Abstract: Researchers from Kanazawa University found that bone morphologic protein 9 (BMP9), which is a prognostic biomarker in patients with hepatocellular carcinoma (HCC), promotes liver cancer stem cell properties, including cell proliferation, cell invasion and migration, by activating the expression of inhibitor of DNA-binding protein 1 (ID1). Inhibiting BMP9-ID1 signaling successfully suppressed cell proliferation in vitro and tumor progression in a mouse model, suggesting that targeting this signaling could have valuable therapeutic applications for advanced HCC patients.
Kanazawa, Japan – Liver cancer stem cells, which are thought to be responsible for the malignant traits of HCC, is considered as the target to eradicate. Now, researchers from Japan have found a signaling pathway in HCC that involves in promoting the properties of liver cancer stem cells.
In a study published last month in Molecular Oncology, researchers from Kanazawa University revealed that bone morphologic protein 9 (BMP9) signaling promotes the properties of liver cancer stem cells through enhancing the expression of inhibitor of DNA-binding protein 1 (ID1).
BMP9 is a known player in liver disease, as it prevents liver cancer cells from dying, encourages their proliferation, and promotes tumor formation in the liver. The team at Kanazawa University aimed to address whether BMP9 specifically has important roles in the activation of liver cancer stem cells, a minority subset of cancer cells that can drive tumor initiation, promote tumor progression, and induce drug resistance.
“Cancer stem cells are thought to be responsible for the malignant traits of cancer such as tumor progression, recurrence, metastasis and drug-resistance” says lead author of the study Han Chen. “Because BMP9 has recently been reported to be associated with liver cancer progression, we wanted to investigate the interaction between BMP9 and cancer stem cells in HCC."
To do this, the researchers examined BMP9 expression in tumor tissue samples from patients with HCC and analyzed the correlation with patient prognosis and the expression of liver cancer stem marker EpCAM.
“The results were very interesting,” explains Kouki Nio, corresponding author. “We found BMP9-high HCC cases show a poorer overall survival. In addition, BMP9 expression was correlated with EpCAM expression in HCC tissues. These suggest BMP9 relates to malignant potential of HCC.”
In fact, BMP9 promoted the expression of EpCAM through the regulation of ID1 expression in HCC cells. Blocking BMP9-ID1 signaling by BMP receptor inhibitors successfully suppressed the tumor growth of HCC and the expression of EpCAM in mice.
“Our findings suggest that BMP9-ID1 signaling is crucial for the activation of liver cancer stem cells. As such, targeting this signaling could be a promising therapy for the patients with advanced HCC in the future,” says Chen.
In terms of future application for HCC patients, some clinical studies using BMP receptor inhibitor monotherapy or in combination with other agents are desired.
[Funder]
This work was supported by JSPS KAKENHI Grant Numbers JP18K15807 and JP20K17044.
[Article]
Title: MP9-ID1 signaling promotes EpCAM-positive cancer stem cell properties in hepatocellular carcinoma
Journal: Molecular Oncology
Authors: Han Chen, Kouki Nio, Taro Yamashita, Hikari Okada, Ru Li, Tsuyoshi Suda, Yingyi Li, Phuong Thi Bich Doan, Akihiro Seki, Hidetoshi Nakagawa, Tadashi Toyama, Takeshi Terashima, Noriho Iida, Tetsuro Shimakami, Hajime Takatori, Kazunori Kawaguchi, Yoshio Sakai, Tatsuya Yamashita, Eishiro Mizukoshi, Masao Honda, Shuichi Kaneko
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