Abstract
BackgroundMultiple myeloma (MM) is one of the most frequently diagnosed hematological malignancy. Dysregulation of circular RNAs (circRNAs) has important impacts on MM process. Herein, this work aimed to investigate the role and mechanism of circ_0058058 in MM progression.MethodsLevels of genes and proteins were detected by real-time reverse transcription PCR (RT-qPCR) and Western blot. CCK-8 assay, colony formation assay, EdU assay, flow cytometry, tube formation assay, transwell assay and Western blot were utilized to detect the proliferation, apoptosis, angiogenesis and metastasis of MM cells. The target relationship between miR-338-3p and circ_0058058 or ATG14 (autophagy related 14) was verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. In vivo experiments were performed using Xenograft assay.ResultsCirc_0058058 was up-regulated in MM bone marrow aspirates and cells, knockdown of circ_0058058 reduced MM cell proliferation, angiogenesis and metastasis, but induced apoptosis in vitro. In a MM xenograft mouse model, circ_0058058 silencing reduced MM tumor growth and cell proliferation. Mechanistically, circ_0058058 acted as a sponge for miR-338-3p to up-regulate ATG14 expression, which was validated to be a target of miR-338-3p. Rescue assay showed that miR-338-3p inhibition reversed the antitumor effects of circ_0058058 knockdown on MM cell. Moreover, forced expression of miR-338-3p suppressed MM cell malignant phenotype, which was abolished by ATG14 up-regulation.ConclusionCirc_0058058 functions as a sponge for miR-338-3p to elevate ATG14 expression to promote MM cell proliferation, metastasis and angiogenesis, affording a potential therapeutic target for MM prevention.
Highlights
Multiple myeloma (MM) is second most frequently diagnosed hematological malignancy [1], characterized by high infiltration and accumulation of clonal malignant plasma cells in the bone marrow with initially asymptomatic [2, 3]
An in-depth investigation on mechanisms underlying MM pathogenesis is of great essence for prolonging the survival of MM patients
Specimen collection Bone marrow aspirates were collected from 37 MM patients diagnosed based on the International Myeloma Working Group (IMWG) updated criteria at the First People’s Hospital of Lianyungang
Summary
Multiple myeloma (MM) is second most frequently diagnosed hematological malignancy [1], characterized by high infiltration and accumulation of clonal malignant plasma cells in the bone marrow with initially asymptomatic [2, 3]. An in-depth investigation on mechanisms underlying MM pathogenesis is of great essence for prolonging the survival of MM patients. Emerging evidence has showed the crucial role of circRNAs in regulating cellular biological processes linked with carcinogenesis, apoptosis, migration, and differentiation [8, 9]. Disturbance of circRNAs expression is implicated in the tumorigenesis of human malignancies [10, 11], including MM [12, 13]. A recent study indicated that circ_0058058 increased EIF5A2 expression through miR-4319 to accelerate cell proliferation, invasion, and migration in hematological malignancy acute myeloid leukemia (AML) [14]. Multiple myeloma (MM) is one of the most frequently diagnosed hematological malignancy. This work aimed to investigate the role and mechanism of circ_0058058 in MM progression
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