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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 5

Tumor-suppressive properties of NDNF in mouse and human lung cancer cell lines.

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Tumor-suppressive properties of NDNF in mouse and human lung cancer cell...
(A–C) Effect of purified Ndnf protein on the growth of human and mouse lung cancer cell lines. Quantitative analysis of cell viability using the CCK-8 assay (A), of colony formation (B), and of growth in soft agar (C) of the A549 and LLC1 cells with or without purified Ndnf (200 ng/mL). Representative images from the colony formation assay and soft agar assay are shown in B and C. (D–F) Effect of shRNA-based knockdown of NDNF on the growth of human A549 cells and knockdown of Ndnf on LLC1 cells. Knockdown efficiency of shRNA targeting human NDNF and mouse Ndnf is shown in Supplemental Figure 10. Quantitative analysis of cell viability using the CCK-8 assay (D), of colony formation (E), and of growth in soft agar (F) of the indicated cells stably expressing shRNA targeting NDNF or Ndnf as appropriate or control scrambled shRNA of cells with or without purified Ndnf (200 ng/mL). In A and D, data are shown as mean ± SD of n > 3 replicates of a single experiment. Data are representative of n ≥ 3 experiments. In B, C, E, and F, data are shown as box-and-whiskers plots of n ≥ 6 replicates from n ≥ 3 experiments. Box plots show 25th to 75th percentile; whiskers extend to the minimum and maximum values. The 2-tailed Mann-Whitney U test (A–C) or 1-way ANOVA followed by Holm-Šídák multiple-comparisons test (D–F) was used for statistical analysis. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. Representative images of the colony formation assay (E) and soft agar assay (F) are shown in Supplemental Figure 11.

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