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

Abstract

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.

Altered BMP2/4 Signaling in Stem Cells and Their Niche: Different Cancers but Similar Mechanisms, the Example of Myeloid Leukemia and Breast Cancer

“…Leukemic BMPR1b high cells respond to BMP4 by amplifying and maintaining their CSCs population, whereas BMP2 favors the expansion of myeloid CML progenitors. A similar role for BMP2 in the maintenance of CSCs was recently reported in hepatocellular carcinoma ( Guo et al, 2021 ). In addition, BMPR1b mutations were linked to Brachydactyly type A1 characterized by bones hyperplasia, indicating that BMPR1b alterations could affect both the HSCs and MSCs in different physiopathological contexts by affecting their response to BMP4 ( Laperrousaz et al, 2013 ; Racacho et al, 2015 ).…”

Bone Morphogenetic Protein Signaling in Cancer; Some Topics in the Recent 10 Years

“…Zhang et al revealed that high-dose exogenous BMP-4 promotes the differentiation of CD133 + CSCs in HCC, whereas low-dose exogenous BMP-4 upregulates CD133 expression, suggesting a concentration-dependent effect of BMPs on CSC maintenance ( Zhang et al, 2012 ). Silencing of BMP-2 in HCC suppresses Erk MAP kinase and inhibits sphere formation and the expression of stemness-related and EMT markers in CSCs from HCC cell lines ( Guo et al, 2021 ). BMP-9 promotes CSC properties in epithelial cell adhesion molecule (EpCAM)-positive HCC subtypes by enhancing ID1 expression ( Chen et al, 2021 ).…”

“…The expression levels of BMP-2/4 and ALK3 were upregulated in tumor tissues. Many of these are correlated with various clinical or biological parameters, such as unfavorable prognosis, tumor grade, TNM stage, vascular invasion, and the expression of the stem cell marker CD133 ( Guo D et al, 2012 ; Zhang et al, 2012 ; Ma et al, 2017 ; Feng et al, 2019 ; Li et al, 2020 ; Guo et al, 2021 ). Increased BMP-9 expression is also observed in HCCs and significantly associated with poor outcomes and the T stage of HCC ( Herrera et al, 2013 ; Li et al, 2013 ; Chen et al, 2021 ).…”

Association between the expression levels of ADAMTS16 and BMP2 and tumor budding in hepatocellular carcinoma

“…As for BMP2, in the present study, patients with BCLC stage B-C had significantly higher BMP2 expression levels than patients with BCLC stage 0-A, suggesting the involvement of BMP2 in the progression and metastasis of HCC. Previous studies have demonstrated that BMP2 may promote HCC cell proliferation and invasion, thereby promoting malignant progression of HCC ( 20 , 21 , 44 ). As such, the results of the present study are in accordance with previously reported results.…”