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.

Calprotectin in Lung Diseases

“…From a pathophysiological and genetic point of view, CLP has been identified as a potent promoter of tumor-mediated immune remodeling. The S100A8/A9 protein acting via specific receptors on the cancer cell surface and increase the nuclear factor kappa B (NF-kB)-dependent transcriptional activity; thus, actively participating in immune modulation responses and inflammation, which play essential roles in the tumor growth and progression [5,142,143,[145][146][147][148][149][150][151][152][153]. More specifically, the activation of NF-kB in tumor cells enhances the expression of several genes (including Ccl7, Cxcl1, Ccl5, Slc39a10, Lcn2, Zc3h12a, and Enpp2) that are implicated in tumor migration, angiogenesis, and formation of pre-metastatic niches [5,148,149].…”

“…Furthermore, the S100A8/A9 receptor neuroplastin-β (A9-NPTNβ) axis in lung cancer has been implicated in the disseminative progression. A newly identified downstream signaling pathway has been described, constituting by tumor necrosis factor (TNF) receptorassociated factor 2 (TRAF2) adaptor, nuclear factor (NF)IA/NFIB heterodimer transcription factor, and SAM pointed-domain containing ETS transcription factor (SPDEF) (TRAF2/RAS-NFIA/NFIB-SPDEF), in linking to the aggressive development of lung cancers [151].…”

Neuroplastin expression is essential for hearing and hair cell PMCA expression

“…Polymorphisms in the regulatory region of the human NPTN gene correlate with cortical thickness and intellectual abilities in adolescents (Desrivières et al 2014) and were detected in individuals suffering from schizophrenia (Saito et al 2007). Recently, the NPTN gene has been associated with heart rate (Choy et al 2018) and lung cancer (Sumardika et al 2019). Expression of the 65 kD neuroplastin (Np65) isoform derived by alternative splicing from the Nptn gene is restricted to brain neurons, whereas the 55 kD isoform (Np55) is present in most cell types but not e.g.…”

“…in glia (Langnaese et al 1997). Neuroplastin has been shown to interact as a ligand with the fibroblast growth factor (FGF) receptor (Owczarek et al 2010), gamma-aminobutyric acid type A (GABAA) receptors (Sarto-Jackson et al 2012), S100A8/A9, basigin (Sakaguchi et al 2016;Sumardika et al 2019), mesencephalic astrocyte-derived neurotrophic factor (MANF) (Yagi et al 2020), tumor necrosis factor receptor-associated factor 6 (TRAF6) (Vemula et al 2020), and with itself undergoing homophilic binding (Langnaese et al 1997;Owczarek et al 2010). Furthermore, plasma membrane trafficking of monocarboxylic acid transporter 2 (MCT-2, SLC16A7) and XK-related protein 8 (Xkr8) may require neuroplastin as chaperone (Wilson et al 2013;Suzuki et al 2016).…”

Histidine-Rich Glycoprotein Stimulates Human Neutrophil Phagocytosis and Prolongs Survival through CLEC1A

“…The HEK293T cell-originated clones, HEK293T-CLEC1A (wild type [wt]) or HEK293T-CLEC1A (Dcyt; a deletion variant of the N-terminal cytoplasmic region [45 aa] of CLEC1A), which permanently express CLEC1A (wt) or CLEC1A (Dcyt) protein, were established by a convenient electroporation gene delivery method using our original plasmid, pSAKA-4B vector (36)(37)(38) and subsequent selection with puromycin at 20 mg/ml.…”