NOVEL ONCOGENIC ROLE FOR NFIA IN GLIOMA
NEURO-ONCOLOGY
Authors: Hoxha, Edlira; Andreas, Kloetgen; Song, Hae-Ri
Abstract
Neuroplastin- mediates S100A8/A9-induced lung cancer disseminative progression
MOLECULAR CARCINOGENESIS
Authors: Sumardika, I. Wayan; Chen, Youyi; Tomonobu, Nahoko; Kinoshita, Rie; Ruma, I. Made Winarsa; Sato, Hiroki; Kondo, Eisaku; Inoue, Yusuke; Yamauchi, Akira; Murata, Hitoshi; Yamamoto, Ken-ichi; Tomida, Shuta; Shien, Kazuhiko; Yamamoto, Hiromasa; Soh, Junichi; Futami, Junichiro; Putranto, Endy Widya; Hibino, Toshihiko; Nishibori, Masahiro; Toyooka, Shinichi; Sakaguchi, Masakiyo
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- (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.