Circular RNA circXPO1 promotes multiple myeloma progression via sponging miR-495 3p and upregulating of DDIT4

Abstract

Background:Multiple myeloma (MM) is a hematologic cancer featured by malignant proliferation of plasma cells. The therapeutic strategies for MM patients include chemotherapy, immune therapy and targeted therapy. However, MM is still an incurable malignancy. To extend therapeutic arsenal for MM, it is important to uncover the molecular mechanism and cellular machinery behind the vicious progression of MM. Circular RNAs (circRNAs) are versatile regulators that affect aggressive behaviors of many cancers. However, the roles and underlying mechanisms of circRNAs in MM are not well elucidated. CircXPO1 (also referred to as hsa_circRNA_102735) is a newly discovered circRNA that is upregulated in multiple myeloma (MM) based on microarray analysis. This study aimed to investigate roles of circXPO1 in MM. Methods: We investigated the expression pattern of circRNAs in primary Multiple myeloma samples using the circRNA microarray. The characteristics, potential diagnostic value, and prognostic significance of circXPO1 were evaluated among 54 newly diagnosed MM patients by analyzing the expression of circXPO1 in different disease stages. Knockdown and overexpression were used to evaluate the effects of circXPO1 on myeloma malignancy in vitro and in vivo. Biotin RNA pulldown assay and dual-luciferase reporter assay were implemented to verify the interaction between circXPO1 and miR-495-3p. Dual-luciferase reporter assay was used to prove the combination miR-495-3p and DDIT4.Results：CircXPO1 was highly expressed in bone marrow (BM)-derived plasma cells of MM patients and MM cell lines than that in iron deficiency anemia (IDA) controls. CircXPO1 promoted the proliferation, cell cycle, and impeded the apoptosis of MM cells. MiR-495-3p was a direct target of circXPO1 in MM cells, and circXPO1 promote myeloma progression via sponging miR-495-3p. DDIT4 could directly bind to miR-495-3p in MM cells and miR-495-3p exerted an anti-tumor role through targeting DDIT4.Conclusion：CircXPO1, acting as an oncogene, could promote the proliferation, cell cycle, and restrain the apoptosis of MM cells through regulating miR-495-3p and DDIT4, which provides novel insights into MM therapy.