title: miR-634 Activates the Mitochondrial Apoptosis Pathway and Enhances Chemotherapy-Induced Cytotoxicity.
abstract: Some tumor-suppressing miRNAs target multiple oncogenes concurrently and therefore may be useful as cancer therapeutic agents. Further, such miRNAs may be useful to address chemotherapeutic resistance in cancer, which remains a primary clinical challenge in need of solutions. Thus, cytoprotective processes upregulated in cancer cells that are resistant to chemotherapy are a logical target for investigation. Here, we report that overexpression of miR-634 activates the mitochondrial apoptotic pathway by direct concurrent targeting of genes associated with mitochondrial homeostasis, antiapoptosis, antioxidant ability, and autophagy. In particular, we show how enforced expression of miR-634 enhanced chemotherapy-induced cytotoxicity in a model of esophageal squamous cell carcinoma, where resistance to chemotherapy remains clinically problematic. Our findings illustrate how reversing miR-634-mediated cytoprotective processes may offer a broadly useful approach to improving cancer therapy.
authors.affiliation: Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo, Japan. Department of Esophageal and General Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Fujiwara
authors.affiliation: Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Inoue
authors.affiliation: Department of Esophageal and General Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tatsuyuki
authors.initials: T
authors.lastname: Kawano
authors.affiliation: Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Tanimoto
authors.affiliation: Department of Dental Pharmacology, Graduate School, Okayama University, Okayama, Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Kozaki
authors.affiliation: Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo, Japan. Department of Genome Medicine, Hard Tissue Genome Research Center, Tokyo Medical and Dental University, Tokyo, Japan. Bioresource Research Center, Tokyo Medical and Dental University, Tokyo, Japan. johinaz.cgen@mri.tmd.ac.jp.
authors.forename: Johji
authors.initials: J
authors.lastname: Inazawa
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics*; D001343:Autophagy / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000628:therapy; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D015316:Genetic Therapy; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000627:therapeutic use; D008928:Mitochondria / Q000502:physiology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D001678:Organelle Biogenesis; D018384:Oxidative Stress; D012334:RNA, Neoplasm / Q000235:genetics* / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D017382:Reactive Oxygen Species; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; C000599270:MIRN-634 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D002945:Cisplatin