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Secretome profiling identifies neuron-derived neurotrophic factor as a tumor-suppressive factor in lung cancer
Ya Zhang, … , Eduardo M. Sotomayor, Xiaoyan Zheng
Ya Zhang, … , Eduardo M. Sotomayor, Xiaoyan Zheng
Published December 19, 2019
Citation Information: JCI Insight. 2019;4(24):e129344. https://doi.org/10.1172/jci.insight.129344.
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Research Article Cell biology

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

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Abstract

Clinical and preclinical studies show tissue-specific differences in tumorigenesis. Tissue specificity is controlled by differential gene expression. We prioritized genes that encode secreted proteins according to their preferential expression in normal lungs to identify candidates associated with lung cancer. Indeed, most of the lung-enriched genes identified in our analysis have known or suspected roles in lung cancer. We focused on the gene encoding neuron-derived neurotrophic factor (NDNF), which had not yet been associated with lung cancer. We determined that NDNF was preferentially expressed in the normal adult lung and that its expression was decreased in human lung adenocarcinoma and a mouse model of this cancer. Higher expression of NDNF was associated with better clinical outcome of patients with lung adenocarcinoma. Purified NDNF inhibited proliferation of lung cancer cells, whereas silencing NDNF promoted tumor cell growth in culture and in xenograft models. We determined that NDNF is downregulated through DNA hypermethylation near CpG island shores in human lung adenocarcinoma. Furthermore, the lung cancer–related DNA hypermethylation sites corresponded to the methylation sites that occurred in tissues with low NDNF expression. Thus, by analyzing the tissue-specific secretome, we identified a tumor-suppressive factor, NDNF, which is associated with patient outcomes in lung adenocarcinoma.

Authors

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

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Figure 3

NDNF expression is decreased in lung adenocarcinoma and associated with better clinical outcome of patients.

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NDNF expression is decreased in lung adenocarcinoma and associated with...
(A) NDNF mRNA in tumor (n = 517) and normal lung tissues (n = 59) from TCGA lung adenocarcinoma database. Box plots show 25th to 75th percentile; whiskers extend to the minimum and maximum values. The 2-tailed Mann-Whitney U test was used for statistical analysis. ****P < 0.0001. (B) Ndnf mRNA in tumor and matched normal lung tissue adjacent to the tumor (NAT) from K-rasLA1 mice (n = 10). Transcript abundance was determined by RT-qPCR analysis. The 2-tailed paired t test was used for statistical analysis. ****P < 0.0001. (C) Western blot analysis of Ndnf in tumor (T) and matched normal lung tissue adjacent to the tumor (NAT) from K-rasLA1 mice (n = 8). (D–F) Kaplan-Meier curves showing the correlation between NDNF expression and clinical outcome, as analyzed for overall survival (OS), progression-free survival (PFS), and postprogression survival (PPS) of lung adenocarcinoma patients. (G–I) Kaplan-Meier curves showing the correlation between NDNF expression and OS of lung adenocarcinoma patients at indicated stages. Number of samples in the high- and low-NDNF groups and a corresponding log-rank P value are indicated on each graph. Kaplan-Meier curves were created using the Kaplan-Meier Plotter (www.kmplot.com) with lung adenocarcinoma patients grouped according to the median expression value of NDNF. Information of lung adenocarcinoma patients involved in the survival analysis is in Supplemental Table 3.

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