title: Cancer affects microRNA expression, release, and function in cardiac and skeletal muscle.
abstract: Circulating microRNAs (miRNA) are emerging as important biomarkers of various diseases, including cancer. Intriguingly, circulating levels of several miRNAs are lower in patients with cancer compared with healthy individuals. In this study, we tested the hypothesis that a circulating miRNA might serve as a surrogate of the effects of cancer on miRNA expression or release in distant organs. Here we report that circulating levels of the muscle-enriched miR486 is lower in patients with breast cancer 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 miR486 were relatively reduced in muscle, where there was elevated expression of the miR486 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 miR486 expression. Conditioned media (CM) obtained from MMTV-PyMT and MMTV-Her2/Neu tumor cells cultured in vitro were sufficient to elicit reduced levels of miR486 and increased PTEN and FOXO1A expression in C2C12 murine myoblasts. Cytokine analysis implicated tumor necrosis factor α (TNFα) and four additional cytokines as mediators of miR486 expression in CM-treated cells. Because miR486 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.
authors: Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
authors: Daohong
authors: D
authors: Chen
authors: Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana.
authors: Chirayu P
authors: CP
authors: Goswami
authors: Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
authors: Riesa M
authors: RM
authors: Burnett
authors: Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
authors: Manjushree
authors: M
authors: Anjanappa
authors: Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
authors: Poornima
authors: P
authors: Bhat-Nakshatri
authors: Molecular Oncology Group, McGill University, Montreal, Canada.
authors: William
authors: W
authors: Muller
authors: Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana. Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana. hnakshat@iupui.edu.
authors: Harikrishna
authors: H
authors: Nakshatri
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D002454:Cell Differentiation / Q000502:physiology; D005260:Female; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology*; D015398:Signal Transduction
chemical_list: C560945:MIRN486 microRNA, human; D035683:MicroRNAs