title: Oct4 plays a crucial role in the maintenance of gefitinib-resistant lung cancer stem cells.
abstract: Several recent studies have suggested that cancer stem cells (CSCs) are involved in resistance to gefitinib in non-small cell lung cancer (NSCLC). Oct4, a member of the POU-domain transcription factor family, has been shown to be involved in CSC properties of various cancers. We previously reported that Oct4 and the putative lung CSC marker CD133 were highly expressed in gefitinib-resistant persisters (GRPs) in NSCLC cells, and GRPs exhibited characteristic features of the CSCs phenotype. The aim of this study was to elucidate the role of Oct4 in the resistance to gefitinib in NSCLC cells with an activating epidermal growth factor receptor (EGFR) mutation. NSCLC cell lines, PC9, which express the EGFR exon 19 deletion mutation, were transplanted into NOG mice, and were treated with gefitinib in vivo. After 14-17 days of gefitinib treatment, the tumors still remained; these tumors were referred to as gefitinib-resistant tumors (GRTs). PC9-GRTs showed higher expression of Oct4 and CD133. To investigate the role of Oct4 in the maintenance of gefitinib-resistant lung CSCs, we introduced the Oct4 gene into PC9 and HCC827 cells carrying an activating EGFR mutation by lentiviral infection. Transfection of Oct4 significantly increased CD133-positive GRPs and the number of sphere formation, reflecting the self-renewal activity, of PC9 and HCC827 cells under the high concentration of gefitinib in vitro. Furthermore, Oct4-overexpressing PC9 cells (PC9-Oct4) significantly formed tumors at 1 × 10 cells/injection in NOG mice as compared to control cells. In addition, PC9-Oct4 tumors were more resistant to gefitinib treatment as compared to control cells in vivo. Finally, immunohistochemical analysis revealed that Oct4 was highly expressed in tumor specimens of EGFR-mutant NSCLC patients with acquired resistance to gefitinib. Collectively, these findings suggest that Oct4 plays a pivotal role in the maintenance of lung CSCs resistant to gefitinib in EGFR mutation-positive NSCLC.
authors.affiliation: Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Kobayashi
authors.affiliation: Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan. Electronic address: fumiyuki@dol.hi-ho.ne.jp.
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Takahashi
authors.affiliation: Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan.
authors.forename: Fariz
authors.initials: F
authors.lastname: Nurwidya
authors.affiliation: Department of Molecular and Cellular Parasitology, Juntendo University, Graduate School of Medicine, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nara
authors.affiliation: Department of Molecular and Cellular Parasitology, Juntendo University, Graduate School of Medicine, Tokyo, Japan.
authors.forename: Muneaki
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Murakami
authors.affiliation: Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan.
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Yagishita
authors.affiliation: Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Tajima
authors.affiliation: Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan.
authors.forename: Moulid
authors.initials: M
authors.lastname: Hidayat
authors.affiliation: Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Leading Center for the Development and Research of Cancer Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Shimada
authors.affiliation: Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Suina
authors.affiliation: Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Yoshioka
authors.affiliation: Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sasaki
authors.affiliation: Pharmaceutical Research and Technology Institute, Kinki University, School of Medicine, Osaka, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Moriyama
authors.affiliation: Pharmaceutical Research and Technology Institute, Kinki University, School of Medicine, Osaka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Moriyama
authors.affiliation: Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Leading Center for the Development and Research of Cancer Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Takahashi
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics; D005091:Exons; D005260:Female; D000077156:Gefitinib; D017353:Gene Deletion; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D008856:Microscopy, Fluorescence; D009154:Mutation; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000502:physiology*; D010455:Peptides / Q000378:metabolism; D010641:Phenotype; D011799:Quinazolines / Q000737:chemistry*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D000970:Antineoplastic Agents; D006023:Glycoproteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: Cancer stem cell; Gefitinib resistance; NSCLC; Oct4