Abstract
Our recent study revealed an important role of the neuroplastin (NPTN)β downstream signal in lung cancer dissemination in the lung. The molecular mechanism of the signal pathway downstream of NPTNβ is a serial activation of the key molecules we identified: tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) adaptor, nuclear factor (NF)IA/NFIB heterodimer transcription factor, and SAM pointed-domain containing ETS transcription factor (SPDEF). The question of how dissemination is controlled by SPDEF under the activated NPTNβ has not been answered. Here, we show that the NPTNβ-SPDEF-mediated induction of solute carrier family 22 member 18 antisense (SLC22A18AS) is definitely required for the epithelial-mesenchymal transition (EMT) through the NPTNβ pathway in lung cancer cells. In vitro, the induced EMT is linked to the acquisition of active cellular motility but not growth, and this is correlated with highly disseminative tumor progression in vivo. The publicly available data also show the poor survival of SLC22A18AS-overexpressing lung cancer patients. Taken together, these data highlight a crucial role of SLC22A18AS in lung cancer dissemination, which provides novel input of this molecule to the signal cascade of NPTNβ. Our findings contribute to a better understanding of NPTNβ-mediated lung cancer metastasis.
Highlights
Cancer metastasis is a grave problem for cancer patients because of its life-threatening nature, which may involve multiple-organ dysfunction due to the disseminated cancer’ growth
NPTNβ is expressed at a significant level in lung cancer cells, and NPTNβ plays a crucial role in its disseminative progression when it functions as a receptor to the extracellular S100A8/A9 [8]
What downstream signal(s) does this axis use as a driving force for cancer progression in the lung? We discovered a key transcription factor, nuclear factor (NF)IA/NFIB, which is positively regulated mostly by tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2), but the growth factor receptor bound protein 2 (GRB2)-RAS pathway contributes to the activation of NFIA/NFIB in an orchestrated manner with TRAF2
Summary
Cancer metastasis is a grave problem for cancer patients because of its life-threatening nature, which may involve multiple-organ dysfunction due to the disseminated cancer’ growth. NPTNβ is expressed at a significant level in lung cancer cells, and NPTNβ plays a crucial role in its disseminative progression when it functions as a receptor to the extracellular S100A8/A9 [8]. Our data support the notion that the newly identified NPTNβ signaling pathway that is initiated by cancer surrounding extracellular S100A8/A9 worsens the disseminating progression of lung cancers. It remained to be addressed how an S100A8/A9NPTNβ signal that led to SPDEF activation might control the upregulation of lung cancer dissemination. These cells were all cultivated in D/F medium (ThermoFisher Scientific, Waltham, MA) supplemented with 10% fetal bovine serum (FBS)
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