Bone morphogenetic protein-9 is a potent growth inhibitor of hepatocellular carcinoma and reduces the liver cancer stem cells population
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Jae Woo Jung1,4, So-Mi Yoon1, Subin Kim1, Yun-Hui Jeon1, Byung-Hak Yoon1, Su-Geun Yang3, Min Kyoung Kim3, Senyon Choe1,2, Mario Meng-Chiang Kuo1,2,5
1Protein Engineering Laboratory, Joint Center for Biosciences, Songdo Smart Valley, Yeonsu-gu, Incheon 406-840, South Korea
2Drug Discovery Collaboratory, University of California, San Diego, La Jolla, CA 92037, United States of America
3Department of New Drug Development, School of Medicine, Inha University, Incheon 400-712, South Korea
4Current address: Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul 151-742, South Korea
5Current address: Polaris Pharmaceuticals, Inc., San Diego, CA 92121, United States of America
Senyon Choe, email: [email protected]
Mario Meng-Chiang Kuo, email: [email protected]
Keywords: bone morphogenetic protein 9, hepatocellular carcinoma, TGF-beta, liver cancer stem cell, p21
Received: April 01, 2016 Accepted: September 02, 2016 Published: September 16, 2016
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.
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