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Inhibition of Bone Morphogenetic Protein 2 Suppresses the Stemness Maintenance of Cancer Stem Cells in Hepatocellular Carcinoma via the MAPK/ERK Pathway

Authors Guo J, Guo M, Zheng J

Received 14 September 2020

Accepted for publication 24 December 2020

Published 27 January 2021 Volume 2021:13 Pages 773—785

DOI https://doi.org/10.2147/CMAR.S281969

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 4

Editor who approved publication: Dr Eileen O'Reilly


Juncheng Guo, Min Guo, Jinfang Zheng

Department of Hepatobiliary Surgery, Hainan General Hospital, Haikou, 570311 Hainan, People’s Republic of China

Correspondence: Jinfang Zheng
Hainan General Hospital, No. 19 Xinhua Road, Xiuying District, Haikou, 570311 Hainan Province, People’s Republic of China
Tel +86 13907571082
Email Zjinfang0310@163.com

Background: Hepatocellular carcinoma (HCC) remains a life-threatening malignant tumor. Cancer stem cells (CSCs) harbor tumor-initiating capacity and can be used as a therapeutic target for human malignancies. Bone morphogenetic proteins (BMPs) play a regulatory role in CSCs. This study investigated the role and mechanism of BMP2 in CSCs in HCC.
Methods: BMP2 expression in HCC tissues and cells, and CSCs from HepG2 cells and SMMC7721 cells (HepG2-CSCs and SMMC7721-CSCs) was measured. The association between BMP2 expression and prognosis of HCC patients was analyzed. CSCs were interfered with BMP2 to evaluate the abilities of colony and tumor sphere formation, levels of stemness-related markers, epithelial–mesenchymal transition (EMT), and invasion and migration. Levels of MAPK/ERK pathway-related proteins in HepG2-CSCs were detected after BMP2 knockdown. The effect of the activated MAPK/ERK pathway on HepG2-CSCs was assessed. Finally, the effect of BMP2 inhibition on CSCs in HCC was verified in vivo.
Results: BMP2 showed obvious upregulation in HCC tissues and cells and was further upregulated in CSCs in HCC, with its higher expression indicative of worse prognosis. Silencing BMP2 inhibited colony and tumor sphere formation, levels of stemness-related markers, as well as EMT, invasion and migration of HepG2-CSCs and SMMC7721-CSCs. The MAPK/ERK pathway was suppressed after BMP2 knockdown, and its activation reversed the inhibitory effect of shBMP2 on hepatic CSCs. BMP2 accelerated tumor growth and EMT of CSCs in HCC in vivo.
Conclusion: We concluded that BMP2 knockdown inhibited the EMT, proliferation and invasion of CSCs in HCC, thereby hindering the stemness maintenance via suppressing the MAPK/ERK pathway.

Keywords: hepatocellular carcinoma, cancer stem cells, bone morphogenetic protein 2, stemness, epithelial-mesenchymal transition, MAPK/ERK pathway

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