Skeletal muscle microRNA's in human cancer cachexia and type 2 diabetes
Abstract
MicroRNAs are powerful post-transcriptional regulators of gene expression and are
biomarkers of chronic diseases such as cancer. This thesis explores the role of
microRNAs in human cancer cachexia and Type 2 diabetes. MicroRNA expression was
measured in skeletal muscle biopsies using RT-qPCR. In pancreatic cancer cachexia
patients, expression of microRNA-1, microRNA-133a, microRNA-133b and
microRNA-206 was negatively related to weight loss. In Type 2 diabetes skeletal
muscle, microRNA-133a and microRNA-206 expression was down-regulated, but there
was no evidence of altered microRNA transcription or processing and target expression
was unchanged. Importantly, microRNA-133a expression predicted fasting glucose,
glucose tolerance and insulin resistance, and therefore may be a biomarker of Type 2
diabetes. Experimental validation of microRNA arrays was unsuccessful in identifying
further novel cancer cachexia and Type 2 diabetes microRNA biomarkers. MicroRNA
knockdown validated CDC42 and PTBP1 as microRNA-133a targets in myoblasts. In
addition, muscle microRNA expression may be regulated by insulin and TNFa. In
conclusion, microRNA-133a may be a skeletal muscle biomarker of Type 2 diabetes
and cancer cachexia, microRNA-133a responds to extracellular insulin and TNFa, but it
remains to be established whether microRNA-133a contributes to cancer cachexia or
Type 2 diabetes pathogenesis.