Neuroplastin-β mediates S100A8/A9-induced lung cancer disseminative progression

I. Wayan Sumardika; Youyi Chen; Nahoko Tomonobu; Rie Kinoshita; I. Made Winarsa Ruma; Hiroki Sato; Eisaku Kondo; Yusuke Inoue; Akira Yamauchi; Hitoshi Murata; Ken ichi Yamamoto; Shuta Tomida; Kazuhiko Shien; Hiromasa Yamamoto; Junichi Sou; Junichiro Futami; Endy Widya Putranto; Toshihiko Hibino; Masahiro Nishibori; Shinichi Toyooka; Masakiyo Sakaguchi

doi:10.1002/mc.22987

Neuroplastin-β mediates S100A8/A9-induced lung cancer disseminative progression

I. Wayan Sumardika, Youyi Chen, Nahoko Tomonobu, Rie Kinoshita, I. Made Winarsa Ruma, Hiroki Sato, Eisaku Kondo, Yusuke Inoue, Akira Yamauchi, Hitoshi Murata, Ken ichi Yamamoto, Shuta Tomida, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Sou, Junichiro Futami, Endy Widya Putranto, Toshihiko Hibino, Masahiro Nishibori, Shinichi ToyookaMasakiyo Sakaguchi

Research output: Contribution to journal › Article › peer-review

16 Citations (Scopus)

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.

Original language	English
Pages (from-to)	980-995
Number of pages	16
Journal	Molecular Carcinogenesis
Volume	58
Issue number	6
DOIs	https://doi.org/10.1002/mc.22987
Publication status	Published - Jun 2019

Keywords

NFI
NPTNβ
S100 protein
S100A8/A9
SPDEF
lung cancer

ASJC Scopus subject areas

Molecular Biology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/mc.22987

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Sumardika, I. W., Chen, Y., Tomonobu, N., Kinoshita, R., Ruma, I. M. W., Sato, H., Kondo, E., Inoue, Y., Yamauchi, A., Murata, H., Yamamoto, K. I., Tomida, S., Shien, K., Yamamoto, H., Sou, J., Futami, J., Putranto, E. W., Hibino, T., Nishibori, M., ... Sakaguchi, M. (2019). Neuroplastin-β mediates S100A8/A9-induced lung cancer disseminative progression. Molecular Carcinogenesis, 58(6), 980-995. https://doi.org/10.1002/mc.22987

Sumardika, IW, Chen, Y, Tomonobu, N , Kinoshita, R, Ruma, IMW, Sato, H, Kondo, E, Inoue, Y, Yamauchi, A, Murata, H , Yamamoto, KI , Tomida, S , Shien, K , Yamamoto, H, Sou, J, Futami, J, Putranto, EW, Hibino, T, Nishibori, M , Toyooka, S & Sakaguchi, M 2019, 'Neuroplastin-β mediates S100A8/A9-induced lung cancer disseminative progression', Molecular Carcinogenesis, vol. 58, no. 6, pp. 980-995. https://doi.org/10.1002/mc.22987

@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",

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TY - JOUR

T1 - Neuroplastin-β mediates S100A8/A9-induced lung cancer disseminative progression

AU - Sumardika, I. Wayan

AU - Chen, Youyi

AU - Tomonobu, Nahoko

AU - Kinoshita, Rie

AU - Ruma, I. Made Winarsa

AU - Sato, Hiroki

AU - Kondo, Eisaku

AU - Inoue, Yusuke

AU - Yamauchi, Akira

AU - Murata, Hitoshi

AU - Yamamoto, Ken ichi

AU - Tomida, Shuta

AU - Shien, Kazuhiko

AU - Yamamoto, Hiromasa

AU - Sou, Junichi

AU - Futami, Junichiro

AU - Putranto, Endy Widya

AU - Hibino, Toshihiko

AU - Nishibori, Masahiro

AU - Toyooka, Shinichi

AU - Sakaguchi, Masakiyo

N1 - 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: © 2019 Wiley Periodicals, Inc.

PY - 2019/6

Y1 - 2019/6

N2 - 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.

AB - 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.

KW - NFI

KW - NPTNβ

KW - S100 protein

KW - S100A8/A9

KW - SPDEF

KW - lung cancer

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Neuroplastin-β mediates S100A8/A9-induced lung cancer disseminative progression

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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