Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Cell biology

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

  • Text
  • PDF
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

×

Figure 7

Cancer-related DNA methylation sites correspond to those associated with tissue-specific expression of NDNF.

Options: View larger image (or click on image) Download as PowerPoint
Cancer-related DNA methylation sites correspond to those associated with...
(A) Schematic diagram of the human NDNF locus. The 16 available CpG sites in the NDNF promoter region from Infinium HumanMethylation450 microarray are indicated as vertical lines. Black boxes, exons; blue box, CpG island; green text, CpG island shore methylation sites. (B) Methylation levels at the 16 CpG sites in tumor (red) compared with that in normal lung tissue adjacent to the tumor (black) using lung adenocarcinoma data from TCGA database. (C) Scatter plot and correlation between NDNF mRNA abundance and the average methylation level across 16 CpG sites in the NDNF promoter region in lung adenocarcinoma samples (n = 422, red dots) and normal lung tissue adjacent to the tumor (n = 21, black dots) from TCGA database. (D) Methylation level averaged across the 16 CpG sites in normal tissue from bladder, breast, kidney, and prostate (blue) compared with that in normal lung tissue (black). Data are from samples adjacent to tumor tissue from TCGA database (Supplemental Table 8). (E) Scatter plot and correlation between NDNF mRNA abundance and the average methylation level across all the 16 CpG sites in the NDNF promoter region in samples from normal lung, bladder, breast, kidney, and prostate tissues adjacent to tumor from TCGA. Lung samples shown as black dots, all others as blue dots. (F) Scatter plot and correlation between alterations in tissue-specific DNA methylation and alterations in cancer-specific methylation at each of the 16 CpG sites in the NDNF promoter region. Each circle represents a CpG site: green circle, CpG island shore; black circle, CpG island. Tissue-specific DNA methylation alterations were calculated as the difference in DNA methylation (ΔM) between the average methylation for 4 other tissues (bladder, breast, kidney, and prostate) and lung (from the averages in D); cancer-specific methylation alterations were calculated as the difference in DNA methylation between the average for lung adenocarcinoma tissues and the average for normal lung from tissue adjacent to tumors (from averages in B; Supplemental Figure 13). Spearman’s r and P values are indicated. 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. n.s., not significant; *P < 0.05; **P < 0.01; ***P < 0.001; and ****P < 0.0001.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts