title: miR-23b-3p regulates the chemoresistance of gastric cancer cells by targeting ATG12 and HMGB2.
abstract: Chemotherapy is an important treatment modality for gastric cancer (GC); however, it usually fails because of drug resistance, especially multidrug resistance (MDR). Previously, we found a novel subset of MDR-associated microRNAs (miRNAs) through high-throughput functional screening. In this report, we investigated the exact roles and mechanisms of miR-23b-3p in the MDR of GC. Using gain or loss-of-function in in vitro and in vivo experiments, we found that overexpression of miR-23b-3p reversed cancer cell resistance to multiple chemotherapeutics in vitro and sensitize tumors to chemotherapy in vivo. Reporter gene assay and western blot analysis showed that ATG12 and HMGB2 were the direct targets of miR-23b-3p. Meanwhile, ATG12 and HMGB2 were positively associated with the occurrence of autophagy. Reducing the expression of these target genes by siRNA or inhibition of autophagy both sensitized GC cells to chemotherapy. These findings suggest that a miR-23b-3p/ATG12/HMGB2/autophagy-regulatory loop has a critical role in MDR in GC. In addition, miR-23b-3p could be used as a prognostic factor for overall survival in GC. In conclusion, our data demonstrated that miR-23b-3p inhibited autophagy mediated by ATG12 and HMGB2 and sensitized GC cells to chemotherapy, and suggested the potential application of miR-23b-3p in drug resistance prediction and treatment.
authors.affiliation: 1] State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 127 Changle Western Road, Xi'an, Shaanxi 710032, China [2] Department of General Surgery, General Hospital of Jinan Military Command, Jinan, China [3] Department of Biochemistry and Molecular Biology, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, Zhejiang 315211, China.
authors.forename: Y
authors.initials: Y
authors.lastname: An
authors.affiliation: 1] State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 127 Changle Western Road, Xi'an, Shaanxi 710032, China [2] Department of Biochemistry and Molecular Biology, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, Zhejiang 315211, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: 1] State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 127 Changle Western Road, Xi'an, Shaanxi 710032, China [2] Department of Biochemistry and Molecular Biology, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, Zhejiang 315211, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Shang
authors.affiliation: 1] State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 127 Changle Western Road, Xi'an, Shaanxi 710032, China [2] Department of Biochemistry and Molecular Biology, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, Zhejiang 315211, China.
authors.forename: X
authors.initials: X
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 127 Changle Western Road, Xi'an, Shaanxi 710032, China.
authors.forename: J
authors.initials: J
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 127 Changle Western Road, Xi'an, Shaanxi 710032, China.
authors.forename: P
authors.initials: P
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 127 Changle Western Road, Xi'an, Shaanxi 710032, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Nie
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 127 Changle Western Road, Xi'an, Shaanxi 710032, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhao
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D001343:Autophagy / Q000235:genetics; D000071192:Autophagy-Related Protein 12; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005472:Fluorouracil / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D024261:HMGB2 Protein / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics*; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014750:Vincristine / Q000627:therapeutic use
chemical_list: C466624:ATG12 protein, human; D000970:Antineoplastic Agents; D000071192:Autophagy-Related Protein 12; D024261:HMGB2 Protein; C552430:MIRN23a microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D025841:Small Ubiquitin-Related Modifier Proteins; D014750:Vincristine; D005472:Fluorouracil