Transcription factor KLF4 modulates microRNA-106a that targets Smad7 in gastric cancer

Abstract

Mounting evidence has revealed that microRNAs (miRNAs, miRNA) play oncogenic or anti-oncogenic roles in many cancer types. Our previous studies have found the ectopic expression of miR-106a in gastric cancer. However, its deregulation and some potential targets have not yet been fully explored. In this investigation, we identified that the upstream transcriptional factor krüppel-like factor 4 (KLF4), a novel regulator, directly bound to the promoter sequence of miR-106a and was responsible for its deregulation. Using real-time PCR and immunohistochemistry, we further verified that the expression level of KLF4 was negatively correlated with the miR-106a expression in tissue samples. Moreover, the downstream locus was also screened and small mothers against decapentaplegic 7 (Smad7) was revealed to be a direct target of miR-106a, with its 3’-UTR region complementarily bound to miR-106a and the protein expression was mediated by miR-106a in gastric cancer cells, which was confirmed by luciferase assay and Western blot. The role of KLF4-miR-106a-Smad7 in gastric cancer invasion was assessed by real-time PCR and transwell assay. The promoting effect of miR-106a on gastric cancer invasion was significantly abolished by the overexpression of KLF4. The silencing of Smad7 partially promoted the cell invasion when miR-106a was suppressed. In conclusion, we suggest that the ectopic expression of miR-106a is modulated by the upstream transcriptional factor KLF4, which influences the invasive ability of gastric cancer through the downstream target Smad7. MiR-106a should, therefore, be considered as a potential molecular phenotype in gastric cancer.