BMP9-ID1 signaling promotes EpCAM-positive cancer stem cell properties in hepatocellular carcinoma.
Carcinoma, Hepatocellular
/ metabolism
Cell Line, Tumor
Cohort Studies
Gene Knockdown Techniques
Growth Differentiation Factor 2
/ metabolism
Humans
Inhibitor of Differentiation Protein 1
/ genetics
Liver Neoplasms
/ metabolism
Neoplastic Stem Cells
/ metabolism
Prognosis
Signal Transduction
Wnt Signaling Pathway
BMP receptor inhibitor
BMP9-ID1 signaling
EpCAM
cancer stem cells
hepatocellular carcinoma
Journal
Molecular oncology
ISSN: 1878-0261
Titre abrégé: Mol Oncol
Pays: United States
ID NLM: 101308230
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
revised:
26
02
2021
accepted:
07
04
2021
pubmed:
10
4
2021
medline:
29
3
2022
entrez:
9
4
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33834612
doi: 10.1002/1878-0261.12963
pmc: PMC8333780
doi:
Substances chimiques
GDF2 protein, human
0
Growth Differentiation Factor 2
0
ID1 protein, human
0
Inhibitor of Differentiation Protein 1
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2203-2218Informations de copyright
© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
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