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

• Published in: Stem cell research & therapy Vol. 10; no. 1; p. 237
• Main Authors: Feng, Peng-Cheng, Ke, Xing-Fei, Kuang, Hui-Lan, Pan, Li-Li, Ye, Qiang, Wu, Jian-Bing
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 06.08.2019; BioMed Central; BMC
• Subjects: Adult; Aged; Aged, 80 and over; Angiogenesis; Animals; Apoptosis; BMP2; Bone Morphogenetic Protein 2 - antagonists & inhibitors; Bone Morphogenetic Protein 2 - genetics; Bone Morphogenetic Protein 2 - metabolism; Bone morphogenetic proteins; Carcinoma, Hepatocellular - blood supply; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Care and treatment; Cell Line, Tumor; Cell Movement; Cell Proliferation; Endothelial Cells - cytology; Endothelial Cells - metabolism; Female; Hep G2 Cells; Hepatocellular carcinoma; Hepatoma; Humans; Imidazoles - pharmacology; Liver Neoplasms - blood supply; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; MAPK/p38 signaling pathway; Mice; Mice, Nude; Middle Aged; Neovascularization; Neovascularization, Pathologic; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Patient outcomes; Pyrimidines - pharmacology; RNA Interference; RNA, Small Interfering - metabolism; Signal Transduction - drug effects; Tumor growth; China; Angiogenesis; Hepatocellular carcinoma; BMP2; MAPK/p38 signaling pathway; Tumor growth
• ISSN: 1757-6512; 1757-6512
• DOI: 10.1186/s13287-019-1301-2

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. 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. 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. 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.