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.

The Interactivity between TGFβ and BMP Signaling in Organogenesis, Fibrosis, and Cancer

“…However, in another study, BMP9 was shown to inhibit the proliferation of HCC cell lines via inducing, in a SMAD-independent mode, the expression of cell cycle inhibitor p21. Consistently, the expression of liver cancer stem cell markers, including CD44, CD90, AFP, GPC3 and ANPEP resulted suppressed by p21 [156]. A partial interactive network involving TGFβ and BMP actions in cancer progression is shown in Figure 4.…”

SMAD1 as a biomarker and potential therapeutic target in drug-resistant multiple myeloma

“…Several studies highlight an important role for SMAD1 in promoting cell invasion and metastasis in different types of cancers [ 8 ]. For example, overexpression of SMAD1 induces proliferation in stomach cancer cells in response to BMP-7 stimulation [ 9 ], and upon activation by BMP-9, SMAD1 promotes ovarian cancer cell growth [ 10 ].…”

Research Progress on Regulating LncRNAs of Hepatocellular Carcinoma Stem Cells

“… 26 Evidence indicates that not only BMP2 and BMP4 are the key regulators of normal SCs and CSCs, but also BMP-9 can directly affect LCSCs. 62 There are two ways to excite the BMP signaling pathway. In the classical pathway, mature BMP dimers bind to receptors, resulting in the transphosphorylation of the receptors.…”