The role of microRNA-33a and sirtuin 6 in colon cancer metabolism and tumor progression in aerobic trained mice

Author(s)

João Lucas Penteado Gomes

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Escola de Educação Física e Esportes (EEFE/BT)
• Defense date: 2022-03-03

Examining board members

Edilamar Menezes de Oliveira; Patricia Chakur Brum; Laura Cristina Sichero Vettorazzo

• Advisor: Edilamar Menezes de Oliveira

Abstract

In the past century beginning Otto Warburg described an anomalous metabolism behave of tumors compared to other tissues. Hanahan and Weinberg in 2011 described that metabolic reprogramming is a common feature in many tumors, this process is related to changes in the expression of genes and proteins that orchestrate cellular metabolism. Therefore, for almost one hundred years tumor metabolism and its implications for tumor progression have been studied. Metabolic reprograming in cancer cells supports the high energy demand generated by the proliferation and growth. In this sense, the present study focused on clarifying the influence of aerobic exercise training (AET) on changes in colon tumor cell metabolism (CT26) and tumor growth. The original hypothesis of this study was that the microRNA-33a / Sirtuin 6 (SIRT6) axis would control tumor growth. In turn, AET would control these genes in the sense of decreasing the expression of microRNA-33a and increasing SIRT6, consequently slowing tumor growth. The initial hypothesis was refuted, on the other hand, the investigations showed that AET leads to slower growth of tumors in the trained group (TR8+CT26) compared to the sedentary group (SED+CT26). There was a decrease in the expression of genes related to the metabolic reprogramming and the glycolytic pathway, for example HIF1 (p=0.01), GLUT1 (p=0.07), PDK1 (p=0.05), LDHa (p=0.03). Furthermore, we showed a decrease in the expression of citric-acid-enzymes genes as a result of TFA, such as IDH2 (p=0.02), and there is a tendency to decrease the expression of the SDHa gene (p=0.053). Decreased protein expression of HIF1 (p=0.04) and lower lactate production (p=0.004) were also observed in tumors from trained animals. It was also demonstrated that primary cells obtained from tumors of the TR8+CT26 group have lower rates of cellular respiration and acidification of the cell environment compared to the SED+CT26 group. Furthermore, microRNA-array analyzes were performed. Six microRNAs were selected for validation by PCR and among these microRNA-16-2-3p stood out. This microRNA showed decreased expression in the TR8+CT26 group compared to the sedentary group (p=0.03) as observed in the scanning analyses. In conclusion, AET alters the tumor metabolism contributing to the lower growth of tumors (AU)

• FAPESP's process: 17/22069-3 - The role of MicroRNA-33a and sirtuine protein 6 in the metabolism and progression of Colon Cancer in mummy submitted to aerobic physical training
• Grantee: João Lucas Penteado Gomes
• Support Opportunities: Scholarships in Brazil - Doctorate