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Metastasis is the major cause for high mortality of lung cancer with the underlying mechanisms poorly understood. The scaffolding protein neural precursor cell expressed, developmentally down-regulated 9 (NEDD9) has been identified as a prometastasis gene in several types of cancers including melanoma and breast cancer. However, the exact role and related mechanism of NEDD9 in regulating lung cancer metastasis still remain largely unknown. Here, we demonstrate that NEDD9 knockdown significantly inhibits migration, invasion and metastasis of lung cancer cells in vitro and in vivo. The pro-metastasis role of Nedd9 in lung cancer is further supported by studies in mice models of spontaneous cancer metastasis. Moreover, we find that NEDD9 promotes lung cancer cell migration and invasion through the induction of epithelial-mesenchymal transition (EMT) potentially via focal adhesion kinase activation. More importantly, NEDD9 expression inversely correlates with Ecadherin expression in human lung cancer specimens, consistent with the findings from in vitro studies. Taken together, this study highlights that NEDD9 is an important mediator promotes lung cancer metastasis via EMT.Lung cancer is a deadly disease with high mortality and its 5-year survival rate is approximately 15% globally. Metastasis, frequently observed in patients initially diagnosed with lung cancer, remains as an important factor in contribution to high mortality of lung cancer.1 Despite great efforts in last decades, the molecular mechanisms involved in lung cancer metastasis process still remain far from being fully understood.Recent studies have shown that NEDD9 (Neural precursor cell expressed, developmentally down-regulated 9, also known as HEF1), a scaffolding protein without known catalytic activity, is important for pro-metastasis behavior in several types of solid tumors. 2,3 In melanoma, NEDD9 is frequently up-regulated by gene allele amplification and activates FAK (focal adhesion kinase) to promote cell invasion and metastasis.2 NEDD9 complexes with DOCK3 and regulates the activation of Rac which are essential for promoting the mesenchymal-type movement of melanoma cells. 4 In glioblastoma, NEDD9 works as an effector of FAK to promote tumor cell aggression.5 Interestingly, Nedd9 2/2 mice displayed much less mammary tumor formation as well as lung metastasis, which is potentially due to the reduction of Fak and Src activation.6 Consistently, we have recently found that NEDD9 is transcriptionally regulated by CRTC1/CREB complex in LKB1-deficient lung cancer and significantly contributes to tumor progression via the promotion of tumor differentiation status.7 However, the roles of NEDD9 in lung

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Lung squamous cell carcinoma (SCC) is one of the major subtypes of lung cancer. Our current knowledge of oncogenic drivers in this specific subtype of lung cancer is largely limited compared with lung adenocarcinoma (ADC). Through exon array analyses, molecular analyses and functional studies, we here identify the TRA2B-DNAH5 fusion as a novel oncogenic driver in lung SCC. We found that this gene fusion occurs exclusively in lung SCC (3.1%, 5/163), but not in lung ADC (0/119). Through mechanistic studies, we further revealed that this TRA2B-DNAH5 fusion promotes lung SCC malignant progression through regulating a SIRT6-ERK1/2-MMP1 signaling axis. We show that inhibition of ERK1/2 activation using selumetinib efficiently inhibits the growth of lung SCC with TRA2B-DNAH5 fusion expression. These findings improve our current knowledge of oncogenic drivers in lung SCC and provide a potential therapeutic strategy for lung SCC patients with TRA2B-DNAH5 fusion.

The involvement of the Notch signaling pathway in the cellular differentiation of the mammalian kidney is established. Recently, the dysregulation of Notch signaling molecules has been identified in acute and chronic renal injuries, fibrosis models, and diabetic kidney biopsies. The canonical Notch ligand , Jagged1, is upregulated in a transforming growth factor-beta- (TGF-β-) dependent manner during chronic kidney disease. TGF-β, a central mediator of renal fibrosis, also is a major contributor to the development of diabetic nephropathy. To explore the roles and possible mechanisms of Notch signaling molecules in the pathogenesis of diabetic nephropathy, we exposed cultured rat mesangial cells to a γ-secretase inhibitor (DAPT) or high glucose and measured the expression of Notch signaling molecules and the fibrosis index. Notch pathway-related molecules, TGF-β, and fibronectin increased with exposure to high glucose and decreased with DAPT treatment. Our results suggest that the Notch signaling pathway may precipitate diabetic nephropathy via TGF-β activation.