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| Author(s): |
Guilherme Zweig Rocha
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas |
| Defense date: | 2014-09-05 |
| Examining board members: |
José Barreto Campello Carvalheira;
Leonardo Oliveira Reis;
José Andrés Yunes;
Carmen Veríssima Ferreira;
Roger Chammas;
Franco Battista Ennio Folli
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| Advisor: | José Barreto Campello Carvalheira |
| Abstract | |
Although obesity is recognized as a major cause of diabetes and cardiovascular disease, the association between obesity and different types of cancer has received much less attention. The association between obesity and the development of colon cancer is one of the major conceptual advances in the pathogenesis of colon cancer in the last decade. Recently the role of subclinical inflammation in obesity and in carcinogenesis gained prominence. Mechanistically it is believed that obesity acts as a tumor promoter, and their pro-tumorigenic effects depend mainly on low-grade inflammatory response caused by obesity, involving the production of inflammatory and pro-tumorigenic cytokines (TNF and IL-6). A key feature of obesity-induced inflammation is the infiltration of macrophages in adipose tissue, producing inflammatory cytokines and other mediators that interfere with insulin signaling. Reticulum stress and inflammation are connected on many levels and work as short period adaptive systems required for the function and survival of the organism, and both are detrimental when chronically activated. In this regard, the activation of PKR during inflammation and subsequent activation of JNK by PKR also interferes and impairs insulin signaling pathway. Thus, PKR can form a metabolically active inflammatory complex which then becomes part of the of insulin pathway and of the pathogens response pathway and control of translation sensible to nutrients. The relationship between colon cancer and obesity may be due to action at the molecular level, subclinical low-grade inflammation and cellular stress caused by this inflammatory signaling. PKR is responsive to inflammatory signaling and also to the insulin pathway in other tissues, and related to carcinogenesis and progression in several types of cancer. Thus, investigation of it's participation is relevant as it provides the understanding of the molecular pathophysiology of colon tumors. Thus, the main objective of the study was to evaluate the role of PKR in the development of colon tumors in mice subjected to a high-fat diet. The absence of PKR prevents the formation of tumors. Moreover, apparently the absence of PKR in myeloid cells also confers protection against resistance to insulin induced by a high-fat diet, reducing inflammation induced by obesity. These observations demonstrate that PKR can be a primary point during carcinogenesis associated with inflammation and may represent a promising target for therapeutic intervention (AU) | |
| FAPESP's process: | 10/14847-7 - The role of dsRNA-dependent protein kinase (PKR) on colon tumor development in obese mice |
| Grantee: | Guilherme Zweig Rocha |
| Support Opportunities: | Scholarships in Brazil - Doctorate |