Secretome profiling identifies neuron-derived neurotrophic factor as a tumor-suppressive factor in lung cancer

Zhang, Ya; Wu, Xuefeng; Kai, Yan; Lee, Chia-Han; Cheng, Fengdong; Li, Yixuan; Zhuang, Yongbao; Ghaemmaghami, Javid; Chuang, Kun-Han; Liu, Zhuo; Meng, Yunxiao; Keswani, Meghana; Gough, Nancy R.; Wu, Xiaojun; Zhu, Wenge; Tzatsos, Alexandros; Peng, Weiqun; Seto, Edward; Sotomayor, Eduardo M.; Zheng, Xiaoyan

doi:10.1172/jci.insight.129344

Cited by 17 publications

(10 citation statements)

References 96 publications

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“…In later studies, NDNF was also found to be upregulated in mouse endothelial cells in response to hindlimb ischemia, where it promotes endothelial cell and cardiomyocyte survival through integrin-mediated activation of AKT/endothelial NOS signaling ( Ohashi et al, 2014 ; Joki et al, 2015 ). Additionally, recent studies have shown that NDNF expression is significantly downregulated in human lung adenocarcinoma (LUAD) and renal cell carcinoma (RCC), indicating that NDNF may also provide a beneficial function as a tumor suppressor ( Xia et al, 2019 ; Zhang et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

The NDNF-like factor Nord is a Hedgehog-induced extracellular BMP modulator that regulates Drosophila wing patterning and growth

Yang

Daoutidou

et al. 2022

eLife

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Hedgehog (Hh) and bone morphogenetic proteins (BMPs) pattern the developing Drosophila wing by functioning as short- and long-range morphogens, respectively. Here, we show that a previously unknown Hh-dependent mechanism fine-tunes the activity of BMPs. Through genome-wide expression profiling of the Drosophila wing imaginal discs, we identify nord as a novel target gene of the Hh signaling pathway. Nord is related to the vertebrate Neuron Derived Neurotrophic Factor (NDNF) involved in Congenital Hypogonadotropic Hypogonadism and several types of cancer. Loss- and gain-of-function analyses implicate Nord in the regulation of wing growth and proper crossvein patterning. At the molecular level, we present biochemical evidence that Nord is a secreted BMP-binding protein and localizes to the extracellular matrix. Nord binds to Decapentaplegic (Dpp) or the heterodimer Dpp-Glass bottom boat (Gbb) to modulate their release and activity. Furthermore, we demonstrate that Nord is a dosage-depend BMP modulator, where low levels of Nord promote and high levels inhibit BMP signaling. Taken together, we propose that Hh-induced Nord expression fine tunes both the range and strength of BMP signaling in the developing Drosophila wing.

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Section: Discussionmentioning

confidence: 99%

The NDNF-like factor Nord is a Hedgehog-induced extracellular BMP modulator that regulates Drosophila wing patterning and growth

Yang

Daoutidou

et al. 2022

eLife

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“…Akt is a downstream effector of PI3K signaling shown to modulate multiple cellular effects (Martin et al 2005 ). Akt signaling is a known regulator of liver I/R injury (Li et al 2019 ), and there is increasing evidence that Akt signaling initiates cell survival through inhibition of apoptosis and improving cell viability (Tsuruta et al 2002 ). Our studies showed that MaR1 increases Akt activation/phosphorylation after I/R injury and this was dependent on ALXR signaling.…”

Section: Discussionmentioning

confidence: 99%

Maresin 1 protects the liver against ischemia/reperfusion injury via the ALXR/Akt signaling pathway

Tang

et al. 2021

Mol Med

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Background Hepatic ischemia/reperfusion (I/R) injury can be a major complication following liver surgery contributing to post-operative liver dysfunction. Maresin 1 (MaR1), a pro-resolving lipid mediator, has been shown to suppress I/R injury. However, the mechanisms that account for the protective effects of MaR1 in I/R injury remain unknown. Methods WT (C57BL/6J) mice were subjected to partial hepatic warm ischemia for 60mins followed by reperfusion. Mice were treated with MaR1 (5-20 ng/mouse), Boc2 (Lipoxin A4 receptor antagonist), LY294002 (Akt inhibitor) or corresponding controls just prior to liver I/R or at the beginning of reperfusion. Blood and liver samples were collected at 6 h post-reperfusion. Serum aminotransferase, histopathologic changes, inflammatory cytokines, and oxidative stress were analyzed to evaluate liver injury. Signaling pathways were also investigated in vitro using primary mouse hepatocyte (HC) cultures to identify underlying mechanisms for MaR1 in liver I/R injury. Results MaR1 treatment significantly reduced ALT and AST levels, diminished necrotic areas, suppressed inflammatory responses, attenuated oxidative stress and decreased hepatocyte apoptosis in liver after I/R. Akt signaling was significantly increased in the MaR1-treated liver I/R group compared with controls. The protective effect of MaR1 was abrogated by pretreatment with Boc2, which together with MaR1-induced Akt activation. MaR1-mediated liver protection was reversed by inhibition of Akt. Conclusions MaR1 protects the liver against hepatic I/R injury via an ALXR/Akt signaling pathway. MaR1 may represent a novel therapeutic agent to mitigate the detrimental effects of I/R-induced liver injury.

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“…nord encodes a Drosophila NDNF protein. Human NDNF acts as a tumor suppressor (Xia et al, 2019; Zhang et al, 2019). NDNF expression is decreased in lung adenocarcinoma, and downregulation of NDNF promotes tumor growth in a mouse xenograft model (Zhang et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Human NDNF acts as a tumor suppressor (Xia et al, 2019; Zhang et al, 2019). NDNF expression is decreased in lung adenocarcinoma, and downregulation of NDNF promotes tumor growth in a mouse xenograft model (Zhang et al, 2019). NDNF is also known as a causative gene for congenital hypogonadotropic hypogonadism (CHH), which is characterized by infertility and delayed/absence of puberty (Messina et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

The feedback regulator Nord controls Dpp/BMP signaling via extracellular interaction with Dally in theDrosophilawing

Akiyama

Gibson

2021

Preprint

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The Drosophila BMP 2/4 homologue Decapentaplegic (Dpp) acts as a morphogen to regulate diverse developmental processes, including wing morphogenesis. Transcriptional feedback regulation of this pathway ensures tightly controlled signaling outputs to generate the precise pattern of the adult wing. Nevertheless, few direct Dpp target genes have been explored and our understanding of feedback regulation remains incomplete. Here, we employ transcriptional profiling following dpp conditional knockout to identify nord, a novel Dpp/BMP feedback regulator. Nord mutants generated by CRISPR/Cas9 mutagenesis produce a smaller wing and display low penetrance venation defects. At the molecular level, nord encodes a heparin-binding protein and we show that its overexpression is sufficient to antagonize Dpp/BMP signaling. Further, we demonstrate that Nord physically and genetically interacts with the Dpp/BMP co-receptor Dally. In sum we propose that Nord acts with Dally to fine tune Dpp/BMP signaling, with implications for both developmental and disease models.

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Secretome profiling identifies neuron-derived neurotrophic factor as a tumor-suppressive factor in lung cancer

Cited by 17 publications

References 96 publications

The NDNF-like factor Nord is a Hedgehog-induced extracellular BMP modulator that regulates Drosophila wing patterning and growth

The NDNF-like factor Nord is a Hedgehog-induced extracellular BMP modulator that regulates Drosophila wing patterning and growth

Maresin 1 protects the liver against ischemia/reperfusion injury via the ALXR/Akt signaling pathway

The feedback regulator Nord controls Dpp/BMP signaling via extracellular interaction with Dally in theDrosophilawing

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