Abstract
The ErbB signaling pathway plays important role in the pathogenesis of lung cancer. We explored the role of miRNA-377 as a tumor suppressor in NSCLC through silencing of some genes in the ErbB pathway. The targeting effect of miRNA-377 on EGFR, MAPK1, ABL2, and PAK2 was evaluated. The expression levels of these genes and miRNA-377 were surveyed in NSCLC and normal human tissues, Calu-6, and A549 cells. Real-time PCR was used to figure out whether miRNA-377 could decrease the target genes mRNAs in transfected lung cancer cell lines. The effects of miRNA-377 on apoptosis cell and proliferation were analyzed. We showed that miRNA-377 targets EGFR, MAPK1, and PAK2 mRNAs in in-silico and luciferase reporter assay. The expression of miRNA-377 was significantly downregulated in human NSCLC tissues, Calu-6 and A549 cells compared to their controls. We observed a negative correlation between EGFR, MAPK1, PAK2, and miRNA-377 expression in human NSCLC tissues. A significant reduction in EGFR, MAPK1, and PAK2 mRNA levels was detected, following miRNA-377 transfection in Calu-6 and A549 cells. The higher levels of miRNA-377 in Calu-6, and A549 cells induced apoptosis and reduced proliferation, significantly. All these data reveal that miRNA-377 functions as a tumor suppressor in NSCLC and may serve as a potential therapeutic target for the treatment of NSCLC.
Highlights
Lung cancer is the first leading cause of cancer death (18.4% of the total cancer deaths), [1] which is classified into two major groups: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC)
In step our results showed that miRNA-377 expression significantly decreased in NSCLC tissue and lung cancer cell lines compared with normal tissue
We found that the mRNAs of EGFR, MAPK1 and PAK2 significantly increased in NSCLC tissue
Summary
Lung cancer is the first leading cause of cancer death (18.4% of the total cancer deaths), [1] which is classified into two major groups: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). The ErbB signaling pathway and its receptors with tyrosine kinase activity performs main roles in the molecular pathogenesis of many types of human cancer [5, 6], including lung cancer [7]. The ErbB receptors family has four members, including EGFR (ErbB1), HER2/neu (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). Homoor heterodimerization of these receptors occurs after ligand binding, leads to activation of downstream signaling cascades like PLCγ, PI3K/AKT, ERK and more with the cell. EGFR mutations are found in some types of lung cancers and this mutation is associated with either HER2 or HER3 activation and triggers downstream signaling pathways like anti-apoptotic signaling [8]. Because overexpression of the EGFR occurs in 40–80% of patients with NSCLC, it has been an attractive target for the development of therapeutic agents [9,10,11]
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