Xiaoli Yuan1, Rongjun Ma1, Shiwei Yang1, Li Jiang1, Zhen Wang1, Zunmin Zhu1, Hongwei Li2. 1. a Department of Hematology, Henan Key Laboratory for Hematology, Henan Provincial People's Hospital , People's Hospital of Zhengzhou University , Zhengzhou , Henan , China. 2. b Department of Neurosurgery , the First Affiliated Hospital of Zhengzhou University , Zhengzhou , Henan , China.
Abstract
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 bortezomib-resistant cell lines. The binding between miRNAs and 3'-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 3'-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.
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 bortezomib-resistant cell lines. The binding between miRNAs and 3'-UTR of APE1 mRNA was confirmed by luciferase reporter assay. The mousebortezomib-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 3'-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.
Authors: María-Victoria Mateos; José-M Hernández; Miguel-T Hernández; Norma-C Gutiérrez; Luis Palomera; Marta Fuertes; Joaquín Díaz-Mediavilla; Juan-J Lahuerta; Javier de la Rubia; María-José Terol; Ana Sureda; Joan Bargay; Paz Ribas; Felipe de Arriba; Adrian Alegre; Albert Oriol; Dolores Carrera; José García-Laraña; Ramón García-Sanz; Joan Bladé; Felipe Prósper; Gemma Mateo; Dixie-Lee Esseltine; Helgi van de Velde; Jesús-F San Miguel Journal: Blood Date: 2006-06-13 Impact factor: 22.113
Authors: Meihua Li; Kyle F Lee; Yuntao Lu; Ian Clarke; David Shih; Charles Eberhart; V Peter Collins; Tim Van Meter; Daniel Picard; Limei Zhou; Paul C Boutros; Piergiorgio Modena; Muh-Lii Liang; Steve W Scherer; Eric Bouffet; James T Rutka; Scott L Pomeroy; Ching C Lau; Michael D Taylor; Amar Gajjar; Peter B Dirks; Cynthia E Hawkins; Annie Huang Journal: Cancer Cell Date: 2009-12-08 Impact factor: 31.743
Authors: Jianxiang Chi; Erica Ballabio; Xiao-He Chen; Rajko Kušec; Steve Taylor; Deborah Hay; Daniela Tramonti; Nigel J Saunders; Timothy Littlewood; Francesco Pezzella; Jacqueline Boultwood; James S Wainscoat; Christian S R Hatton; Charles H Lawrie Journal: Biol Direct Date: 2011-05-18 Impact factor: 4.540