Downregulation of microRNA-21 expression restrains non-small cell lung cancer cell proliferation and migration through upregulation of programmed cell death 4

Abstract

Preliminary studies showed that miR-21 is overexpressed in some human cancers. However, the role of miR-21 in cancer is still unclear and even controversial. Our purpose was to investigate the biological effects of miR-21 on A549 non-small cell lung cancer (NSCLC) cells and the underlying mechanisms of those effects. The expression of miR-21 was quantified in serum samples from patients with NSCLC. A549 cells were transfected with miR-NC-sponge or miR-21-sponge only, or with miR-21-sponge plus PDCD4 small-interfering RNA (siRNA). The expression of miR-21 and PDCD4 mRNA in transfected cells was quantified by real-time polymerase chain reaction and the expression of PDCD4 protein by Western blot. Cell proliferation, apoptosis, migration, and invasion assays were performed to determine the biological effects of miR-21 expression and PDCD4 inhibition. miR-21 was overexpressed in serum from patients with NSCLC. Reduced miR-21 expression was observed following transfection with miR-21-sponge in A549 NSCLC cells. Co-transfection of miR-21-sponge with PDCD4 siRNA upregulated miR-21 expression in these cells. PDCD4 mRNA and protein levels were increased 2.14-fold and 2.16-fold, respectively, following inhibition of miR-21 expression. Inhibition of miR-21 expression following transfection of miR-21-sponge reduced cell proliferation, migration, and invasion of A549 cells. Depletion of PDCD4 by siRNA transfection reversed the reduction of cell proliferation, migration, and invasion induced by inhibition of miR-21 in A549 cells. It indicates that miR-21 is highly expressed in patients with NSCLC and inhibition of miR-21 expression reduces proliferation, migration, and invasion of A549 cells by upregulating PDCD4 expression. Modulation of miR-21 or PDCD4 expression may provide a potentially novel therapeutic approach for NSCLC.

Polyethylenimine-coated SPION exhibits potential intrinsic anti-metastatic properties inhibiting migration and invasion of pancreatic tumor cells

“…microRNA-21 targets (such as Sprouty-1, PTEN or PDCD4) aid the regulation of cell migration. PDCD4 limits lung cancer cell invasion after microRNA-21 downmodulation [63], Sprouty-1 inhibits ovarian cancer cell growth and migration through phospho-AKT downregulation [53], and PTEN is linked to vimentin loss and E-cadherin overexpression, which reverse the epithelial-mesenchymal transition (EMT) in tumor cells [75], and thus inhibits their invasion. We observed an early reduction in microRNA-21 expression after PMag treatment (2 h), after which PTEN and PDCD4 transcripts were upregulated, even after 24 h. An early decrease in Sprouty-1 transcript levels was not reflected at the protein level, which increased starting at 2 h post-PMag treatment.…”

“…Of these pathways, the addictive oncomiR microRNA-21 is a natural small RNA implicated in the regulation of several pathways [62] and associated with tumor cell migration [63,64]. microRNA-21 appears to positively modulate cell migration through three of its natural targets, PDCD4 [54,65], PTEN [66], and Sprouty-1 [53].…”

A New Mouse Avatar Model of Non-Small Cell Lung Cancer

“…miR-21 acts as an oncogenic miRNA and is involved in the regulation of cell cycle, apoptosis, invasion, and metastasis. Recent studies demonstrated that miR-21 promoted cell proliferation (31, 32) and its inhibition induced a cell cycle arrest at G2/M phase (31). MiR-210 is a hypoxia-inducible miRNA in lung cancer and melanoma (33) and it has been detected in exosome in vitro and in vivo (34).…”

Discriminant Score (D Score) a Model to Predict Lung Cancer Based on the Expression Study of Panel of Genes and Micrornas in the Plasma.

“…Particularly the use of cell free nuclei acid in the plasma as tumor markers [7,8,9]. The present work was based on studying the expression of genes and microRNAs that are the cause or the result of lung cancer formation, namely P53 [10,11], KRAS [12], c-MYC [13], Her-2/neu [14], microRNAs-21 [16,17], 34a [18], 92 [19], and 98 [20] genes in the plasma of patient diagnosed as cancer and benign lung diseases in order to obtain a discrimination score for differentiating malignant from benign lung conditions.…”