Acquisition of Chemo- or Radioresistance and Epithelial to Mesenchymal Transition (EMT) Phenotypes in Docetaxel-Resistant Lung Adenocarcinoma Cells was Linked with Downregulation of Let-7c
Menée sur des lignées cellulaires d'adénocarcinome du poumon résistantes au docétaxel, cette étude montre que l'acquisition de la chimio- ou radiorésistance des cellules tumorales et les phénotypes associés à leur transition épithélio-mésenchymateuse sont liés à une réduction de l'expression de Let-7c
MicroRNA (miRNA) expression and functions have been reported to contribute to phenotypic features of tumor cells. Although targets and functional roles for many microRNAs have been described in lung adenocarcinoma (LAD), their pathophysiologic roles in phenotypes of chemoresistant LAD cells are still largely unclear. Previously, docetaxel-resistant LAD cell lines (SPC-A1/DTX and H1299/DTX) were established by our lab and displayed chemoradioresistance and mesenchymal features with enhanced invasiveness and motility. MiRNA microarray data indicated that Let-7c was significantly downregulated in SPC-A1/DTX cells. Ectopic Let-7c expression could increase the in vitro and in vivo chemo- or radiosensitivity of docetaxel-resistant LAD cells by enhancing apoptosis, reverse their EMT phenotypes and inhibit their metastatic potential in vivo by inactivation of Akt phosphorylation, whereas Let-7c inhibitor could decrease the chemo- or radiosensitivity of parental cells. Further investigation suggested that Let-7c could significantly reduce the luciferase activity of a Bcl-xL 3' untranslated region-based reporter construct and inhibit the endogenous protein level of Bcl-xL. Additionally, siRNA-mediated Bcl-xL knockdown could mimic the same effects of Let-7c precursor and enforced Bcl-xL expression could partially rescue the effects of Let-7c precursor in docetaxel-resistant LAD cells. Furthermore, we found that Bcl-xL was significantly upregulated in docetaxel-nonresponding LAD tissues, and its expression was inversely correlated with Let-7c expression. This study suggests an important role of Let-7c in the molecular etiology of chemoresistant LAD cells and implicates a potential target to reverse chemo- or radioresistance and EMT phenotype in human LADs.