miR-19 Promotes Cell Proliferation, Invasion, Migration, and EMT by Inhibiting SPRED2-mediated Autophagy in Osteosarcoma Cells

Abstract

Osteosarcoma is an aggressive malignancy with rapid development and poor prognosis. microRNA-19 (miR-19) plays an important role in several biological processes. Sprouty-related EVH1 domain protein 2 (SPRED2) is a suppressor of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling to inhibit tumor development and progression by promoting autophagy. In this study, we investigated the roles of miR-19, SPRED2, and autophagy in osteosarcoma. We detected the expression of miR-19, SPRED2, epithelial–mesenchymal transition (EMT) markers, and autophagy-related proteins via quantitative real-time polymerase chain reaction or western blot. To evaluate the function of miR-19 and SPRED2, we used MTT and colony formation assays to detect cell proliferation, Transwell, and wound-healing assays to detect cell invasion and migration. Targetscan and luciferase reporter assays confirmed the relationship between SPRED2 and miR-19. The expression of miR-19 was significantly upregulated in osteosarcoma, while SPRED2 was downregulated. miR-19 inhibitor reduced cell proliferation, invasion, migration, and EMT, while its cell biological effects were partially reversed by addition of autophagy inhibitor 3-methyladenine (3-MA) or SPRED2 siRNA in osteosarcoma. SPRED2, a suppressor of ERK/MAPK pathway that is known to trigger autophagy, was identified as a direct target of miR-19. SPRED2 overexpression increased cell proliferation, invasion, migration, and EMT by promoting autophagy, and the effects could be inhibited by 3-MA. Collectively, these findings reveal an underlying mechanism for development of osteosarcoma. miR-19 was upregulated in osteosarcoma cells, and negatively regulated SPRED2, thus promoting the malignant transformation of osteosarcoma cells via inhibiting SPRED2-induced autophagy. Therefore, miR-19/SPRED2 may be a potential target for the treatment of osteosarcoma.

Exosomal microRNA‐19b targets FBXW7 to promote colorectal cancer stem cell stemness and induce resistance to radiotherapy

“…These results indicate that the upregulation of miR‐19b may be responsible for stemness maintenance and radioresistance in CRC. Consistently, miR‐19 promoted cell proliferation, invasion, and migration in osteosarcoma cells 19 . More relevantly, overexpression of miR‐19b was associated with metastasis and poor prognosis in patients with CRC 20 .…”

Potential Anti-Metastatic Role of the Novel miR-CT3 in Tumor Angiogenesis and Osteosarcoma Invasion

“…By downregulating the expression of PIK3R5 and regulating the AKT/mTOR signaling pathway, miR-210-5p promoted the cellular process called epithelial–mesenchymal transition (EMT), which is characterized by cells progressively losing epithelial features and acquiring mesenchymal properties, peculiar aspects of invasive and metastatic cells [ 43 ]. An oncogenic miRNA, member of the miR-17-92 cluster, was upregulated in OS cells and negatively regulated SPRED2, thus promoting the malignant transformation of osteosarcoma cells [ 44 ].…”

Studies on a novel mechanisms of VCP-mediated metastasis of osteosarcoma based on cell autophagy and EMT pathway

“…Other studies also reported that TGF-β can promote tumor metastasis by inducing EMT [24][25][26]. Although osteosarcoma is derived from mesenchymal cells, a large number of recent studies [27][28][29] have found that EMT also plays a key role in the metastasis of osteosarcoma. Whether EMT process involved in VCP-mediated metastasis of osteosarcoma is remained unknown.…”