The role of MicroRNA-33a and sirtuine protein 6 in the metabolism and progression of Colon Cancer in mummy submitted to aerobic physical training

Abstract

The metabolism of neoplastic cells is not intended to maintain homeostasis; rather, there is an imbalance that allows synthetic pathways to be enhanced and supports exaggerated and uncontrolled cell proliferation and growth. Cancer cells have the characteristic of metabolic reprogramming, which may be due to the activation of several oncogenes. This change in the metabolism of cancer cells in most cases has as a priority the use of glucose as an energetic substrate, however using exclusively glycolysis, in this way without the oxidation of this substrate in the mitochondria. The advantages of cancer cells in prioritizing glycolysis are related to the possibility of evading signs of growth suppression and also by the production of compounds that can be used in cell proliferation. Sirtuin 6 (SIRT6) is a protein that is closely related to metabolic control and tumorigenesis. SIRT6 deacetylase histone H3H9 and inhibits the translation of several proteins, in addition to inhibiting translation of induction factor of 1-alpha (HIF1-alpha) and MYC. The action of SIRT6 is important, because HIF1-alpha promotes gene growth of the glycolytic pathway, MYC in turn regulates the metabolism of the ribosomes and in cancerous cells induces increased cell proliferation. The literature shows that in several human tumors has a decrease of SIRT6, it is associated with the increase of the expression of genes responsible for the glycolytic profile, in addition to increased glucose uptake. Inhibition of SIRT6 in tumors of animal models leads to increased growth and aggressiveness, such as increased glucose uptake and lactate production. Thus, the literature indicates that the deficiency of SIRT6 supports an extremely glycolytic profile and is related to the greater tumor progression. On the other hand, aerobic physical training (TFA) also promotes the change in the metabolism of several tissues. However, in opposition to what happens in cancer, the metabolism changes to the oxidative profile and genes involved in this pathway are more expressed. The literature indicates that physical exercise is able to partially control tumor progression and recently our research group found the same result in animals with Colon Cancer, where we observed lower tumor growth in trained animals. We also know that TFA is able to modulate the expression of microRNAs; a class of small molecules responsible for the control of biological processes in a post-transcriptional mode. MicroRNA-33a-3p has as one of its targets the SIRT6 protein, however there are no studies that show the participation of this microRNA in the control of tumor metabolism, although there are descriptions in the literature about its participation in the control of proliferation and initiation pathways tumor. In our preliminary studies we observed that animals with Colon Cancer that perform submitted to TFA shows lower tumor growth when compared to sedentary animals. In addition, these animals submitted to TFA showed an increase gene expression of SIRT6 when compared to sedentary animals. Since there are no studies that show the role of TFA by regulating the expression of genes that control tumor metabolism, our objective is to test the following hypotheses: 1- If the previous TFA decreases the tumor progression and increases the survival of the animals; 2- Whether the increase in tumor progression is related to the decrease in expression of the SIRT6 protein in the tumor caused by the increased expression of the 33a-3p microRNA leading to a glycolytic profile in the tumor. Also, to evaluate if the TFA will lead to an antagonistic effect in this axis promoting less tumor progression; 3- If the microRNA array will show other microRNAs differently expressed between sedentary and trained cancer animals, which may be related to other metabolic pathways related to tumor progression. (AU)