@article{87562cae13194c8082d12ae34b0c2a06,
title = "Neuroplastin-β mediates S100A8/A9-induced lung cancer disseminative progression",
abstract = "Compiling evidence indicates an unusual role of extracellular S100A8/A9 in cancer metastasis. S100A8/A9 secreted from either cancer cells or normal cells including epithelial and inflammatory cells stimulates cancer cells through S100A8/A9 sensor receptors in an autocrine or paracrine manner, leading to cancer cell metastatic progression. We previously reported a novel S100A8/A9 receptor, neuroplastin-β (NPTNβ), which plays a critical role in atopic dermatitis when it is highly activated in keratinocytes by an excess amount of extracellular S100A8/A9 in the inflammatory skin lesion. Interestingly, our expression profiling of NPTNβ showed significantly high expression levels in lung cancer cell lines in a consistent manner. We hence aimed to determine the significance of NPTNβ as an S100A8/A9 receptor in lung cancer. Our results showed that NPTNβ has strong ability to induce cancer-related cellular events, including anchorage-independent growth, motility and invasiveness, in lung cancer cells in response to extracellular S100A8/A9, eventually leading to the expression of a cancer disseminative phenotype in lung tissue in vivo. Mechanistic investigation revealed that binding of S100A8/A9 to NPTNβ mediates activation of NFIA and NFIB and following SPDEF transcription factors through orchestrated upstream signals from TRAF2 and RAS, which is linked to anchorage-independent growth, motility and invasiveness. Overall, our results indicate the importance of the S100A8/A9-NPTNβ axis in lung cancer disseminative progression and reveal a pivotal role of its newly identified downstream signaling, TRAF2/RAS-NFIA/NFIB-SPDEF, in linking to the aggressive development of lung cancers.",
keywords = "NFI, NPTNβ, S100 protein, S100A8/A9, SPDEF, lung cancer",
author = "Sumardika, {I. Wayan} and Youyi Chen and Nahoko Tomonobu and Rie Kinoshita and Ruma, {I. Made Winarsa} and Hiroki Sato and Eisaku Kondo and Yusuke Inoue and Akira Yamauchi and Hitoshi Murata and Yamamoto, {Ken ichi} and Shuta Tomida and Kazuhiko Shien and Hiromasa Yamamoto and Junichi Sou and Junichiro Futami and Putranto, {Endy Widya} and Toshihiko Hibino and Masahiro Nishibori and Shinichi Toyooka and Masakiyo Sakaguchi",
note = "Funding Information: This research was supported in part by the Project for Cancer Research and Therapeutic Evolution (P-CREATE) from the Japan Agency for Medical Research and Development (AMED, Grant Number JP17cm0106216) to MS., JSPS KAKENHI (Grant Number 17H03577) to MS., Takeda Science Foundation to MS., Princess Takamatsu Cancer Research Fund to MS., Kobayashi Foundation for Cancer Research to MS., and Fujii Memorial Medical Science Foundation to MS. Funding Information: IWS, HM, and MS were involved in conceptual guidance and data interpretation. IWS and MS wrote the manuscript. IWS performed in vitro experiments and WB. MS performed plasmid DNA construction, EMSA and WB. RK performed bioinformatics analysis of RNAseq data and protein purification. IWS, NT, and HS performed animal study. YI and ST performed RT-PCR and RNA seq analysis. EK provided clinical samples and performed IHC. JF, HM, RK and KiY prepared the S100A8/A9 recombinant protein. AY, KS, HY and JS prepared and performed HE staining of the animal tissue. YC, IMW, and EWP performed the confirmation of the in vitro experimental results. ST, TH and MN provided a critical review of the manuscript. MS proposed and supervised the study. All authors read and approved the manuscript. This research was supported in part by the Project for Cancer Research and Therapeutic Evolution (P-CREATE) from the Japan Agency for Medical Research and Development (AMED, Grant Number JP17cm0106216) to MS., JSPS KAKENHI (Grant Number 17H03577) to MS., Takeda Science Foundation to MS., Princess Takamatsu Cancer Research Fund to MS., Kobayashi Foundation for Cancer Research to MS., and Fujii Memorial Medical Science Foundation to MS. Funding Information: the Project for Cancer Research and Therapeutic Evolution (P-CREATE) from the Japan Agency for Medical Research and Development (AMED), Grant number: JP17cm0106216; Takeda Science Foundation; JSPS KAKENHI, Grant number: 17H03577; Princess Takamatsu Cancer Research Fund; Kobayashi Foundation for Cancer Research; Fujii Memorial Medical Science Foundation Publisher Copyright: {\textcopyright} 2019 Wiley Periodicals, Inc.",
year = "2019",
month = jun,
doi = "10.1002/mc.22987",
language = "English",
volume = "58",
pages = "980--995",
journal = "Molecular Carcinogenesis",
issn = "0899-1987",
publisher = "Wiley-Liss Inc.",
number = "6",
}
