BMP4 derived from human gastrointestinal carcinoma cells impairs myogenic differentiation: A possible in vitro mechanism of cancer‑induced cachexia.

Abstract

Gastrointestinal cancer (GIC) frequently causes cancer cachexia, the major feature of which is the loss of skeletal muscle mass. The degradation of muscular proteins by cancer‑derived factors in the major pathogenesis of cancer‑induced muscle wasting is a known phenomenon. However, this mechanism has mainly been demonstrated using rodent cancer cells, and it may not always be applicable to human cancer types. Impaired skeletal muscle differentiation and regeneration have attracted attention as alternative inducers of cancer cachexia. The present study revealed that conditioned medium from four human GIC cell lines inhibited C2C12 myoblast differentiation by inducing the expression of the inhibitor of DNA binding (Id) proteins Id1 and Id3, which mediated via bone morphogenetic protein (BMP)‑Smad signaling. The results suggested that BMP‑Smad1/5/8‑Id signaling inhibited the expression of a MRF member, myogenin and its downstream myogenic genes, thus leading to unsuccessful differentiation into myotubes. Furthermore, the present study identified high levels of BMP4 secretion from these four human GIC cell lines and demonstrated that an inhibitor of BMP receptor, dorsomorphin or abrogation of BMP4 by siRNA in the GIC cells restored myogenic differentiation in C2C12 cells. The present study uncovered, for the first time, that BMP4 derived from human GIC cells exogenously inhibited myoblast differentiation by activating the Smad1/5/8‑Id signaling axis. In the future, this in vitro study may help to elucidate the complicated mechanisms underlying cancer‑induced cachexia in humans.