BMP9‐ID1 signaling promotes EpCAM‐positive cancer stem cell properties in hepatocellular carcinoma

Molecular Oncology

Ru Li¹  Takeshi Terashima¹  Hajime Takatori¹  Eishiro Mizukoshi¹  Akihiro Seki¹  Shuichi Kaneko¹  Tsuyoshi Suda¹  Yingyi Li¹  Noriho Iida¹  Han Chen¹  Hikari Okada¹  Hidetoshi Nakagawa¹  Tetsuro Shimakami¹  Yoshio Sakai¹  Masao Honda¹  Kouki Nio¹  Tatsuya Yamashita¹  Kazunori Kawaguchi¹  Phuong Thi Bich Doan¹  Taro Yamashita²  Tadashi Toyama³ 

[1] Department of Gastroenterology Kanazawa University Hospital Japan;Department of General Medicine Kanazawa University Hospital Japan;Innovative Clinical Research Center Kanazawa University Japan;

关键词: BMP receptor inhibitor;    BMP9‐ID1 signaling;    cancer stem cells;    EpCAM;    hepatocellular carcinoma;   

DOI  :  10.1002/1878-0261.12963

来源: DOAJ

【 摘 要 】

The malignant nature of hepatocellular carcinoma (HCC) is closely related to the presence of cancer stem cells (CSCs). Bone morphologic protein 9 (BMP9), a member of the transforming growth factor‐beta (TGF‐β) superfamily, was recently reported to be involved in liver diseases including cancer. We aimed to elucidate the role of BMP9 signaling in HCC‐CSC properties and to assess the therapeutic effect of BMP receptor inhibitors in HCC. We have identified that high BMP9 expression in tumor tissues or serum from patients with HCC leads to poorer outcome. BMP9 promoted CSC properties in epithelial cell adhesion molecule (EpCAM)‐positive HCC subtype via enhancing inhibitor of DNA‐binding protein 1 (ID1) expression in vitro. Additionally, ID1 knockdown significantly repressed BMP9‐promoted HCC‐CSC properties by suppressing Wnt/β‐catenin signaling. Interestingly, cells treated with BMP receptor inhibitors K02288 and LDN‐212854 blocked HCC‐CSC activation by inhibiting BMP9‐ID1 signaling, in contrast to cells treated with the TGF‐β receptor inhibitor galunisertib. Treatment with LDN‐212854 suppressed HCC tumor growth by repressing ID1 and EpCAM in vivo. Our study demonstrates the pivotal role of BMP9‐ID1 signaling in promoting HCC‐CSC properties and the therapeutic potential of BMP receptor inhibitors in treating EpCAM‐positive HCC. Therefore, targeting BMP9‐ID1 signaling could offer novel therapeutic options for patients with malignant HCC.

【 授权许可】

Unknown