Background: Nowadays, microRNAs (miRNAs) attract much attention in regulating anticancer drug resistance in cancers including multiple myeloma (MM). Bortezomib is the first-line choice in MM treatment, and bortezomib resistance caused by aberrant DNA repair leads to the recurrence and therapeutic failure of MM. Objective: Our study aims to identify a miRNA that overcomes bortezomib resistance in MM. Methods: We established bortezomib-resistant MM cell lines, and screened several miRNAs that have aberrant expressions in MM cell lines. The expression of DNA-repair-related proteins were assessed by western blot, and cell viability was determined by the MTT assay in bortezomibresistant cell lines. The binding between miRNAs and 3ʹ-UTR of APE1 mRNA was confirmed by luciferase reporter assay. The mouse bortezomib-resistant xenograft was established to verify the therapeutic effect of miRNA overexpression. Results: miR-520g and miR-520h were significantly downregulated in bortezomib-resistant MM cell lines, and overexpression of miR-520g and miR-520h together inhibited expression of homologous recombination-related protein Rad51 and cell viability of bortezomib-resistant MM cells in vitro by binding with 3ʹ-UTR of APE1 mRNA. Combined overexpression of miR-520g and miR-520h inhibited bortezomib-resistant MM tumor growth in vivo. Conclusion: Our findings demonstrated that combined overexpression of miR-520g and miR-520h overcomes bortezomib resistance in MM through inhibition of DNA repair, offering a promising therapeutic target for MM treatment.
A B S T R A C TWe compared the outcomes of immunosuppressive therapy (IST) with those of T cell-replete haploidentical donor hematopoietic stem cell transplantation (haplo-HSCT) in children and adolescents with severe aplastic anemia (SAA). The medical records of 49 patients with SAA who received frontline IST (n = 29) or frontline haplo-HSCT (n = 20) between 2012 and 2016 were analyzed retrospectively. Fourteen patients responded after the first IST, and 1 patient responded after the second IST in the frontline IST group; 12 patients underwent salvage HSCT after IST failure. Sixteen of the 20 patients who underwent frontline haplo-HSCT survived without treatment failure. The 3-year overall survival of the frontline IST group was comparable to that of the frontline haplo-HSCT group (79.3 § 7.5% versus 85.0 § 8.0%; x 2 = 0.110; P = .740). The 3-year failure-free survival was lower in the frontline IST group compared with the frontline haplo-HSCT group (35.9 § 10.9% versus 80.0 § 8.9%; x 2 = 4.089; P = .043). Five patients of the IST group who underwent salvage HSCT achieved long survival without event. The event-free survival was lower in the salvage HSCT group compared with the haplo-HSCT group (41.7 § 14.2% versus 80.0 § 8.9%; x 2 = 3.992; P = .046), and the incidences of acute GVHD, grade II-IV acute GVHD, chronic GVHD, and severe infection were comparable between the 2 groups. Our results suggest that frontline haplo-HSCT may be a better treatment than IST for children and adolescents with SAA who lack an HLA age-matched familial donor.
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