Journal
MOLECULAR CARCINOGENESIS
Volume 58, Issue 6, Pages 980-995Publisher
WILEY
DOI: 10.1002/mc.22987
Keywords
lung cancer; NFI; NPTN; S100 protein; S100A8; A9; SPDEF
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Funding
- Project for Cancer Research and Therapeutic Evolution (P-CREATE) from the Japan Agency for Medical Research and Development (AMED) [JP17cm0106216]
- Takeda Science Foundation
- JSPS KAKENHI [17H03577]
- Princess Takamatsu Cancer Research Fund
- Kobayashi Foundation for Cancer Research
- Fujii Memorial Medical Science Foundation
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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- (NPTN), 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 NPTN showed significantly high expression levels in lung cancer cell lines in a consistent manner. We hence aimed to determine the significance of NPTN as an S100A8/A9 receptor in lung cancer. Our results showed that NPTN 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 NPTN 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-NPTN 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.
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