BMP9‐ID1 signaling promotes EpCAM‐positive cancer stem cell properties in hepatocellular carcinoma
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 a...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333780/ https://www.ncbi.nlm.nih.gov/pubmed/33834612 http://dx.doi.org/10.1002/1878-0261.12963 |
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author | Chen, Han Nio, Kouki Yamashita, Taro Okada, Hikari Li, Ru Suda, Tsuyoshi Li, Yingyi Doan, Phuong Thi Bich Seki, Akihiro Nakagawa, Hidetoshi Toyama, Tadashi Terashima, Takeshi Iida, Noriho Shimakami, Tetsuro Takatori, Hajime Kawaguchi, Kazunori Sakai, Yoshio Yamashita, Tatsuya Mizukoshi, Eishiro Honda, Masao Kaneko, Shuichi |
author_facet | Chen, Han Nio, Kouki Yamashita, Taro Okada, Hikari Li, Ru Suda, Tsuyoshi Li, Yingyi Doan, Phuong Thi Bich Seki, Akihiro Nakagawa, Hidetoshi Toyama, Tadashi Terashima, Takeshi Iida, Noriho Shimakami, Tetsuro Takatori, Hajime Kawaguchi, Kazunori Sakai, Yoshio Yamashita, Tatsuya Mizukoshi, Eishiro Honda, Masao Kaneko, Shuichi |
author_sort | Chen, Han |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8333780 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-83337802021-08-09 BMP9‐ID1 signaling promotes EpCAM‐positive cancer stem cell properties in hepatocellular carcinoma Chen, Han Nio, Kouki Yamashita, Taro Okada, Hikari Li, Ru Suda, Tsuyoshi Li, Yingyi Doan, Phuong Thi Bich Seki, Akihiro Nakagawa, Hidetoshi Toyama, Tadashi Terashima, Takeshi Iida, Noriho Shimakami, Tetsuro Takatori, Hajime Kawaguchi, Kazunori Sakai, Yoshio Yamashita, Tatsuya Mizukoshi, Eishiro Honda, Masao Kaneko, Shuichi Mol Oncol Research Articles 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. John Wiley and Sons Inc. 2021-05-02 2021-08 /pmc/articles/PMC8333780/ /pubmed/33834612 http://dx.doi.org/10.1002/1878-0261.12963 Text en © 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Chen, Han Nio, Kouki Yamashita, Taro Okada, Hikari Li, Ru Suda, Tsuyoshi Li, Yingyi Doan, Phuong Thi Bich Seki, Akihiro Nakagawa, Hidetoshi Toyama, Tadashi Terashima, Takeshi Iida, Noriho Shimakami, Tetsuro Takatori, Hajime Kawaguchi, Kazunori Sakai, Yoshio Yamashita, Tatsuya Mizukoshi, Eishiro Honda, Masao Kaneko, Shuichi BMP9‐ID1 signaling promotes EpCAM‐positive cancer stem cell properties in hepatocellular carcinoma |
title | BMP9‐ID1 signaling promotes EpCAM‐positive cancer stem cell properties in hepatocellular carcinoma |
title_full | BMP9‐ID1 signaling promotes EpCAM‐positive cancer stem cell properties in hepatocellular carcinoma |
title_fullStr | BMP9‐ID1 signaling promotes EpCAM‐positive cancer stem cell properties in hepatocellular carcinoma |
title_full_unstemmed | BMP9‐ID1 signaling promotes EpCAM‐positive cancer stem cell properties in hepatocellular carcinoma |
title_short | BMP9‐ID1 signaling promotes EpCAM‐positive cancer stem cell properties in hepatocellular carcinoma |
title_sort | bmp9‐id1 signaling promotes epcam‐positive cancer stem cell properties in hepatocellular carcinoma |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333780/ https://www.ncbi.nlm.nih.gov/pubmed/33834612 http://dx.doi.org/10.1002/1878-0261.12963 |
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