Bone Morphogenesis Protein 4 Pathway as Treatment Target in Hepatocellular Carcinoma

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Bone morphogenesis protein 4 (BMP4), which belongs to the transforming growth factor (TGF)-β family, is a multifunctional cytokine that is known to be involved in human carcinogenesis. The cytokine exerts its effects through pathways dependent on and independent of SMAD proteins, which are the intracellular effectors of TGF-β signaling.

In a study evaluating the potential role of BMP4 in hepatocellular carcinoma, Chiu and colleagues from National Sun Yat-Sen University in Kaohsiung, Taiwan, showed that BMP4 and the BMP4 receptor BMPR1A are overexpressed in a majority of primary hepatocellular carcinomas, that BMP4 promotes the growth and migration of hepatocellular carcinoma cell lines in vitro, and that BMP4 can induce hepatocellular carcinoma cyclin-dependent kinase (CDK)1 and cyclin B1 upregulation to accelerate cell-cycle progression.

Induction of hepatocellular carcinoma cell proliferation was independent of the SMAD signaling pathway, as evidenced by upregulation of CDK1 and cyclin B1 expression with BMP4 treatment despite Smad4 knockdown of hepatocellular carcinoma cell lines. Induction of CDK1 and cyclin B1 mRNA and protein was dependent on the activation of MEK (MAPK/ERK) signaling. Xenograft studies confirmed that the BMPR1A-knockdown cells were significantly less tumorigenic than control cells.

The investigators stated, “BMP4 signaling pathways may have potential as new therapeutic targets in [hepatocellular carcinoma] treatment.” ■

Chiu C-Y, et al: Mol Cancer Res 10:415-427, 2012.





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