Anorexia and muscle wasting represent severe and disabling clinical features of cancer. Changes in inflammatory pathways may be responsible for interacting with central mechanisms that regulate appetite-centrally, and energy expenditure¿peripherally, and promote the activation of transcription factors and mediators involved in muscle derangement, including circulating muscle tissue-specific microRNAs (miRs).
Considering the high prevalence of nutritional changes in lung cancer, we aim to define:
1.mechanisms of anorexia identifying epigenetic modulation of inflammation
2.mechanisms of tissue wasting studying muscle tissue derangement by miRs profiling
3.the potential of epigenetic changes for preventing muscle mass tissue wasting, hypothesizing that epigenetic features and circulating miRs concentrations may be possible biomarkers for diagnosis, prognosis and therapeutic targets.
Anorexic and non-anorexic cancer patients and healthy individuals will be studied. Muscularity will be assessed by CT-scan. Plasma proinflammatory cytokines and their genes methylation and histone acetylation in peripheral blood cells will be analyzed and specific miRs expression profile for muscle tissue wasting will be assessed.
MiR dysregulation will be investigated in vivo. Gain and loss of function experiments will be performed in tumor-bearing mice in order to overexpress the downregulated miRs or to knock-down the upregulated ones. Since muscle-produced miRs can be secreted, muscle electroporation will produce both local and systemic effects, allowing to measure the direct anti-catabolic action in the muscle. We will test the effectiveness of epigenetic drugs in counteracting these epigenetic modifications in mice.
The results will be useful to treat cancer anorexia and muscle wasting aimed at reducing morbidity, mortality and improving the quality of life of lung cancer patients through more specific diagnostic tools and personalized nutritional and/or pharmacological interventions
