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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
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.
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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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