatment centers in 2020-2021 who were randomly divided into four groups of control, exercise, exercise + supplementation, and supplementation (Figure 1)




The patients in the exercise group participated in the aerobic exercise program for eight weeks, three sessions per week, each for 60-90 minutes. Each session of the aerobic exercise program was performed in three parts including warm-up, main activity, and cool-down. The warm-up was for 10-15 minutes and included stretching and softening movements, and then the participants performed the main activity for 35-65 minutes on a stationary bike with an intensity of 50-70% of the maximum heart rate. At the end of each session, there was a 10-min stretching and softening movements for cooling down. During this period, no exercises were performed by the control group. The patients in the supplementation and exercise+supplementation groups received 100 cc of natural pomegranate juice one day in the evenings after exercises.




Results
The Kolmogorov-Smirnov test was used to check the normal distribution of the data, and Levene's test was used to check the equality of variances. Considering the significance of the tests, dependent t-test and analysis of variance (ANOVA) along with LSD post hoc test were used to examine the differences between groups. A P<0.05 was statistically significant.
Discussion
The purpose of this study was to investigate the effect of eight weeks of aerobic training and consumption of pomegranate juice on some Micro RNAs and tumor suppressor proteins in men with prostate cancer. The results showed that eight weeks of aerobic exercise combined with consumption of pomegranate juice caused a significant increase in the level of tumor suppressor protein P53. The type and severity of cellular stress may control p53 function by acting on the surface or the activity of p53 protein inducing it. This suggests that proteins that regulate the expression of apoptotic genes associate p53 binding with lower affinity for targets of cell cycle arrest. The P53 plays an important role in metabolism, and since most cancer cells depend on anaerobic glycolysis for energy, the increase in p53 protein due to aerobic exercise can lead to a decrease in anaerobic glycolysis and interrupt the tumor growth.
Eight weeks of aerobic exercise combined with consumption of pomegranate juice and 8 weeks of pomegranate juice consumption alone caused a significant decrease in miR-21 in men with prostate cancer, where the reduction was higher in the group received combined intervention. The miR-21 is considered to be a common oncomiR that limits the activity of signaling pathways such as AKT and MAPK by inhibiting the expression of phosphatases.
Eight weeks of aerobic exercise combined with consumption of pomegranate juice and 8 weeks of pomegranate juice consumption alone caused a significant decrease in miR-155 in men with prostate cancer, where the reduction was higher in the group received combined intervention. The effect of this microRNA is exerted through the reduction of the FOXO3a transcription factor. Aberrant expression of miR-155 increases the survival of cancer cells and increases the resistance of these cells to chemotherapy. Reduction in miR-155 expression can improve cell sensitivity to chemotherapy and promote apoptosis. This suggests a possible functional link between inflammation and cancer by miR-155. Moreover, it has been reported that caspase-3, which is a strong suppressor of apoptosis, is another target of miR-155; in this way, it can also contribute to the occurrence of cancer.
Ethical Considerations
Compliance with ethical guidelines
This article is taken from the research plan approved by Qom University, No. 99/14973/D. And its protocols have been approved by the code of ethics IR.GOM.IEC.1398.021 issued by the Ethics Committee of Qom University. 
Funding
This study was supported by Qom University.
Authors' contributions
All authors equally contributed to preparing this article.
Conflicts of interest
The authors declared no conflict of interest.
Acknowledgements
The authors of this article thank Qom University and all the participants.

 

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