Significance MicroRNAs (miRNAs) are small, noncoding RNAs regulating gene expression. The aberrant expression of miRNAs is commonly associated with cancer. miRNAs can be packaged in exosomes/microvesicles secreted by the cells and involved in cell-to-cell signaling and communication; tumor-secreted miRNAs promote tumor spread and growth in the surrounding microenvironment. Apoptosis is reported to take place in wasting muscle in cancer cachexia, a debilitating syndrome associated with multiple types of cancer, although the mechanism remains elusive. This study shows that tumor-secreted microvesicles contain an elevated expression of miR-21 and induce myoblast apoptosis in cancer cachexia via a Toll-like receptor 7-c-Jun N-terminal kinase-dependent pathway.
Gamma interferon (IFN-␥) is an inflammatory cytokine that has complex effects on myogenesis. Here, we show that the IFN-␥-induced inhibition of myogenesis is mediated by the major histocompatibility complex (MHC) class II transactivator, CIITA, which binds to myogenin and inhibits its activity. In IFN-␥-treated myoblasts, the inhibition of muscle-specific genes includes the expression of myogenin itself, while in myotubes, myogenin expression is unaffected. Thus, CIITA appears to act by both repressing the expression and inhibiting the activity of myogenin at different stages of myogenesis. Stimulation by IFN-␥ in skeletal muscle cells induces CIITA expression as well as MHC class II gene expression. The IFN-␥-mediated repression is reversible, with myogenesis proceeding normally upon removal of IFN-␥. Through overexpression studies, we confirm that the expression of CIITA, independent of IFN-␥, is sufficient to inhibit myogenesis. Through knockdown studies, we also demonstrate that CIITA is necessary for the IFN-␥-mediated inhibition of myogenesis. Finally, we show that CIITA, which lacks DNA binding activity, is recruited to muscle-specific promoters coincident with reductions in RNA polymerase II recruitment. Thus, this work reveals how IFN-␥ modulates myogenesis and demonstrates a key role for CIITA in this process.Gamma interferon (IFN-␥) is an inflammatory cytokine that was first identified as an antiviral factor. IFN-␥ is a pleiotropic cytokine that regulates different immune responses and influences many physiological processes. Many studies have also shown that IFN-␥ influences skeletal muscle homeostasis and repair. Transient administration of exogenous IFN-␥ has been shown to improve healing of skeletal muscle and limit fibrosis (14). Endogenous IFN-␥ is required for efficient muscle regeneration, as mice lacking IFN-␥ show impaired muscle regeneration following cardiotoxin-induced damage (6). Expression of IFN-␥ is robust in proliferating C2C12 cells, but expression is diminished in differentiated C2C12 cells (6). Exogenous IFN-␥ influences the proliferation and differentiation of cultured myoblasts and appears to have a direct role on gene expression (25,26,28,48).Myoblasts have been shown to express immunological properties such as the complement component of both the classical and alternative pathways and major histocompatibility complex (MHC) genes. Exogenous IFN-␥ treatment has been shown to increase the expression of MHC class II genes, complement C components, intracellular adhesion molecule (Icam1), chemokine (C-C motif) ligand 5 (Ccl5; RANTES), chemokine (C-C motif) ligand 2 (Ccl2), and chemokine (C-X-C motif) ligand 10 (Cxcl10; Ip10) (15,25,28,48). It is not currently known how IFN-␥ mediates these transcriptional effects in myoblasts.The positive role for IFN-␥ established in muscle healing and repair suggests that this cytokine plays an important role in muscle biology. However, IFN-␥ signaling is likely to be tightly regulated, as negative effects of IFN-␥ have been observed as well. Whe...
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