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.
Highlights
Lung cancer is the most common cancer and the leading cause of cancer deaths
To evaluate the correlation between the expression levels of long non-coding RNA (lncRNA)-Low Expression in Tumor (LET) and the prognosis of patients with non-small cell lung cancer (NSCLC), the 66 NSCLC patients were divided into a high lncRNA-LET expression group (n=32) and a low lncRNA-LET expression group (n=34) using the median as the cut-off value based on the lncRNALET expression levels obtained by quantitative RT-PCR (qRT-PCR)
As dysregulation of cell cycle transition is a hallmark of cancer cells [15], we further investigated whether the effect of lncRNA-LET on NSCLC cell proliferation was due to altered cell cycle progression
Summary
Lung cancer is the most common cancer and the leading cause of cancer deaths. The non-small cell lung cancers (NSCLC) account for approximately 85% of all lung cancer cases, which are at locally advanced or metastatic stage at diagnosis [1, 2]. NSCLC has a large worldwide prevalence with a high mortality rate, there remains a lack of specific and sensitive tools for early diagnosis and targeted therapies. In NSCLC patients, some of these lncRNAs are associated with different TNM stages or overexpressed in one of the lung cancer subtypes while others are involved in drug resistance [8,9,10]. Those findings suggest the important roles of lncRNAs in the pathogenesis of NSCLC. Only a small number of lncRNAs have been well characterized, whereas functions of most lncRNAs remain to be elucidated [11]
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