ABSTRACT
Epidemiological studies provide evidence that physical activity reduces the risk of cancer, particularly of breast cancer. However, little is known about the underlying molecular mechanisms as related to microRNAs. The goal of the herein presented study is to explore the involvement of miRNAs in beneficial effects exerted by physical activity in breast cancer prevention. Thirty subjects (mean age: 57.1 ± 14.7 years) underwent 45 minutes of treadmill walking under standardized conditions. The levels of extracellular miRNAs were evaluated in blood plasma before and after structured exercise by means of microarray analysis of 1,900 miRNAs identifying mostly modulated miRNAs. Structured exercise has been found to modulate the expression of 14 miRNAs involved in pathways relevant to cancer. The different expression of two miRNAs involved in breast cancer progression, i. e. up-regulation of miR-206 and down-regulation of anti-miR-30c, were the most striking effects induced by exercise. The biological effects of these miRNAs were investigated in MCF-7 human breast cancer cells. miR-206 transfection and anti-miR-30c silencing, inhibited cell growth and increased apoptosis of MCF-7 cells. Moreover, the combined use of the two miRNAs further enhanced apoptosis and induced growth arrest in the G1/S phase of cell cycle. Our results support that physical activity effectively change the expression of extracellular miRNAs. Specifically, miR-206 up-regulation and anti-miR-30c down-regulation act as suppressors in breast cancer cells. The evaluation of these miRNAs in blood can be used as non-invasive biomarkers for breast cancer prevention.
INTRODUCTION
The relevance of structured exercise for public health has been addressed by the World Health Organization, and its lack is estimated to be the main risk factor for 21–25% of breast and colon cancer cases, 27% of diabetes cases, and 30% of ischemic heart disease cases [1, 2]. Several epidemiological studies demonstrated the dose-dependent protective effect of regular and moderate structured exercise against chronic degenerative diseases, with a particular reference to both the primary (prevention of cancer onset) and tertiary (prevention of cancer relapses) prevention of cancer [2]. These findings refer only to structured physical activities, i. e. those proposed according to international guidelines such as those proposed by the American College of Sports and Medicine [3]. Breast cancer survivors engaging in structured exercise increase the drainage of lymph from their upper limbs, thereby decreasing the side effects of mastectomy, significantly lowering their risk of a cancer relapse and improving their immune functions [4]. Conversely, no beneficial effects of an unstructured structured exercise (e. g., household work) have been observed [5]. Moderate-intensity aerobic exercise combined with resistance training benefited early adjuvant breast cancer treatment; after 18 weeks of an exercise program, there was a positive effect on physical fatigue, cardiopulmonary function, and muscle strength among participating patients [6].
Randomized clinical trials have shown that structured exercise interventions can change biomarkers of cancer risk [7].
The main preventive molecular mechanisms activated by structured exercise, include regulation of insulin-like growth factors (IGFs) and aromatase inhibition. Insulin resistance, hyperinsulinaemia, hyperglycaemia and type 2 diabetes have been linked to increased risk of breast, colon, pancreas and endometrial cancers. Structured exercise improves insulin resistance, reduces hyperinsulinaemia and reduces risk for diabetes, which could explain the link between increased structured exercise and reduced risk for these cancers [8].
A lack of structured exercise enhances the activity of aromatase, an enzyme mainly locates in white adipose tissue responsible for a key step in the biosynthesis of estrogens, thus increasing estradiol levels in the serum, a major risk factor for breast cancer onset and progression. Recent findings indicate that women with a history of breast cancer who engage in more than 9 metabolic equivalent (MET)·h/week of structured structured exercise (corresponding to 3 h per week of brisk walking) after breast cancer diagnosis had a significantly lower risk of death or breast cancer recurrence than women who were physically inactive [9, 10].
However, the mechanisms underlying the preventive effect of structured exercise against cancer have been only partially depicted. MicroRNAs (miRNAs) play pivotal roles in carcinogenesis and cancer outcomes [11], including breast cancer [12]. miRNAs function as regulators of myogenesis and muscle mass, and structured exercise modulates miRNA expression, especially in skeletal muscle. These muscle-specific miRNAs are known as ‘myomiRs’ [13]; among them, miR-1, miR-133a, miR-133b, and miR-206, account for nearly 25% of miRNA expression in skeletal muscle in both humans and mice [13]. Structured exercise adaptively changes the level of circulating miRNAs in animals and human beings [13] and this effect is related to the different type of structured exercise [14].
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