title: MIR34A regulates autophagy and apoptosis by targeting HMGB1 in the retinoblastoma cell.
abstract: MIR34A (microRNA 34a) is a tumor suppressor gene, but how it regulates chemotherapy response and resistance is not completely understood. Here, we show that the microRNA MIR34A-dependent high mobility group box 1 (HMGB1) downregulation inhibits autophagy and enhances chemotherapy-induced apoptosis in the retinoblastoma cell. HMGB1 is a multifaceted protein with a key role in autophagy, a self-degradative, homeostatic process with a context-specific role in cancer. MIR34A inhibits HMGB1 expression through a direct MIR34A-binding site within the HMGB1 3' untranslated region. MIR34A inhibition of HMGB1 leads to a decrease in autophagy under starvation conditions or chemotherapy treatment. Inhibition of autophagy promotes oxidative injury and DNA damage and increases subsequent CASP3 activity, CASP3 cleavage, and PARP1 [poly (ADP-ribose) polymerase 1] cleavage, which are important to the apoptotic process. Finally, upregulation of MIR34A, knockdown of HMGB1, or inhibition of autophagy (e.g., knockdown of ATG5 and BECN1) restores chemosensitivity and enhances tumor cell death in the retinoblastoma cell. These data provide new insights into the mechanisms governing the regulation of HMGB1 expression by microRNA and their possible contribution to autophagy and drug resistance.
authors.affiliation: Department of Ophthalmology; The Second Xiangya Hospital; Central South University; Hunan, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Orthopedics; The Second Xiangya Hospital; Central South University; Hunan, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Pediatrics; Xiangya Hospital; Central South University; Changsha, Hunan China.
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Pediatrics; Xiangya Hospital; Central South University; Changsha, Hunan China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Pediatrics; Xiangya Hospital; Central South University; Changsha, Hunan China.
authors.forename: Shan
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Surgery; Hillman Cancer Center; University of Pittsburgh Cancer Institute; Pittsburgh, PA USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Kang
authors.affiliation: Department of Pediatrics; Xiangya Hospital; Central South University; Changsha, Hunan China.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Surgery; Hillman Cancer Center; University of Pittsburgh Cancer Institute; Pittsburgh, PA USA.
authors.forename: Daolin
authors.initials: D
authors.lastname: Tang
authors.affiliation: Department of Ophthalmology; The Second Xiangya Hospital; Central South University; Hunan, China.
authors.forename: Xuanchu
authors.initials: X
authors.lastname: Duan
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D012175:Retinoblastoma / Q000235:genetics / Q000378:metabolism*; D013217:Starvation / Q000235:genetics; D015854:Up-Regulation
chemical_list: D024243:HMGB1 Protein; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C505407:CASP3 protein, human; D053148:Caspase 3
keywords: Hmbg1; apoptosis; autophagy; chemotherapy; microRNA