title: Let-7c governs the acquisition of chemo- or radioresistance and epithelial-to-mesenchymal transition phenotypes in docetaxel-resistant lung adenocarcinoma.
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.
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, 315 Zhongshan East Road, Nanjing, Jiangsu 210002, PR China.
authors.forename: Shi-Yun
authors.initials: SY
authors.lastname: Cui
authors.forename: Jia-Yuan
authors.initials: JY
authors.lastname: Huang
authors.forename: Yi-Tian
authors.initials: YT
authors.lastname: Chen
authors.forename: Hai-Zhu
authors.initials: HZ
authors.lastname: Song
authors.forename: Bing
authors.initials: B
authors.lastname: Feng
authors.forename: Gui-Chun
authors.initials: GC
authors.lastname: Huang
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Long-Bang
authors.initials: LB
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: De
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D000077143:Docetaxel; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D043823:Taxoids / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D043823:Taxoids; D051020:bcl-X Protein; C487931:mirnlet7 microRNA, human; D000077143:Docetaxel; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3