Downregulation of long non-coding RNA LET predicts poor prognosis and increases Notch signaling in non-small cell lung cancer

// Shengwen Li 1, 2, 3 , Hui Zhao 2 , Jianqiang Li 2 , Aizheng Zhang 3 and Haibin Wang 3, 4 1 Shanxi Medical University, Taiyuan, Shanxi 030001, China 2 Department of Respiratory and Critical Medicine, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China 3 Department of Respiratory and Critical Medicine, Shanxi Provincial People’s Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi 030012, China 4 Division of Allergy and Immunology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA Correspondence to: Jianqiang Li, email: ljqhx@sina.com Haibin Wang, email: hwang1@bidmc.harvard.edu Keywords: long non-coding RNA-LET; NSCLC; prognosis; Notch signaling Abbreviations: NSCLC: non-small cell lung cancer; lncRNA: long non-coding RNA; lncRNA-LET: lncRNA low expression in tumor; Notch signaling, Notch1 intracellular domain (NICD1) Received: June 23, 2017     Accepted: December 09, 2017     Published: December 19, 2017 ABSTRACT Long non-coding RNAs (lncRNAs) have been found to be dysregulated in a variety of tumors. The lncRNA-Low Expression in Tumor (LET) is a recently identified lncRNA, but its expression pattern and biological significance in human non-small cell lung cancer (NSCLC) are still largely unknown. In this study, we found that lncRNA-LET was significantly downregulated in human NSCLC lung tissues and cell lines. Decreased lncRNA-LET expression was strongly associated with advanced tumor stages and poorer overall survival of NSCLC patients. Functionally, overexpression of lncRNA-LET in NSCLC H292 cells significantly suppressed cell proliferation, migration and invasion, and promoted cell cycle arrest and apoptosis, while knockdown of lncRNA-LET in NSCLC H1975 cells showed an opposite effect, pointing to a tumor-suppressive role for lncRNA-LET in NSCLC. Mechanistically, we demonstrated that lncRNA-LET overexpression significantly reduced the expression of Notch1 intracellular Domain (NICD1) in H292 cells while knockdown of lncRNA-LET increased NICD1 expression in H1975 cells. Similarly, NSCLC lung tissues with high levels of lncRNA-LET had lower NICD1 expression. Thus, our results provide a strong rationale for lncRNA-LET to be used as a prognostic indicator and a potent therapeutic target for NSCLC patients, and highlight a novel lncRNA-LET/Notch axis in regulating NSCLC cell fate and tumor progression.