Microvesicles containing miRNAs promote muscle cell death in cancer cachexia via TLR7

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. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression and, in cancers, are often packaged within secreted microvesicles. The cachexia syndrome is a debilitating state of cancer that predominantly results from the loss of skeletal muscle mass, which is in part associated with apoptosis. How tumors promote apoptosis in distally located skeletal muscles has not been explored. Using both tumor cell lines and patient samples, we show that tumor-derived microvesicles induce apoptosis of skeletal muscle cells. This proapoptotic activity is mediated by a microRNA cargo, miR-21, which signals through the Toll-like 7 receptor (TLR7) on murine myoblasts to promote cell death. Furthermore, tumor microvesicles and miR-21 require c-Jun N-terminal kinase activity to regulate this apoptotic response. Together, these results describe a unique pathway by which tumor cells promote muscle loss, which might provide a great insight into elucidating the causes and treatment options of cancer cachexia.