Abstract
MicroRNAs (miRNAs) have been identified as important posttranscriptional regulators involved in various biological and pathological processes of cells, but their association with tumor chemoresistance has not been fully understood. We detected miR-15b expression in two lung adenocarcinoma cell lines, A549 and A549/CDDP, and then investigated the effects of miR-15b on the metastasis and the chemosensitivity of cancer cells, using both gain- and loss-of-function studies. The correlation between miR-15b level and chemoresistance was further investigated in clinical lung adenocarcinoma specimens. miR-15b was significantly upregulated in cisplatin-resistant lung adenocarcinoma A549/CDDP cells compared with parental A549 cells. miR-15b regulates epithelial–mesenchymal transition (EMT) and cisplatin resistance in vitro and modulates response of lung adenocarcinoma cells to cisplatin in vivo. Further studies identified phosphatidylethanolamine-binding protein 4 (PEBP4) as a direct and functional target of miR-15b. Small-interfering RNA-mediated PEBP4 knockdown revealed similar effects as that of ectopic miR-15b expression, whereas overexpression of PEBP4 attenuated the function of miR-15b in lung adenocarcinoma cells. Increased miR-15b expression was also detected in tumor tissues sampled from lung adenocarcinoma patients treated with cisplatin-based chemotherapy and was proved to be correlated with low expression of PEBP4, decreased sensitivity to cisplatin and poor prognosis. Our results suggest that upregulation of miR-15b could suppress PEBP4 expression and in turn contribute to chemoresistance of lung adenocarcinoma cells to cisplatin.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Wang N, Liang H, Zhou Y, Wang C, Zhang S, Pan Y et al. miR-203 suppresses the proliferation and migration and promotes the apoptosis of lung cancer cells by targeting SRC. PLoS One 2014; 9: e105570.
Lee YH, Kim SY, Bae YS . Upregulation of miR-760 and miR-186 is associated with replicative senescence in human lung fibroblast cells. Mol Cells 2014; 37: 620–627.
Zhang Y, Yang Q, Wang S . MicroRNAs: a new key in lung cancer. Cancer Chemother Pharmacol 2014; 74: 1105–1111.
Wu G, Ji Z, Li H, Lei Y, Jin X, Yu Y et al. Selective TRAIL-induced cytotoxicity to lung cancer cells mediated by miRNA response elements. Cell Biochem Funct 2014; 32: 547–556.
Kurioka D, Takeshita F, Tsuta K, Sakamoto H, Watanabe S, Matsumoto K et al. NEK9-dependent proliferation of cancer cells lacking functional p53. Sci Rep 2014; 4: 6111.
Li J, Wang Y, Song Y, Fu Z, Yu W . miR-15b regulates cisplatin resistance and metastasis by targeting PEBP4 in human lung adenocarcinoma cells. Mol Cancer 2014; 13: 193.
Kim MK, Jung SB, Kim JS, Roh MS, Lee JH, Lee EH et al. Expression of microRNA miR-126 and miR-200c is associated with prognosis in patients with non-small cell lung cancer. Virchows Arch 2014; 465: 463–471.
Zhong KZ, Chen WW, Hu XY, Jiang AL, Zhao J . Clinicopathological and prognostic significance of microRNA-107 in human non small cell lung cancer. Int J Clin Exp Pathol 2014; 7: 4545–4551.
Zhong Z, Xia Y, Wang P, Liu B, Chen Y . Low expression of microRNA-30c promotes invasion by inducing epithelial mesenchymal transition in non-small cell lung cancer. Mol Med Rep 2014; 10: 2575–2579.
Xue W, Dahlman JE, Tammela T, Khan OF, Sood S, Dave A et al. Small RNA combination therapy for lung cancer. Proc Natl Acad Sci USA 2014; 111: E3553–E3561.
Horie M, Saito A, Noguchi S, Yamaguchi Y, Ohshima M, Morishita Y et al. Differential knockdown of TGF-β ligands in a three-dimensional co-culture tumor- stromal interaction model of lung cancer. BMC Cancer 2014; 14: 580.
Chen C, Chen J, Zhao KN . Editorial: Signalling pathways in anti-cancer drug resistance. Curr Med Chem 2014; 21: 3007–3008.
Gu Y, Cheng Y, Song Y, Zhang Z, Deng M, Wang C et al. MicroRNA-493 suppresses tumor growth, invasion and metastasis of lung cancer by regulating E2F1. PLoS One 2014; 9: e102602.
Zhao Y, Wei Q, Hu L, Chen FP, Hu Z, Heist RS et al. Polymorphisms in microRNAs are associated with survival in non-small cell lung cancer. Cancer Epidemiol Biomarkers Prev 2014; 23: 2503–2511.
Zhang X, Xiao D, Wang Z, Zou Y, Huang L, Lin W et al. MicroRNA-26a/b regulate DNA replication licensing, tumorigenesis and prognosis by targeting CDC6 in lung cancer. Mol Cancer Res 2014; 12: 1535–1546.
Zhu W, Xu B . MicroRNA-21 identified as predictor of cancer outcome: a meta-analysis. PLoS One 2014; 9: e103373.
Loriot A, Van Tongelen A, Blanco J, Klaessens S, Cannuyer J, van Baren N et al. A novel cancer-germline transcript carrying pro-metastatic miR-105 and TET-targeting miR-767 induced by DNA hypomethylation in tumors. Epigenetics 2014; 9: 1163–1171.
Won KJ, Im JY, Yun CO, Chung KS, Kim YJ, Lee JS et al. Human Noxin is an anti-apoptotic protein in response to DNA damage of A549 non-small cell lung carcinoma. Int J Cancer 2014; 134: 2595–2604.
Nakadate Y, Kodera Y, Kitamura Y, Tachibana T, Tamura T, Koizumi F . Silencing of poly(ADP-ribose) glycohydrolase sensitizes lung cancer cells to radiation through the abrogation of DNA damage checkpoint. Biochem Biophys Res Commun 2013; 441: 793–798.
Ren XS, Yin MH, Zhang X, Wang Z, Feng SP, Wang GX et al. Tumor-suppressive microRNA-449a induces growth arrest and senescence by targeting E2F3 in human lung cancer cells. Cancer Lett 2014; 344: 195–203.
Fujita Y, Takeshita F, Kuwano K, Ochiya T . RNAi therapeutic platforms for lung diseases. Pharmaceuticals (Basel) 2013; 6: 223–250.
Fujita Y, Takeshita F, Mizutani T, Ohgi T, Kuwano K, Ochiya T . A novel platform to enable inhaled naked RNAi medicine for lung cancer. Sci Rep 2013; 3: 3325.
Zhang M, Luo W, Huang B, Liu Z, Sun L, Zhang Q et al. Overexpression of JAM-A in non-small cell lung cancer correlates with tumor progression. PLoS One 2013; 8: e79173.
Takagi S, Oh-hara T, Sato S, Gong B, Takami M, Fujita N . Expression of Aggrus/podoplanin in bladder cancer and its role in pulmonary metastasis. Int J Cancer 2014; 134: 2605–2614.
Morandell S, Reinhardt HC, Cannell IG, Kim JS, Ruf DM, Mitra T et al. A reversible gene-targeting strategy identifies synthetic lethal interactions between MK2 and p53 in the DNA damage response in vivo. Cell Rep 2013; 5: 868–877.
Sok JC, Lee JA, Dasari S, Joyce S, Contrucci SC, Egloff AM et al. Collagen type XI α1 facilitates head and neck squamous cell cancer growth and invasion. Br J Cancer 2013; 109: 3049–3056.
Zhang T, Rong N, Chen J, Zou C, Jing H, Zhu X et al. SIRT1 expression is associated with the chemotherapy response and prognosis of patients with advanced NSCLC. PLoS One 2013; 8: e79162.
Banning A, Regenbrecht CR, Tikkanen R . Increased activity of mitogen activated protein kinase pathway in flotillin-2 knockout mouse model. Cell Signal 2014; 26: 198–207.
Tian H, Ge C, Li H, Zhao F, Hou H, Chen T et al. Ribonucleotide reductase M2B inhibits cell migration and spreading by early growth response protein 1-mediated phosphatase and tensin homolog/Akt1 pathway in hepatocellular carcinoma. Hepatology 2014; 59: 1459–1470.
Bailis JM, Gordon ML, Gurgel JL, Komor AC, Barton JK, Kirsch IR . An inducible, isogenic cancer cell line system for targeting the state of mismatch repair deficiency. PLoS One 2013; 8: e78726.
Hong SH, Minai-Tehrani A, Chang SH, Jiang HL, Lee S, Lee AY et al. Knockdown of the sodium-dependent phosphate co-transporter 2b (NPT2b) suppresses lung tumorigenesis. PLoS One 2013; 8: e77121.
Youngren SR, Tekade RK, Gustilo B, Hoffmann PR, Chougule MB . STAT6 siRNA matrix-loaded gelatin nanocarriers: formulation, characterization, and ex vivo proof of concept using adenocarcinoma cells. Biomed Res Int 2013; 2013: 858946.
He Y, Meng XM, Huang C, Wu BM, Zhang L, Lv XW et al. Long noncoding RNAs: Novel insights into hepatocelluar carcinoma. Cancer Lett 2014; 344: 20–27.
Lai CH, Park KS, Lee DH, Alberobello AT, Raffeld M, Pierobon M et al. HSP-90 inhibitor ganetespib is synergistic with doxorubicin in small cell lung cancer. Oncogene 2013; 33: 4867–4876.
Rodríguez-Montes JA, Menéndez Sánchez P . Role of micro-RNA in colorectal cancer screening. Cir Esp 2014; 92: 654–658.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Zhao, Z., Zhang, L., Yao, Q. et al. miR-15b regulates cisplatin resistance and metastasis by targeting PEBP4 in human lung adenocarcinoma cells. Cancer Gene Ther 22, 108–114 (2015). https://doi.org/10.1038/cgt.2014.73
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/cgt.2014.73
This article is cited by
-
PEBP4 deficiency aggravates LPS-induced acute lung injury and alveolar fluid clearance impairment via modulating PI3K/AKT signaling pathway
Cellular and Molecular Life Sciences (2024)
-
The protein and miRNA profile of plasma extracellular vesicles (EVs) can distinguish feline mammary adenocarcinoma patients from healthy feline controls
Scientific Reports (2023)
-
Prospects of microRNAs as therapeutic biomarkers in non-small cell lung cancer
Medical Oncology (2023)
-
MicroRNA in lung cancer—a novel potential way for early diagnosis and therapy
Journal of Applied Genetics (2023)
-
The role and mechanisms of action of microRNAs in cancer drug resistance
Clinical Epigenetics (2019)