RETRACTED ARTICLE: BMP2 secretion from hepatocellular carcinoma cell HepG2 enhances angiogenesis and tumor growth in endothelial cells via activation of the MAPK/p38 signaling pathway

Abstract

Background Hepatocellular carcinoma (HCC) is one of the most common tumors globally, with varying prevalence based on endemic risk factors. Bone morphogenetic protein (BMP) exhibits a broad spectrum of biological activities in various tissues including angiogenesis. Here, this study aimed to investigate the mechanism of BMP2 in HCC by mediating the mitogen-activated protein kinase (MAPK)/p38 signaling pathway. Methods BMP2 expression was quantified in HCC and adjacent tissues. BMP2 gain- and loss-of-function experiments were conducted by infection with lentivirus over-expressing BMP2 or expressing shRNA against BMP2. The angiogenesis was evaluated with HepG2 cells co-cultured with ECV304 cells. SB-239063 was applied to inhibit the activation of the MAPK/p38 signaling pathway so as to identify the significance of this pathway in HCC progression. Finally, in vivo experiments were conducted to identify the role of BMP2 and the MAPK/p38 signaling pathway in tumor growth and angiogenesis. Results BMP2 was highly expressed in HCC. Over-expression of BMP2 was found to accelerate cell proliferation, migration, invasion, microvascular density, and angiogenesis and decrease cell apoptosis in vitro and in vivo. BMP2 silencing exhibited inhibitory effects on HCC cell invasion and angiogenesis. The co-culture system illustrated that HepG2 cells secreted BMP2 in ECV304, and silenced BMP2 in HepG2 cells resulted in the inactivation of the MAPK/p38 signaling pathway, thus suppressing cancer progression, tumor growth, and angiogenesis in HCC. Conclusion Taken together, the key findings of this study propose that silencing of BMP2 inhibits angiogenesis and tumor growth in HCC, highlighting BMP2 silencing as a potential strategy for the treatment of HCC.

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

“…Silencing BMP2 helps to prevent HCC cell migration and invasion. 22 In conclusion, BMP2 knockdown inhibited the EMT and then the invasion and migration of CSCs in HCC.…”

“…In agreement with this, a previous study has also demonstrated the abnormal upregulation of BMP2 in HCC. 22 CSCs, showing presence in primary cancers, are identified to drive cancer growth with the potent self-renewing ability, and consequently targeting CSCs has been recognized as a promising therapy for cancer treatment. 25 Compared with HepG2 and SMMC7721 cells, HepG2-CSCs and SMMC7721-CSCs showed dramatically increased sphere formation rate and colony numbers, and markedly elevated levels of CSC markers (CD44 and ALDH1) and pluripotent transcription factors (Bmil, SOX2 and OCT4), demonstrating the stemness of HepG2-CSCs and SMMC7721-CSCs.…”

“… 21 BMP2 positively regulates cancer cell malignant behavior and tumor growth in HCC. 22 Nevertheless, the role of BMP2 in CSCs in HCC remains to be elucidated.…”

RETRACTED ARTICLE: Effects of miR-672 on the angiogenesis of adipose-derived mesenchymal stem cells during bone regeneration

“…Among different kinds of angiogenic factors, bone morphogenetic protein 2 (BMP2) has been proven to be valuable. Studies have shown that BMP2 could regulate the promotion of cell angiogenesis, proliferation, and migration via the p38 signaling pathway [ 23 ]. Besides, studies also have shown that BMP2 could promote vascularization and was involved in tumorous angiogenesis possibly through Id1 and p38 MAPK pathways, for example, BMP2 had effects on the angiogenesis of hepatocellular carcinoma [ 17 , 47 ].…”

Immunological characterization of hepatocellular carcinoma

“…For example, activation of the EGFR-RAS-MAPK pathway leads to dysregulated cell proliferation in HCC [113] . The MAPK/p38 signaling has been shown to promote angiogenesis and drive tumor cell metastasis (migration and invasion) [114,115] . In addition, activation of the MAPK/p38 endows resistance against apoptosis to HCC cells [116] .…”