Abstract
Abnormal microRNA-370 (miR-370) expression has been frequently reported in several types of cancers, including lung cancer. However, the role and molecular mechanisms of miR-370 in regulating the growth and metastasis of lung cancer have not been clarified. Here, we show higher levels of epidermal growth factor receptor (EGFR), but lower levels of miR-370 expression in most human lung cancer cells and non-tumor cells. Induction of miR-370 over-expression significantly reduced the levels of EGFR expression and the EGFR 3′untranslated region (UTR)-regulated luciferase activity in XWLC-05 and H157 cells, suggesting that miR-370 may bind to the 3′UTR of EGFR mRNA. Compared with the control cells, induction of miR370 overexpression significantly inhibited the proliferation, clone formation capacity, migration and invasion of XWLC-05 and H157 cells while miR-370 inhibitor over-expression enhanced their tumor behaviors in vitro. Furthermore, miR-370 over-expression down-regulated the EGFR and hypoxia-inducible factor (HIF)-1α expression, and attenuated the extracellular single-regulated kinase (ERK)1/2 and AKT phosphorylation in XWLC-05 and H157 cells. In contrast, miR370 inhibitor over-expression increased the EGFR and HIF-1α expression as well as the ERK1/2 and AKT phosphorylation in XWLC-05 and H157 cells. Moreover, miR-370 over-expression significantly reduced the levels of EGFR and CD31 expression and inhibited the growth and lung metastasis of xenograft NSCLC tumors in mice. Our study indicates that miR-370 may bind to the 3′UTR of EGFR to inhibit EGFR expression and the growth, angiogenesis and metastasis of non-small cell lung cancer by down-regulating the ERK1/2 and AKT signaling.
Highlights
Lung cancer is the leading cause of cancer-related deaths worldwide [1,2,3]
High levels of epidermal growth factor receptor (EGFR) expression were detected in A549, XWLC-05 and H157 cells, but much lower levels of EGFR were detected in large cell lung cancer H460 and non-tumor bronchial epithelial Beas2b cells (Figure 1B and 1C)
We found that the 3’untranslated region (UTR) of the EGFR contained a potential binding site of miR-370 and the levels of EGFR were negatively associated with the levels of miR-370 expression in several human lung cancer cell lines and non-tumor bronchial epithelial cells
Summary
Lung cancer is the leading cause of cancer-related deaths worldwide [1,2,3]. Patients with lung cancer have a5-year survival rate of about 10~15% diagnosis, surgical technique and new therapies for lung cancers have advanced during the past several years [4,5,6]. Lung cancers are usually accompanied by the mutation of the epithelial growth factor receptor (EGFR) and its high www.impactjournals.com/oncotarget expression [7,8,9]. High levels of EGFR expression can activate the downstream PI3K/AKT and MAPK/ERK to promote the proliferation and metastasis of lung cancers [10,11,12]. Understanding the molecular pathogenesis of lung cancer, for the high levels of EGFR expression-related signaling and development of new therapeutic strategies will be of great significance in management of patients with lung cancers. There are more than 1000 miRNAs [16], which will target about 60% of human genes [17] to regulate the biological process, such as proliferation, angiogenesis, migration and invasion and others of cancers [18]. Previous studies have shown that miR-138, miR-34 and miR-200c regulate the tumorigenesis and metastasis of lung cancers [19,20,21]
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