RAGE signaling deficiency in rhabdomyosarcoma cells causes upregulation of PAX7 and uncontrolled proliferation

Embryonal rhabdomyosarcomas (ERMSs) show elevated levels of PAX7, a transcription factor that marks quiescent adult muscle stem (satellite) cells and is important for proliferation and survival of activated satellite cells and whose timely repression is required for myogenic differentiation. However, the mechanism of PAX7 accumulation in ERMSs and whether high PAX7 is causative of ERMS uncontrolled proliferation remain to be elucidated. The receptor for advanced glycation end-products (RAGE) transduces a myogenic and anti-proliferative signal in myoblasts, and stable transfection of the RAGE-devoid ERMS cell line, TE671, with AGER, results in reduced proliferation and formation of tumor masses in vivo, enhanced apoptosis and myogenic differentiation. Herein we show that RAGE expression is low or absent in human ERMSs. We also show that in ERMS cells (i) PAX7 accumulates due to absent or low RAGE signaling; (ii) elevated PAX7 levels reduce RAGE expression and levels of MyoD and myogenin, muscle-specific transcription factors required for myoblast proliferation arrest and differentiation, respectively; (iii) PAX7 supports myoblast proliferation by reducing the levels of MyoD, primarily by promoting its degradation; and, (iv) when ectopically expressed in ERMS cells, RAGE upregulates myogenin which upregulates MyoD and downregulates PAX7, with consequent inhibition of proliferation and stimulation of differentiation. Thus, failure to express RAGE and, hence, MyoD and myogenin above a critical level in ERMS cells may result in deregulated PAX7 expression leading to uncontrolled proliferation and, potentially, to rhabdomyosarcomagenesis.