title: Loss of YAP1 defines neuroendocrine differentiation of lung tumors.
abstract: YAP1, the main Hippo pathway effector, is a potent oncogene and is overexpressed in non-small-cell lung cancer (NSCLC); however, the YAP1 expression pattern in small-cell lung cancer (SCLC) has not yet been elucidated in detail. We report that the loss of YAP1 is a special feature of high-grade neuroendocrine lung tumors. A hierarchical cluster analysis of 15 high-grade neuroendocrine tumor cell lines containing 14 SCLC cell lines that depended on the genes of Hippo pathway molecules and neuroendocrine markers clearly classified these lines into two groups: the YAP1-negative and neuroendocrine marker-positive group (n = 11), and the YAP1-positive and neuroendocrine marker-negative group (n = 4). Among the 41 NSCLC cell lines examined, the loss of YAP1 was only observed in one cell line showing the strong expression of neuroendocrine markers. Immunostaining for YAP1, using the sections of 189 NSCLC, 41 SCLC, and 30 large cell neuroendocrine carcinoma (LCNEC) cases, revealed that the loss of YAP1 was common in SCLC (40/41, 98%) and LCNEC (18/30, 60%), but was rare in NSCLC (6/189, 3%). Among the SCLC and LCNEC cases tested, the loss of YAP1 correlated with the expression of neuroendocrine markers, and a survival analysis revealed that YAP1-negative cases were more chemosensitive than YAP1-positive cases. Chemosensitivity test for cisplatin using YAP1-positive/YAP1-negative SCLC cell lines also showed compatible results. YAP1-sh-mediated knockdown induced the neuroendocrine marker RAB3a, which suggested the possible involvement of YAP1 in the regulation of neuroendocrine differentiation. Thus, we showed that the loss of YAP1 has potential as a clinical marker for predicting neuroendocrine features and chemosensitivity.
authors.affiliation: Molecular Pathology Laboratory, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ito
authors.affiliation: Molecular Pathology Laboratory, Institute of Medical Science, University of Tokyo, Tokyo, Japan. vzv07574@nifty.com.|Department of Integrative Pathology, Jichi Medical University, Tochigi, Japan. vzv07574@nifty.com.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Matsubara
authors.affiliation: Division of Molecular Oncology, Aichi Cancer Center Research Institute, Aichi, Japan.
authors.forename: Ichidai
authors.initials: I
authors.lastname: Tanaka
authors.affiliation: Molecular Pathology Laboratory, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Kanae
authors.initials: K
authors.lastname: Makiya
authors.affiliation: Molecular Pathology Laboratory, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Zen-Ichi
authors.initials: ZI
authors.lastname: Tanei
authors.affiliation: Molecular Pathology Laboratory, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kumagai
authors.affiliation: Molecular Pathology Laboratory, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Shu-Jen
authors.initials: SJ
authors.lastname: Shiu
authors.affiliation: Molecular Pathology Laboratory, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Hiroki J
authors.initials: HJ
authors.lastname: Nakaoka
authors.affiliation: Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shumpei
authors.initials: S
authors.lastname: Ishikawa
authors.affiliation: Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Isagawa
authors.affiliation: Department of Human Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.affiliation: Department of Human Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Shinozaki-Ushiku
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Goto
authors.affiliation: Department of Thoracic Surgery, Jichi Medical University, Tochigi, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nakano
authors.affiliation: Department of Thoracic Surgery, University of Tokyo, Tokyo, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Tsuchiya
authors.affiliation: Department of Thoracic Surgery, Jichi Medical University Saitama Medical Center, Saitama, Japan.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Tsubochi
authors.affiliation: Division of Genome Science, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Komura
authors.affiliation: Division of Genome Science, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.affiliation: Department of Pathology, Jichi Medical University Saitama Medical Center, Saitama, Japan.
authors.forename: Yoh
authors.initials: Y
authors.lastname: Dobashi
authors.affiliation: Department of Thoracic Surgery, University of Tokyo, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Nakajima
authors.affiliation: Department of Thoracic Surgery, Jichi Medical University, Tochigi, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Endo
authors.affiliation: Department of Human Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.affiliation: Division of Molecular Oncology, Aichi Cancer Center Research Institute, Aichi, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sekido
authors.affiliation: Department of Integrative Pathology, Jichi Medical University, Tochigi, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Niki
authors.affiliation: Molecular Pathology Laboratory, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Murakami
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D016000:Cluster Analysis; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D056726:Genetic Association Studies; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D060787:Neoplasm Grading; D018358:Neuroendocrine Tumors / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D010750:Phosphoproteins / Q000172:deficiency*; D014157:Transcription Factors; D059467:Transcriptome; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D002945:Cisplatin
keywords: Chemosensitivity; Hippo pathway; YAP1; neuroendocrine differentiation; small-cell lung cancer