Abstract
BackgroundHepatocellular 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.MethodsBMP2 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.ResultsBMP2 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.ConclusionTaken 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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common tumors globally, with varying prevalence based on endemic risk factors
Based on the aforementioned information, we proposed a hypothesis that BMP2 affects the progression of HCC by regulating the mitogen-activated protein kinase (MAPK)/p38 signaling pathway and aim to verify this hypothesis to provide some novel insights for HCC treatment
Subsequent Western blot analysis results (Fig. 1c) displayed that in comparison with the THLE3 cell lines, the protein levels of BMP2 were significantly increased in the MHCC97, Hep3BLIP-I, HepG2, HCCLM3, and Huh7 cell lines, among which the HepG2 cell line exhibited the highest BMP2 protein expression, and HepG2 was selected for subsequent experimentation
Summary
Hepatocellular carcinoma (HCC) is one of the most common tumors globally, with varying prevalence based on endemic risk factors. This study aimed to investigate the mechanism of BMP2 in HCC by mediating the mitogen-activated protein kinase (MAPK)/p38 signaling pathway. A recent study suggested that the bone morphogenetic protein (BMP) family is not solely involved in liver damage response, and plays a significant role in the promotion of tumor development in HCC [9]. Another study suggests that BMP2 regulates the promotion of cell angiogenesis, proliferation, and migration via the p38 signaling pathway [11]. The mitogen-activated protein kinase (MAPK)/p38 signaling pathway is well known to exert a crucial role in balancing cell survival and cell death in various cancers [12]. A study suggested that activation of BMP2 by hypoxia can promote the activation of the MAPK/p38 signaling pathway in human articular chondrocytes [16]. Based on the aforementioned information, we proposed a hypothesis that BMP2 affects the progression of HCC by regulating the MAPK/p38 signaling pathway and aim to verify this hypothesis to provide some novel insights for HCC treatment
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