The Molecular Mechanism by which LINC00461 Regulates Carfilzomib Resistance in Multiple Myeloma

Abstract

Multiple myeloma (MM) is a frequent haematological malignancy of the bone marrow. Carfilzomib, a first-line treatment for MM, has excellent antitumour effects, but its efficacy eventually decreases due to primary or acquired chemoresistance. Therefore, the regulatory mechanism of carfilzomib resistance has attracted much attention for improving the survival outcomes of patients with MM. By using database analysis combined with quantitative real-time polymerase chain reaction (qRT‒PCR), aberrant lncRNAs in MM were screened in carfilzomib-resistant cells versus carfilzomib-sensitive cells, and the resistance index of cultured carfilzomib-resistant cells was analysed compared to that of parental cells. Furthermore, cell viability, proliferation, and apoptosis in response to treatment with carfilzomib were measured after treatment with LINC00461 by the cell counting kit-8 (CCK-8) method and flow cytometry. The expression of LINC00461 was also verified through qRT‒PCR. Then, the possible miRNA molecules on which LINC00461 may act were investigated by RNA immunoprecipitation (RIP) and dual-luciferase reporter assays. Next, tumorigenesis in mice was evaluated to verify the effect of LINC00461 on carfilzomib-resistant cells. Increased expression of LINC00461 was related to drug resistance in MM patients. Mechanistically, LINC00461 overexpression attenuated the effect of miR-539-3p overexpression and decreased the expression of the downstream protein RAB5A. Moreover, compared with the control group, the LINC00461 knockdown group treated with carfilzomib exhibited decreases in tumour volume and weight. Furthermore, LINC00461 sensitized carfilzomib-sensitive cells by promoting the release of exosomes. These data suggest that LINC00461 plays an important role in the development of carfilzomib resistance.