ADAM9 Up-Regulates N-Cadherin via miR-218 Suppression in Lung Adenocarcinoma Cells

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

doi:10.1371/journal.pone.0094065

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.

Highlights

Lung cancer represents the leading cause of cancer-related death in the Western world
We further demonstrated that A disintegrin and metalloprotease 9 (ADAM9) could inhibit the expression of miR-218 and its precursor pri-miR218-1 and could, in turn, up-regulate the expression of CDH2 to increase the mobility of lung adenocarcinoma cells
These results indicated that ADAM9 is able to activate CDH2 in aggressive lung adenocarcinoma cells

Summary

Introduction

Lung cancer represents the leading cause of cancer-related death in the Western world. This disease has a 5-year overall survival rate of only 15%, and this has not improved during recent decades [1]. In Taiwan, lung cancer is the leading cause of cancer death [2], and adenocarcinoma is the major histological type (52.5%). Metastasis is a major cause of morbidity and mortality in lung cancer. Surgical resection of primary lung cancer is frequently followed by tumor recurrence at distant sites, such as the lymph nodes [3], bone [4], and brain [5]. 30% of patients with lung cancer develop brain metastasis [5]. The mechanisms mediating lung cancer metastasis to the brain remain unclear

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Conclusion