ADAM9 up-regulates N-cadherin via miR-218 suppression in lung adenocarcinoma cells

Yuh-Pyng Sher; Li-Ju Wang; Li-Ling Chuang; Mong-Hsun Tsai; Ting-Ting Kuo; Cheng-Chung Huang; Eric Y Chuang; Liang-Chuan Lai

doi:10.1371/journal.pone.0094065

ADAM9 up-regulates N-cadherin via miR-218 suppression in lung adenocarcinoma cells

PLoS One. 2014 Apr 4;9(4):e94065. doi: 10.1371/journal.pone.0094065. eCollection 2014.

Authors

Yuh-Pyng Sher¹, Li-Ju Wang², Li-Ling Chuang³, Mong-Hsun Tsai⁴, Ting-Ting Kuo⁵, Cheng-Chung Huang⁵, Eric Y Chuang⁶, Liang-Chuan Lai⁷

Affiliations

¹ Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.
² Graduate Institute of Physiology, National Taiwan University, Taipei, Taiwan.
³ Department of Physical Therapy and Graduate Institute of Rehabilitation Science, Chang Gung University, Taoyuan, Taiwan.
⁴ Institute of Biotechnology, National Taiwan University, Taipei, Taiwan; Bioinformatics and Biostatistics Core, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan.
⁵ Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
⁶ Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan; Bioinformatics and Biostatistics Core, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan.
⁷ Graduate Institute of Physiology, National Taiwan University, Taipei, Taiwan; Bioinformatics and Biostatistics Core, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan.

Abstract

Lung cancer is the leading cause of cancer death worldwide, and brain metastasis is a major cause of morbidity and mortality in lung cancer. CDH2 (N-cadherin, a mesenchymal marker of the epithelial-mesenchymal transition) and ADAM9 (a type I transmembrane protein) are related to lung cancer brain metastasis; however, it is unclear how they interact to mediate this metastasis. Because microRNAs regulate many biological functions and disease processes (e.g., cancer) by down-regulating their target genes, microRNA microarrays were used to identify ADAM9-regulated miRNAs that target CDH2 in aggressive lung cancer cells. Luciferase assays and western blot analysis showed that CDH2 is a target gene of miR-218. MiR-218 was generated from pri-mir-218-1, which is located in SLIT2, in non-invasive lung adenocarcinoma cells, whereas its expression was inhibited in aggressive lung adenocarcinoma. The down-regulation of ADAM9 up-regulated SLIT2 and miR-218, thus down-regulating CDH2 expression. This study revealed that ADAM9 activates CDH2 through the release of miR-218 inhibition on CDH2 in lung adenocarcinoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions
ADAM Proteins / genetics
ADAM Proteins / metabolism*
Adenocarcinoma / genetics*
Adenocarcinoma / metabolism*
Adenocarcinoma / pathology
Adenocarcinoma of Lung
Antigens, CD / chemistry
Antigens, CD / genetics
Base Sequence
Binding Sites
Cadherins / chemistry
Cadherins / genetics*
Cell Line, Tumor
Cell Movement / genetics
Cluster Analysis
Gene Expression Profiling
Gene Expression Regulation, Neoplastic*
Humans
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism*
Lung Neoplasms / pathology
Membrane Proteins / genetics
Membrane Proteins / metabolism*
MicroRNAs / chemistry
MicroRNAs / genetics*
RNA Interference
Transcriptional Activation

Substances

3' Untranslated Regions
Antigens, CD
CDH2 protein, human
Cadherins
MIRN218 microRNA, human
Membrane Proteins
MicroRNAs
ADAM Proteins
ADAM9 protein, human

Grants and funding

This research was supported by grants 101-2325-B-039-008 and 101-2320-B-002-015 from the National Science Council, Taiwan, ROC.(http://web1.nsc.gov.tw/mp.aspx?mp=7). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.