406921

MIR132

MicroRNAs (miRNAs) are small, non-coding RNAs which can function as oncogenes or tumor suppressor genes in human cancers. Emerging evidence reveals that deregulation of miRNAs contributes to the human non-small cell lung cancer (NSCLC). In the present study, we demonstrated that the expression levels of miR-132 were dramatically decreased in examined NSCLC cell lines and clinical NSCLC tissue samples. Then, we found that introduction of miR-132 significantly suppressed the migration and invasion of lung cancer cells in vitro, suggesting that miR-132 may be a novel tumor suppressor. Further studies indicated that the EMT-related transcription factor ZEB2 was one direct target genes of miR-132, evidenced by the direct binding of miR-132 with the 3' untranslated region (3' UTR) of ZEB2. Further, miR-132 could decrease the expression of ZEB2 at the levels of mRNA and protein. Notably, the EMT marker E-cadherin or vimentin, a downstream of ZEB2, was also down-regulated or up-regulated upon miR-132 treatment. Additionally, over-expressing or silencing ZEB2 was able to elevate or inhibit the migration and invasion of lung cancer cells, parallel to the effect of miR-132 on the lung cancer cells. Meanwhile, knockdown of ZEB2 reversed the enhanced migration and invasion mediated by anti-miR-132. These results indicate that miR-132 suppresses the migration and invasion of NSCLC cells through targeting ZEB2 involving the EMT process. Thus, our finding provides new insight into the mechanism of NSCLC progression. Therapeutically, miR-132 may serve as a potential target in the treatment of human lung cancer.

Glucocorticoids (GCs) such as dexamethasone (DEX) are administered as cancer cotreatment for palliative purposes due to their proapoptotic effects in lymphoid cancer and limited side effects associated with cancer growth and chemotherapy. However, there is emerging evidence that GCs induce therapy resistance in most epithelial tumors. Our recent data reveal that DEX promotes the progression of pancreatic ductal adenocarcinoma (PDA). In the present study, we examined 1 primary and 2 established PDA cell lines, and 35 PDA tissues from patients who had received (n=14) or not received (n=21) GCs prior to surgery. Through microRNA microarray analysis, in silico, and RTqPCR analyses, we identified 268 microRNAs differentially expressed between DEXtreated and untreated cells. With a focus on cancer progression, we selected miR132 and its target gene, transforming growth factor-beta2 (TGFbeta2), as top candidates. miR132 mimics directly bound to the 3' untranslated region (3'UTR) of a TGFbeta2 luciferase construct and enhanced expression, as shown by increased luciferase activity. By contrast, DEX inhibited miR132 expression via promoter methylation. miR132 mimics also reduced DEXinduced clonogenicity, migration and expression of vimentin and Ecadherin in vitro and in tumor xenografts. In patients, GC intake prior to surgery enhanced global hypermethylation and expression of TGFbeta2 in tissues; expression of miR132 was detected but could not be quantified. Our results demonstrate that DEXmediated inhibition of miR132 is a key mediator in the progression of pancreatic cancer, and the findings provide a foundation for miRNAbased therapies.