title: Chemotherapy-Regulated microRNA-125-HER2 Pathway as a Novel Therapeutic Target for Trastuzumab-Mediated Cellular Cytotoxicity in Small Cell Lung Cancer.
abstract: Small cell lung cancer (SCLC) accounts for 15% of all lung cancer cases and is a highly lethal disease. For the last several decades, the standard treatment for SCLC has been deadlocked, and new therapeutic strategies are urgently needed. HER2 is a member of the HER family and has been reported to be overexpressed in 30% of SCLC cases with poor prognosis. However, the clinical relevance of HER2-targeted therapy for SCLC remains unclear. Here, we first identify that cytotoxic drugs induce significant HER2 overexpression through microRNA-125a (miR-125a) and miR-125b downregulation, which in turn act as a novel therapeutic target for trastuzumab-mediated cellular cytotoxicity in SCLC. In this study, we showed that treatment of the HER2-positive SCLC cells, SBC-3 and SBC-5, with cytotoxic drugs induced a significant upregulation of HER2. Cisplatin (CDDP) treatment of SCLC cells resulted in a significant downregulation of miR-125a and miR-125b. We confirmed that miR-125a and miR-125b bound to the 3'-untranslated regions of HER2 mRNA, and that downregulation of miR-125a and miR-125b resulted in upregulation of HER2 in SCLC cells, suggesting a relationship between cytotoxic drug exposure and miR-125/HER2 dysregulation. Furthermore, using a calcein assay, we demonstrated a significantly enhanced cytotoxic effect of CDDP and trastuzumab that was mediated via antibody-dependent cellular cytotoxicity. Finally, we clearly demonstrated the enhanced antitumor effect of these agents in an orthotopic lung cancer model in vivo. Our results offer a novel therapeutic strategy for HER2-positive SCLCs by using trastuzumab combined with cytotoxic drugs.
authors.affiliation: Shien-Lab, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan. Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Yagishita
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo, Japan. Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Nishi-shinbashi, Minato-ku, Tokyo, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Shien-Lab, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan. Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Kitazono
authors.affiliation: Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Ko
authors.affiliation: Shien-Lab, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakadate
authors.affiliation: Shien-Lab, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sawada
authors.affiliation: Shien-Lab, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kitamura
authors.affiliation: Department of Chemotherapy, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Bunkyo-ku, Tokyo, Japan.
authors.forename: Tatsu
authors.initials: T
authors.lastname: Shimoyama
authors.affiliation: Department of Chemotherapy, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Takahashi
authors.affiliation: Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan.
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
authors.affiliation: Shien-Lab, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan. Department of Laboratory Medicine and Division of Clinical Research Support, Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, Bunkyo-ku, Tokyo, Japan. fkoizumi@cick.jp.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Koizumi
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D008297:Male; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000068878:Trastuzumab / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; D002945:Cisplatin; D035683:MicroRNAs; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C531888:MIRN125 microRNA, human