Recombinant bone morphogenetic protein-2 attenuates colorectal cancer progression by orchestrating Hippo pathway activation, Yes-associated protein inhibition, and epithelial– mesenchymal transition suppression

다국어 초록 (Multilingual Abstract)

Bone morphogenetic protein-2 (BMP-2) regulates cell differentiation andproliferation. However, its role in colorectal cancer (CRC) remains debatable owing topotential oncogenic effects. Here, we investigated the role of BMP-2 in modulatingCRC progression, particularly in regulating the Hippo signaling pathway. Exposureto recombinant human BMP-2 (rhBMP-2) resulted in a concentration-dependent decreasein CRC cell proliferation, leading to G1 cell cycle arrest. This effect was associatedwith the increased expression of p53, p21, and Smad4, while the levels of cyclinD1, cyclin-dependent kinase 4 (CDK4), and CDK6 decreased. Additionally, rhBMP-2promoted apoptosis by decreasing poly (ADP-ribose) polymerase and caspase-9expression while increasing their cleaved forms. It also activated the Hippo signalingcascade, enhancing the expression of mammalian sterile 20-like kinase 1/2, Mps OneBinder 1 (MOB1), phosphorylated MOB1, and Salvador homolog, along with elevatedlevels of phosphorylated yes-associated protein (YAP), while concurrently suppressingtotal YAP expression. This resulted in cytoplasmic sequestration and subsequentdegradation of YAP, thereby attenuating the transcription of YAP-responsive genessuch as Connective Tissue Growth Factor. Silencing of Ras association domain familymember 1 restored the rhBMP-2-induced decrease in cell viability, whereas silencingYAP further reduced the viability of CRC cell lines. Administering rhBMP-2 significantlysuppressed tumor expansion in a mouse model of CRC, further supportingits potential as an antitumor agent. Collectively, these results indicate that rhBMP-2mitigates CRC progression by activating the Hippo signaling pathway and suppressingYAP-mediated oncogenic processes, thereby highlighting its potential as a therapeuticagent that warrants further clinical evaluation