Bone morphogenetic protein-9 is a potent growth inhibitor of hepatocellular carcinoma and reduces the liver cancer stem cells population.
Bone morphogenetic protein-9 is a potent growth inhibitor of hepatocellular carcinoma and reduces the liver cancer stem cells population.
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DOI：
10.18632/oncotarget.12062
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发表时间：
2016-11-08
期刊：
影响因子：
--
通讯作者：
Kuo MM
中科院分区：
文献类型：
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作者：
Jung JW;Yoon SM;Kim S;Jeon YH;Yoon BH;Yang SG;Kim MK;Choe S;Kuo MM
BMP-9 信号传导在肝癌中的生物学作用仍然值得怀疑。为了探索 BMP-9 信号传导在抗癌治疗中的潜在用途，我们使用重组人 BMP-9（我们称为 MB109）来研究对 15 种肝细胞癌 (HCC) 细胞系生长的影响。 MB109 在体外有效抑制九种 HCC 细胞的增殖。研究发现，抗增殖作用是通过开启 p21 信号传导来诱导的，p21 信号传导会导致生存素抑制和 G0/G1 细胞周期停滞。 ID3 被鉴定为 MB109 诱导的 p21 表达的介体。阻断 p38 MAPK 的活性会减少 ID3 和 p21 的表达，表明 MB109 通过 p38 MAPK/ID3/p21 途径发出信号来阻止细胞周期进程。此外，长期的 MB109 治疗抑制了五种重要的肝癌干细胞 (LCSC) 标志物的表达，包括 CD44、CD90、AFP、GPC3 和 ANPEP。异种移植模型证实了 MB109 体内的抗肿瘤和 LCSC 抑制能力。与抑制 BMP-9 信号传导以抑制癌组织血管生成的持续努力相反，这些结果表明 MB109 在刺激 BMP-9 信号传导以进行抗癌治疗方面具有意想不到的治疗潜力。
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.