Cancer impacts microRNA expression, release and function in cardiac and skeletal muscle

Abstract

Circulating microRNAs are emerging as important biomarkers of various diseases including cancer. Intriguingly, circulating levels of several microRNAs are lower in cancer patients compared with healthy individuals. In this study, we tested the hypothesis that a circulating microRNA might serve as a surrogate of the effects of cancer on microRNA expression or release in distant organs. Here we report that circulating levels of the muscle-enriched miR-486 is lower in breast cancer patients compared with healthy individuals, and that this difference is replicated faithfully in MMTV-PyMT and MMTV-Her2 transgenic mouse models of breast cancer. In tumor-bearing mice, levels of miR-486 were relatively reduced in muscle, where there was elevated expression of the miR-486 target genes PTEN and FOXO1A and dampened signaling through the PI3K/AKT pathway. Skeletal muscle expressed lower levels of the transcription factor MyoD which controls miR-486 expression. Conditioned media (CM) obtained from MMTV-PyMT and MMTV-Her2/Neu tumor cells cultured in vitro was sufficient to elicit reduced levels of miR-486 and increased PTEN and FOXO1A expression in C2C12 murine myoblasts. Cytokine analysis implicated TNFα and four additional cytokines as mediators of miR-486 expression in CM-treated cells. Since miR-486 is a potent modulator of PI3K/AKT signaling and the muscle-enriched transcription factor network in cardiac/skeletal muscle, our findings implicated TNFα-dependent miRNA circuitry in muscle differentiation and survival pathways in cancer.