Bone morphogenetic protein-9 is a potent growth inhibitor of hepatocellular carcinoma and reduces the liver cancer stem cells population.

Abstract

The biological role of BMP-9 signaling in liver cancer remains dubious. To explore the potential use of BMP-9 signaling for anti-cancer therapy, we used recombinant human BMP-9, which we referred to as MB109, to study the effect on growth of fifteen hepatocellular carcinoma (HCC) cell lines. MB109 effectively inhibits the proliferation of nine HCC cells in vitro. The anti-proliferative effect was found to be induced by turning on p21 signaling, which caused survivin suppression and G0/G1 cell cycle arrest. ID3 was identified to be the mediator of the MB109-induced p21 expression. Blocking the activity of p38 MAPK diminished ID3 and p21 expression, indicating that MB109 signals through a p38 MAPK/ID3/p21 pathway to arrest cell cycle progression. Moreover, prolonged MB109 treatment suppressed the expression of five prominent liver cancer stem cell (LCSC) markers, including CD44, CD90, AFP, GPC3 and ANPEP. Xenograft model confirmed the anti-tumor and LCSC-suppression capability of MB109 in vivo. Contrary to ongoing efforts of suppressing BMP-9 signaling to inhibit angiogenesis of cancer tissue, these results demonstrate an unexpected therapeutic potential of MB109 to stimulate BMP-9 signaling for anti-cancer therapies.

• Authors: Jae Woo Jung, So-Mi Yoon, Subin Kim, Yun-Hui Jeon, Byung-Hak Yoon, Su-Geun Yang, Min Kyoung Kim, Senyon Choe, Mario Meng-Chiang Kuo
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 45 Pg. 73754-73768 (Nov 08 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27650540 (Publication Type: Journal Article)

Chemical References

• Cyclin-Dependent Kinase Inhibitor p21
• Growth Differentiation Factor 2
• Inhibitor of Differentiation Proteins
• Neoplasm Proteins
• Transforming Growth Factor beta
• ID3 protein, human
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Carcinoma, Hepatocellular (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism)
• Disease Models, Animal
• G1 Phase Cell Cycle Checkpoints (drug effects)
• Gene Expression Regulation, Neoplastic
• Growth Differentiation Factor 2 (genetics, metabolism, pharmacology)
• Humans
• Inhibitor of Differentiation Proteins (metabolism)
• Liver Neoplasms (genetics, metabolism, pathology)
• Mice
• Models, Biological
• Neoplasm Proteins (metabolism)
• Neoplastic Stem Cells (drug effects, metabolism)
• Phosphorylation
• Signal Transduction (drug effects)
• Transforming Growth Factor beta (metabolism)
• Xenograft Model Antitumor Assays
• p38 Mitogen-Activated Protein Kinases (metabolism)