title: hsa-miR-631 resensitizes bortezomib-resistant multiple myeloma cell lines by inhibiting UbcH10.
abstract: Although bortezomib (BTZ) remains a first-line agent for multiple myeloma (MM) therapy, the development of BTZ resistance has become an indicator of poor prognosis in MM patients. It is thus urgent to develop strategies to restore the vulnerability of MM to BTZ. This study demonstrated, for the first time, that UbcH10 is highly expressed in BTZ-resistant myeloma cell lines U-266/BTZ, NCI-H929/BTZ and RPMI-8226/BTZ, which is attributed to the inactivation of post-transcriptional control. The in-depth study revealed that during the development of BTZ resistance in these cells, the hsa-miR-631 levels were decreased, which resulted in the increased expression of the target gene UbcH10. We also found that the multiple drug-resistant protein MDR1 exhibited a positive correlation with UbcH10 due to the reduced ubiquitination of MDR1, which was caused by high UbcH10 expression. Following overexpression of miR-631, both BTZ sensitivity and BTZ-induced apoptosis were enhanced in the resistant cells. Meanwhile, resensitization by miR-631 overexpression was blocked by exogenous expression of UbcH10, which was not regulated by intracellular miR-631. In conclusion, the miR-631/UbcH10/MDR1 pathway is closely associated with the development of BTZ resistance in myeloma cells, and the overexpression of miR-631 can significantly improve BTZ sensitivity in resistant myeloma cells.
authors.affiliation: Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Xi
authors.affiliation: Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China.
authors.forename: Lu
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China.
authors.forename: Ran
authors.initials: R
authors.lastname: An
authors.affiliation: Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China.
authors.forename: Rong
authors.initials: R
authors.lastname: Fan
authors.affiliation: Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Respiratory Diseases, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, P.R. China.
authors.forename: Yin-Xiang
authors.initials: YX
authors.lastname: Wu
authors.affiliation: Grade Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Shu-Xie
authors.initials: SX
authors.lastname: Wu
authors.affiliation: Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Hou
authors.affiliation: Department of Respiratory Diseases, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, P.R. China.
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Zhao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D000069286:Bortezomib / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C000607908:MIRN631 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D000069286:Bortezomib; C105156:UBE2C protein, human; D044763:Ubiquitin-Conjugating Enzymes