Open AccessLoss of YAP 1 defines neuroendocrine differentiation of lung tumors
Author(s) -
Ito Takeshi,
Matsubara Daisuke,
Tanaka Ichidai,
Makiya Kanae,
Tanei Zenichi,
Kumagai Yuki,
Shiu ShuJen,
Nakaoka Hiroki J.,
Ishikawa Shumpei,
Isagawa Takayuki,
Morikawa Teppei,
ShinozakiUshiku Aya,
Goto Yasushi,
Nakano Tomoyuki,
Tsuchiya Takehiro,
Tsubochi Hiroyoshi,
Komura Daisuke,
Aburatani Hiroyuki,
Dobashi Yoh,
Nakajima Jun,
Endo Shunsuke,
Fukayama Masashi,
Sekido Yoshitaka,
Niki Toshiro,
Murakami Yoshinori
Publication year - 2016
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13013
Subject(s) - small cell lung carcinoma , hippo signaling pathway , neuroendocrine tumors , cancer research , neuroendocrine differentiation , biology , immunostaining , oncogene , medicine , pathology , lung cancer , cancer , immunohistochemistry , small cell carcinoma , effector , immunology , cell cycle , prostate cancer
YAP 1 , the main Hippo pathway effector, is a potent oncogene and is overexpressed in non‐small‐cell lung cancer ( NSCLC ); however, the YAP 1 expression pattern in small‐cell lung cancer ( SCLC ) has not yet been elucidated in detail. We report that the loss of YAP 1 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 YAP 1 ‐negative and neuroendocrine marker‐positive group ( n = 11), and the YAP 1 ‐positive and neuroendocrine marker‐negative group ( n = 4). Among the 41 NSCLC cell lines examined, the loss of YAP 1 was only observed in one cell line showing the strong expression of neuroendocrine markers. Immunostaining for YAP 1, using the sections of 189 NSCLC , 41 SCLC , and 30 large cell neuroendocrine carcinoma ( LCNEC ) cases, revealed that the loss of YAP 1 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 YAP 1 correlated with the expression of neuroendocrine markers, and a survival analysis revealed that YAP 1‐negative cases were more chemosensitive than YAP 1‐positive cases. Chemosensitivity test for cisplatin using YAP 1‐positive/ YAP 1‐negative SCLC cell lines also showed compatible results. YAP 1 ‐sh‐mediated knockdown induced the neuroendocrine marker RAB 3a , which suggested the possible involvement of YAP 1 in the regulation of neuroendocrine differentiation. Thus, we showed that the loss of YAP 1 has potential as a clinical marker for predicting neuroendocrine features and chemosensitivity.