1. Let-7c governs the acquisition of chemo- or radioresistance and epithelial-to-mesenchymal transition phenotypes in docetaxel-resistant lung adenocarcinoma.
- Author
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Cui SY, Huang JY, Chen YT, Song HZ, Feng B, Huang GC, Wang R, Chen LB, and De W
- Subjects
- Adenocarcinoma enzymology, Adenocarcinoma genetics, Adenocarcinoma of Lung, Animals, Apoptosis drug effects, Apoptosis genetics, Base Sequence, Caspase 3 metabolism, Cell Line, Tumor, Docetaxel, Down-Regulation drug effects, Down-Regulation genetics, Enzyme Activation drug effects, Gene Expression Regulation, Neoplastic drug effects, Humans, Lung Neoplasms enzymology, Lung Neoplasms genetics, Mice, Mice, Nude, MicroRNAs genetics, Molecular Sequence Data, Neoplasm Metastasis, Oligonucleotide Array Sequence Analysis, Phenotype, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction drug effects, Signal Transduction genetics, Up-Regulation drug effects, Up-Regulation genetics, bcl-X Protein metabolism, Adenocarcinoma pathology, Drug Resistance, Neoplasm drug effects, Epithelial-Mesenchymal Transition drug effects, Lung Neoplasms pathology, MicroRNAs metabolism, Radiation Tolerance drug effects, Taxoids pharmacology
- Abstract
MicroRNA (miRNA) expression and functions have been reported to contribute to phenotypic features of tumor cells. Although targets and functional roles for many miRNAs have been described in lung adenocarcinoma (LAD), their pathophysiologic roles in phenotypes of chemoresistant LAD cells are still largely unclear. Previously, docetaxel (DTX)-resistant LAD cell lines (SPC-A1/DTX and H1299/DTX) were established by our laboratory and displayed chemo- or radioresistance and mesenchymal features with enhanced invasiveness and motility. Unbiased miRNA profiling indicated that let-7c (MIRLET7C) was significantly downregulated in SPC-A1/DTX cells. Ectopic let-7c expression increased the in vitro and in vivo chemo- or radiosensitivity of DTX-resistant LAD cells through enhanced apoptosis, reversal of epithelial-to-mesenchymal phenotypes, and inhibition of in vivo metastatic potential via inactivation of Akt phosphorylation, whereas a let-7c inhibitor decreased the chemo- or radiosensitivity of parental cells. Further investigation suggested that let-7c significantly reduced the luciferase activity of a Bcl-xL 3'-UTR-based reporter, concordant with reduced Bcl-xL protein levels. Additionally, siRNA-mediated Bcl-xL knockdown mimicked the same effects of let-7c precursor, and enforced Bcl-xL expression partially rescued the effects of let-7c precursor in DTX-resistant LAD cells. Furthermore, we found that Bcl-xL was significantly upregulated in DTX-nonresponding LAD tissues, and its expression was inversely correlated with let-7c expression. This study suggests an important role for let-7c in the molecular etiology of chemoresistant lung adenocarcinoma., (©2013 AACR)
- Published
- 2013
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