MicroRNA-182 downregulates Wnt/β-catenin signaling, inhibits proliferation, and promotes apoptosis in human osteosarcoma cells by targeting HOXA9
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Zi-Feng Zhang1,*, Yong-Jian Wang1,*, Shao-Hua Fan1, Shi-Xin Du2, Xue-Dong Li2, Dong-Mei Wu1, Jun Lu1 and Yuan-Lin Zheng1
1Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, P.R. China
2Department of Orthopedics, The Third Affiliated Hospital, Shenzhen University, Shenzhen 518002, P.R. China
Dong-Mei Wu, email: firstname.lastname@example.org
Jun Lu, email: email@example.com
Yuan-Lin Zheng, email: firstname.lastname@example.org
Keywords: microRNA-182, homeobox A9, wingless-type/β-catenin signaling pathway, osteosarcoma
Received: April 14, 2017 Accepted: September 04, 2017 Published: September 22, 2017
We investigated the mechanisms by which microRNA (miR)-182 promotes apoptosis and inhibits proliferation in human osteosarcoma (OS) cells. Levels of miR-182 and Homeobox A9 (HOXA9) expression were compared between human OS and normal cells. Subjects were divided into OS and normal groups. We analyzed the target relationship of miR-182 and Homeobox A9 (HOXA9). Cells were then assigned into blank, negative control, miR-182 mimics, miR-182 inhibitors, siRNA-HOXA9, or and miR-182 inhibitors + siRNA-HOXA9 groups. Cell function was assayed by CCK-8, flow cytometry and wound healing assay. Additionally, we analyzed OS tumor growth in a xenograft mouse model. Dual-luciferase reporter assays indicated miR-182 directly targets HOXA9. Reverse transcription quantitative PCR and western blotting revealed elevated expression of miR-182, WIF-1, BIM, and Bax, and reduced expression of HOXA9, Wnt, β-catenin, Survivin, Cyclin D1, c-Myc, Mcl-1, Bcl-xL, and Snail in osteosarcoma cells treated with miR-182 mimic or siRNA-HOXA9 as compared to controls. Osteosarcoma cells also exhibited decreased cell proliferation, migration, and tumor growth, and increased apoptosis when treated with miR-182 mimic or siRNA-HOXA9. Correspondingly, in a xenograft mouse model, osteosarcoma tumor volume and growth were increased when cells were treated with miR-182 inhibitor and decreased by miR-182 mimic or siRNA-HOXA9. These results indicate that miR-182 downregulates Wnt/β-catenin signaling, inhibits cell proliferation, and promotes apoptosis in osteosarcoma cells by suppressing HOXA9 expression.
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