RRC ID 64556
Author Ito T, Matsubara D, Tanaka I, Makiya K, Tanei ZI, Kumagai Y, Shiu SJ, Nakaoka HJ, Ishikawa S, Isagawa T, Morikawa T, Shinozaki-Ushiku A, Goto Y, Nakano T, Tsuchiya T, Tsubochi H, Komura D, Aburatani H, Dobashi Y, Nakajima J, Endo S, Fukayama M, Sekido Y, Niki T, Murakami Y.
Title Loss of YAP1 defines neuroendocrine differentiation of lung tumors.
Journal Cancer Sci
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.
Volume 107(10)
Pages 1527-1538
Published 2016-10-1
DOI 10.1111/cas.13013
PMID 27418196
PMC PMC5084673
MeSH Adaptor Proteins, Signal Transducing / deficiency* Animals Antineoplastic Agents / pharmacology Biomarkers, Tumor Cell Line, Tumor Cisplatin / pharmacology Cluster Analysis Disease Models, Animal Drug Resistance, Neoplasm / genetics Female Gene Expression Profiling Gene Expression Regulation, Neoplastic Gene Knockdown Techniques Genetic Association Studies Heterografts Humans Immunohistochemistry Lung Neoplasms / drug therapy Lung Neoplasms / genetics* Lung Neoplasms / pathology* Male Mice Neoplasm Grading Neuroendocrine Tumors / drug therapy Neuroendocrine Tumors / genetics* Neuroendocrine Tumors / pathology* Phosphoproteins / deficiency* Transcription Factors Transcriptome YAP-Signaling Proteins
IF 4.966
Human and Animal Cells LC-2/ad(RCB0440)