Abstract
This study aimed to explore the regulatory mechanisms of miR-338-3p and matrix metalloproteinase-2 (MMP-2) in neuroblastoma. Putative target interaction regions of miR-338-3p on MMP-2 were predicted by miRcode and miRbase bioinformatics tools. Relative expression of miRNA-338-3p and MMP-2 in neuroblastoma tissues and GI-LI-N and SK-N-SH cells was determined by reverse transcription polymerase chain reaction experiment. Furthermore, the cell proliferation was determined by Cell Counting Kit-8 assay, the cell apoptosis rate was analyzed by flow cytometry assay, and the cell invasion was evaluated by transwell assay. miR-338-3p expression was downregulated, whereas MMP-2 expression was upregulated in metastasis tissue site compared to that in primary tissue site in total. Furthermore, miR-338-3p overexpression suppressed proliferation, invasion, and epithelial–mesenchymal transition (EMT) of neuroblastoma cells but promoted apoptosis, and the knockdown of MMP-2 triggered similar effects. Furthermore, MMP-2 was directly targeted by miR-338-3p, and overexpression of MMP-2 rescued the inhibitory effects of miR-338-3p on human neuroblastoma cell progression. Collectively, these data demonstrated that miR-338-3p could suppress cell growth, invasion, and EMT pathway and induce apoptosis in neuroblastoma cells by targeting MMP-2. MiR-338-3p sponged MMP-2 to regulate the PI3K/AKT pathway in human neuroblastoma cells.
Highlights
As the most common extracranial solid tumor in infancy, neuroblastoma is derived from cells of neural crest origin and is notable for its broad range of clinical behaviors [1–3]
Our study indicated that miR-338-3p had an inhibitive effect on neuroblastoma cell growth, invasion, and epithelial–mesenchymal transition (EMT) process through targeting matrix metalloproteinase-2 (MMP-2)
Our data showed that miR-338-3p was downregulated in neuroblastoma metastasis tissue in total, which was consistent with results obtained in gastric and epithelial ovarian cancer studies [14,15]
Summary
As the most common extracranial solid tumor in infancy, neuroblastoma is derived from cells of neural crest origin and is notable for its broad range of clinical behaviors [1–3]. It has been reported that miRNAs may function as tumor suppressors, oncogenes, or candidate biomarkers in various cancers, including neuroblastoma, by regulating proliferation, angiogenesis, invasion, metastasis, and apoptosis [6]. It was found that miR-338-3p was downregulated and - through the specific targets - suppressed the cell growth and invasion in various cancers, such as ovarian cancer, gastric cancer, breast tumor, prostate cancer, non-small cell lung cancer, glioblastoma, and neuroblastoma [13–20]. MiR-338-3p inhibits neuroblastoma progression by targeting MMP-2 199 extracellular matrix to facilitate the progression of cell migration and invasion, regulation of vascular cell proliferation and apoptosis via regulating protein cleavage, and modulation of bioactive molecules and relevant signaling pathways [22]. Those research findings confirmed the hypothesis that miR-338-3p could inhibit the cell invasion and EMT process in neuroblastoma by targeting MMP-2
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