title: Repression of Smad3 by Stat3 and c-Ski/SnoN induces gefitinib resistance in lung adenocarcinoma.
abstract: Cancer-associated inflammation develops resistance to the epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancers (NSCLCs) harboring oncogenic EGFR mutations. Stat3-mediated interleukin (IL)-6 signaling and Smad-mediated transforming growth factor-β (TGF-β) signaling pathways play crucial regulatory roles in cancer-associated inflammation. However, mechanisms how these pathways regulate sensitivity and resistance to EGFR-TKI in NSCLCs remain largely undetermined. Here we show that signal transducer and activator of transcription (Stat)3 represses Smad3 in synergy with the potent negative regulators of TGF-β signaling, c-Ski and SnoN, whereby renders gefitinib-sensitive HCC827 cells resistant. We found that IL-6 signaling via phosphorylated Stat3 induced gefitinib resistance as repressing transcription of Smad3, whereas TGF-β enhanced gefitinib sensitivity as activating transcription of Smad3 in HCC827 cells with gefitinib-sensitizing EGFR mutation. Promoter analyses showed that Stat3 synergized with c-Ski/SnoN to repress Smad2/3/4-induced transcription of the Smad3 gene. Smad3 was found to be an apoptosis inducer, which upregulated pro-apoptotic genes such as caspase-3 and downregulated anti-apoptotic genes such as Bcl-2. Our results suggest that derepression of Smad3 can be a therapeutic strategy to prevent gefitinib-resistance in NSCLCs with gefitinib-sensitizing EGFR mutation.
authors.affiliation: Department of Surgery, Tokyo Medical University, Tokyo, Japan.
authors.forename: Yojiro
authors.initials: Y
authors.lastname: Makino
authors.affiliation: Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan; Biomedical Research Institute, Kyungpook National University Hospital, Daegu, Republic of Korea.
authors.forename: Jeong-Hwan
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Eunjin
authors.initials: E
authors.lastname: Bae
authors.affiliation: Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
authors.forename: Mitsuyasu
authors.initials: M
authors.lastname: Kato
authors.affiliation: Departments of Biochemistry, University of Yamanashi, Yamanashi, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Miyazawa
authors.affiliation: Department of Surgery, Tokyo Medical University, Tokyo, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Ohira
authors.affiliation: Department of Surgery, Tokyo Medical University, Tokyo, Japan.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Ikeda
authors.affiliation: Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kuroda
authors.affiliation: Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan; Biomedical Research Institute, Kyungpook National University Hospital, Daegu, Republic of Korea; Physician, Student and Researcher Support Center, Tokyo Medical University, Tokyo, Japan. Electronic address: mamumik@tokyo-med.ac.jp.
authors.forename: Mizuko
authors.initials: M
authors.lastname: Mamura
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology*; D066246:ErbB Receptors / Q000235:genetics; D000077156:Gefitinib; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D011799:Quinazolines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; C060615:SKIL protein, human; C497790:SMAD3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051900:Smad3 Protein; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: Cell cycle; Gefitinib resistance; Lung cancer; Smad3; Stat3; c-Ski/SnoN