Content area
Non-small cell lung cancer (NSCLC) accounts for more than 80% of lung cancer cases, and the 5-year survival rate of patients remains unsatisfactory. MicroRNAs (miRNAs) are small endogenous noncoding RNAs that are considered essential posttranscriptional regulators of tumorigenesis, including NSCLC. In this study, we aimed to investigate the biological role of miR-3074-5p in NSCLC cells and the underlying molecular mechanisms. We showed that miR-3074-5p expression was decreased in human NSCLC specimens and cell lines. Moreover, miR-3074-5p overexpression inhibited cell proliferation, migration and invasion and induced apoptosis and cell cycle arrest. In addition, miR-3074-5p overexpression not only suppressed tumor growth but also enhanced the antitumor effect of paclitaxel (PTX) on NSCLC cells in vitro and in vivo. A transcriptome sequencing assay revealed genes that were differentially expressed after miR-3074-5p overexpression, and among the genes whose expression levels were most significantly decreased, tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) was a target of miR-3074-5p. The regulatory effect of miR-3074-5p on YWHAZ expression was verified by Western blotting and dual-luciferase reporter assays. The inhibition of A549 cell growth, migration and invasion was reversed by YWHAZ overexpression. Furthermore, we showed that PTX stimulated the expression of the YWHAZ and Hsp27 proteins and promoted the phosphorylation of Hsp27 (at S15 and S78). YWHAZ was confirmed to interact with Hsp27 in A549 cells, and downregulating YWHAZ expression promoted the degradation of the Hsp27 protein. Taken together, these results suggest that the miR-3074-5p/YWHAZ/Hsp27 axis may be a novel therapeutic target for NSCLC treatment.Non-small cell lung cancer (NSCLC) accounts for more than 80% of lung cancer cases, and the 5-year survival rate of patients remains unsatisfactory. MicroRNAs (miRNAs) are small endogenous noncoding RNAs that are considered essential posttranscriptional regulators of tumorigenesis, including NSCLC. In this study, we aimed to investigate the biological role of miR-3074-5p in NSCLC cells and the underlying molecular mechanisms. We showed that miR-3074-5p expression was decreased in human NSCLC specimens and cell lines. Moreover, miR-3074-5p overexpression inhibited cell proliferation, migration and invasion and induced apoptosis and cell cycle arrest. In addition, miR-3074-5p overexpression not only suppressed tumor growth but also enhanced the antitumor effect of paclitaxel (PTX) on NSCLC cells in vitro and in vivo. A transcriptome sequencing assay revealed genes that were differentially expressed after miR-3074-5p overexpression, and among the genes whose expression levels were most significantly decreased, tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) was a target of miR-3074-5p. The regulatory effect of miR-3074-5p on YWHAZ expression was verified by Western blotting and dual-luciferase reporter assays. The inhibition of A549 cell growth, migration and invasion was reversed by YWHAZ overexpression. Furthermore, we showed that PTX stimulated the expression of the YWHAZ and Hsp27 proteins and promoted the phosphorylation of Hsp27 (at S15 and S78). YWHAZ was confirmed to interact with Hsp27 in A549 cells, and downregulating YWHAZ expression promoted the degradation of the Hsp27 protein. Taken together, these results suggest that the miR-3074-5p/YWHAZ/Hsp27 axis may be a novel therapeutic target for NSCLC treatment.
Details
Animals;
Cell Movement -- drug effects;
Cell Line, Tumor;
Mice, Nude;
Apoptosis -- drug effects;
Male;
Mice;
Heat-Shock Proteins -- metabolism;
Heat-Shock Proteins -- genetics;
Mice, Inbred BALB C;
Female;
Molecular Chaperones -- metabolism;
A549 Cells;
Signal Transduction;
MicroRNAs -- genetics (major);
MicroRNAs -- metabolism (major);
Carcinoma, Non-Small-Cell Lung -- metabolism (major);
Carcinoma, Non-Small-Cell Lung -- genetics (major);
Carcinoma, Non-Small-Cell Lung -- pathology (major);
Carcinoma, Non-Small-Cell Lung -- drug therapy (major);
Lung Neoplasms -- genetics (major);
Lung Neoplasms -- metabolism (major);
Lung Neoplasms -- pathology (major);
Lung Neoplasms -- drug therapy (major);
14-3-3 Proteins -- metabolism (major);
14-3-3 Proteins -- genetics (major);
Paclitaxel -- pharmacology (major);
Paclitaxel -- therapeutic use (major);
Gene Expression Regulation, Neoplastic -- drug effects (major);
Cell Proliferation -- drug effects (major);
HSP27 Heat-Shock Proteins -- metabolism (major);
HSP27 Heat-Shock Proteins -- genetics (major)
1 Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China [email protected]; [email protected]
2 NHC Key Laboratory of Reproduction Regulation, Shanghai Engineering Research Center of Reproductive Health Drug and Devices, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200237, China