ADAM10 promotes cell growth, migration, and invasion in osteosarcoma via regulating E-cadherin/β-catenin signaling pathway and is regulated by miR-122-5p

Abstract

Background: Osteosarcoma is a malignant bone tumor. Increasing evidences have revealed that a disintegrin and metalloproteinase 10 (ADAM10) is implicated in tumor development. The main purpose of this study is to explore the effects of ADAM10 on osteosarcoma cell functions and the underlying molecular mechanisms. Methods: Western blot and quantitative real-time PCR were performed to detect the expression of ADAM10 in one osteoblast (hFOB 1.19) and six osteosarcoma cells (Saos-2, SW1353, HOS, U-2OS, MG63, and 143B). The biological functions of ADAM10 in osteosarcoma cells were measured by cell counting kit-8 assay, flow cytometry, wound healing assay, and transwell assay. The interaction between miR-122-5p and ADAM10 was validated using dual-luciferase reporter assay. The effect of ADAM10 on the tumorigenicity of osteosarcoma cells was evaluated in a nude mice model in vivo. Results: We found that the expression of ADAM10 was relatively high in osteosarcoma cells compared with that in osteoblast. ADAM10 promoted osteosarcoma cell growth, migration, and invasion. Mechanism studies showed that knockdown of ADAM10 inactivated E-cadherin/β-catenin signaling pathway, as evidenced by increased the level of E-cadherin, reduced nuclear translocation of β-catenin, and decreased the levels of MMP-9, Cyclin D1, c-Myc, and Survivin. Downregulation of ADAM10 suppressed the tumorigenicity of osteosarcoma cells in vivo. Furthermore, ADAM10 was validated to be a downstream target of microRNA-122-5p (miR-122-5p). MiR-122-5p-induced inhibition of cell proliferation, migration, and invasion was reversed by overexpression of ADAM10 in osteosarcoma cells. Conclusions: Collectively, the key findings of this study are that ADAM10 promotes osteosarcoma cell proliferation, migration, and invasion by regulating E-cadherin/β-catenin signaling pathway, and miR-122-5p can target ADAM10, indicating that miR-122-5p/ADAM10 axis might serve as a therapeutic target of osteosarcoma.

Global scientific trends on matrix metalloproteinase and osteosarcoma: A bibliometric and visualized analysis

“…A number of studies have been reported the molecular mechanism by which MMP regulates the prognosis of OS. On the one hand, A series of studies have reported that MMP promoted OS invasion and metastasis ( 41 , 52 – 61 ). Specifically, MMP is an enzyme that plays an important role in the degradation of extracellular matrix components, affecting cell metabolism, survival, migration, proliferation and differentiation, excessive secretion can cause degradation to the human vascular basement membrane, accelerate the migration rate of neutral mitochondrial cells, and lead to the intensification of local inflammatory response of tissue cells ( 62 ).…”

MicroRNA-122 in human cancers: from mechanistic to clinical perspectives

“…They reported that TP53 up-regulation by miR-122-5p overexpression may reduce the proliferation and enhance the apoptosis of osteosarcoma cells by suppressing the activation of the PI3K-Akt-mTOR signaling pathway [ 63 ]. In addition, an experimental investigation by Yuankey et al disclosed that ADAM metallopeptidase domain 10 (ADAM10) promotes osteosarcoma cell proliferation, migration, and invasion by regulating E-cadherin/β-catenin signaling pathway and miR-122-5p can target ADAM10, indicating that miR-122-5p/ADAM10 axis might serve as a therapeutic target of osteosarcoma [ 64 ].…”

Novel Potential Therapeutic Targets in Autosomal Dominant Polycystic Kidney Disease from the Perspective of Cell Polarity and Fibrosis

“…ADAMs (disintegrin and metalloproteinase) constitute a family of versatile proteins involved in both cell adhesion and proteolysis ( Shiu et al ., 2018 ; Wang and Cao, 2023 ). The ADAM substrate comprises molecules that play important roles in the plasma membrane by enhancing the release of E-cadherin ( Kato et al ., 2018 ; Yuan et al ., 2020 ). The subsequent cleavage of the ectodomain fragment of E-cadherin results in the translocation of β-catenin from the cell membrane to the nucleus ( Lichtenthaler et al ., 2018 ).…”