Role of tumor-derived microRNAs in inducing muscle mass loss in patients with Cancer Cachexia

Abstract

Cachexia is a wasting syndrome and is a consequence of Cancer and other diseases, such as Chronic Obstructive Lung Disease, Multiple Sclerosis, Congestive Heart Failure, Tuberculosis, and AIDS, among others, with a high impact on quality of life. Cancer Cachexia, which affects approximately half of all patients with Cancer. In advanced stages, this figure rises up to 80%. The loss of adipose tissue and skeletal muscle mass precedes any decrease in food intake. These tissues exhibit impaired homeostasis and altered metabolism, resulting in increased lipolysis in the adipose tissue and augmented proteolysis in the skeletal muscle. This phenomenon is associated with high levels blood circulation of pro-inflammatory cytokines. The increase in the circulation of TNF-±, IFN³, IL-6 and IL-1 in the condition of Cachexia are capable of activating lipolysis in adipose tissue and promote a reduction of synthesis and increase the protein degradation in muscle tissue. Recently, a new mechanism has been investigated and related to the inflammatory process and the development of Cancer Cachexia. Studies have demonstrated that changes in metabolism and in inflammatory responses can be modulated by microRNAs (miRNA). The miRNAs are a family of small, noncoding RNA molecules, 19-24 nucleotides in length, and these noncoding RNA function by regulating gene expression through mRNA degradation or the inhibition of protein translation. It was observed that the miRNA participate in important functions for the development of Cancer, as in the proliferation, apoptosis, migration and invasion process. The loss of muscle mass during the process of Cachexia is due to an increase in protein degradation and metabolic changes in muscle in response to the tumor progression. The paracrine and/or endocrine communication of miRNA, for the spread of systemic inflammation, metastasis development and the activation of pathways that promote the loss of muscle mass seems to be associated with the existence of exossomos. The exossomos formation is associated to the biogenesis of miRNAs. miRNA biogenesis involves the transcription of genomic DNA by RNA polymerase II to produce primary miRNA transcripts (pri-miRNA). In sequence, the Drosha-DGCR8 RNase complex initiates miRNA maturation through the cleavage of a stem loop into the primary transcript. The newly produced pre-miRNA is then transported to the cytoplasm by exportin5 and processed to a double-stranded RNA molecule of about 19 to 25 nucleotides in length by yet another enzyme, the Dicer. Once incorporated into the eector complex miRISC (miRNA-induced silencing complex), one strand of the recently produced RNA molecule remains as a mature miRNA, while the other strand may be either degraded, incorporated into another miRISC, or exported to the periphery by exosomes to exert its eects in a paracrine or endocrine way. In this way, observing the role of miRNAs in the regulation of systemic inflammation and its participation in the process of Muscle Atrophy Due to Cancer Cachexia, the study of miRNAs is a promising field for the development of new treatments, as well as of early diagnosis for Cachexia. Thus, in order to get a better understanding of this complex mechanism associated with systemic inflammation, exossomos of miRNA and loss of muscle mass in patients with Cachexia, the development of this project seeks to answer the question: The exossomos derived from tumor, containing miRNA can regulate/induce the spoliation of skeletal muscle? (AU)