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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2016

Open Access 01-12-2016 | Research

Radiation-induced miR-208a increases the proliferation and radioresistance by targeting p21 in human lung cancer cells

Authors: Yiting Tang, Yayun Cui, Zengpeng Li, Zhuqing Jiao, Yong Zhang, Yan He, Guangxia Chen, Qunyan Zhou, Wenjie Wang, Xifa Zhou, Judong Luo, Shuyu Zhang

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2016

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Abstract

Background

Lung cancer has long been the most dangerous malignant tumor among males in both well developed and poorly developed countries. Radiotherapy plays a critical role in the curative management of inoperable non-small cell lung cancer (NSCLC) and is also used as a post-surgical treatment in lung cancer patients. Radioresistance is an important factor that limits the efficacy of radiotherapy for NSCLC patients. Increasing evidence suggests that microRNAs (miRNAs) possess diverse cellular regulatory roles in radiation responses.

Methods

In this study, we used miRNA microarray technology to identify serum miRNAs that were differentially expressed before and after radiotherapy in lung cancer patients. We further examined the biological function of miR-208a on cell viability, apoptotic death and cell cycle distribution in human lung cancer cells and explored the probable mechanism.

Results

Nine miRNAs, including miR-29b-3p, miR-200a-3p, and miR-126-3p were significantly down-regulated, whereas miR-208a was the only miRNA that was up-regulated in the serum of the patients after radiation treatment (P < 0.05). The expression of miR-208a could be induced by X-ray irradiation in lung cancer cells. Forced expression of miR-208a promoted cell proliferation and induced radioresistance via targeting p21 with a corresponding activation of the AKT/mTOR pathway in lung cancer cells, whereas down-regulation of miR-208a resulted in the opposite effects. In addition, down-regulation of miR-208a increased the percentage of cells undergoing apoptosis and inhibited the G1 phase arrest in NSCLC cells. Moreover, miR-208a from the serum exosome fraction of lung cancer patients could shuttle to A549 cells in a time-dependent manner, which was likely to contribute to the subsequent biological effects.

Conclusions

The present study provides evidence that miR-208a can affect the proliferation and radiosensitivity of human lung cancer cells by targeting p21 and can be transported by exosomes. Thus, miR-208a may serve as a potential therapeutic target for lung cancer patients.
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Literature
1.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.PubMedCrossRef
2.
3.
Koh PK, Faivre-Finn C, Blackhall FH, De Ruysscher D. Targeted agents in non-small cell lung cancer (NSCLC): clinical developments and rationale for the combination with thoracic radiotherapy. Cancer Treat Rev. 2012;38:626–40.PubMedCrossRef
4.
Chang JY, Senan S, Paul MA, Mehran RJ, Louie AV, Balter P, et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol. 2015;16:630–7.PubMedCrossRef
5.
Toulany M, Rodemann HP. Phosphatidylinositol 3-kinase/Akt signaling as a key mediator of tumor cell responsiveness to radiation. Semin Cancer Biol. 2015;3:180–90.CrossRef
6.
Raja R, Kale S, Thorat D, Soundararajan G, Lohite K, Mane A, et al. Hypoxia-driven osteopontin contributes to breast tumor growth through modulation of HIF1alpha-mediated VEGF-dependent angiogenesis. Oncogene. 2014;33:2053–64.PubMedCrossRef
7.
Gu Q, He Y, Ji J, Yao Y, Shen W, Luo J, et al. Hypoxia-inducible factor 1alpha (HIF-1alpha) and reactive oxygen species (ROS) mediates radiation-induced invasiveness through the SDF-1alpha/CXCR4 pathway in non-small cell lung carcinoma cells. Oncotarget. 2015;6:10893–907.PubMedPubMedCentralCrossRef
8.
9.
Esquela-Kerscher A, Slack FJ. Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–69.PubMedCrossRef
10.
Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res. 2004;64:3753–56.PubMedCrossRef
11.
Hayashita Y, Osada H, Tatematsu Y, Yamada H, Yanagisawa K, Tomida S, et al. A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res. 2005;65:9628–32.PubMedCrossRef
12.
Igney FH, Krammer PH. Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer. 2002;2:277–88.PubMedCrossRef
13.
Yang XD, Xu XH, Zhang SY, Wu Y, Xing CG, Ru G, et al. Role of miR-100 in the radioresistance of colorectal cancer cells. Am J Cancer Res. 2015;5:545–59.PubMedPubMedCentral
14.
Hummel R, Hussey DJ, Haier J. MicroRNAs: predictors and modifiers of chemo- and radiotherapy in different tumour types. Eur J Cancer. 2010;46:298–311.PubMedCrossRef
15.
Grosso S, Doyen J, Parks SK, Bertero T, Paye A, Cardinaud B, et al. MiR-210 promotes a hypoxic phenotype and increases radioresistance in human lung cancer cell lines. Cell Death Dis. 2013;4:e544.PubMedPubMedCentralCrossRef
16.
Liu ZL, Wang H, Liu J, Wang ZX. MicroRNA-21 (miR-21) expression promotes growth, metastasis, and chemo- or radioresistance in non-small cell lung cancer cells by targeting PTEN. Mol Cell Biochem. 2013;372:35–45.PubMedCrossRef
17.
Majka M, Janowska-Wieczorek A, Ratajczak J, Ehrenman K, Pietrzkowski Z, Kowalska MA, et al. Numerous growth factors, cytokines, and chemokines are secreted by human CD34(+) cells, myeloblasts, erythroblasts, and megakaryoblasts and regulate normal hematopoiesis in an autocrine/paracrine manner. Blood. 2001;97:3075–85.PubMedCrossRef
18.
Morel O, Toti F, Hugel B, Freyssinet JM. Cellular microparticles: a disseminated storage pool of bioactive vascular effectors. Curr Opin Hematol. 2004;11:156–64.PubMedCrossRef
19.
Rustom A, Saffrich R, Markovic I, Walther P, Gerdes HH. Nanotubular highways for intercellular organelle transport. Science. 2004;303:1007–10.PubMedCrossRef
20.
Ratajczak J, Wysoczynski M, Hayek F, Janowska-Wieczorek A, Ratajczak MZ. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia. 2006;20:1487–95.PubMedCrossRef
21.
Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.PubMedCrossRef
22.
Zhang S, Hao J, Xie F, Hu X, Liu C, Tong J, et al. Downregulation of miR-132 by promoter methylation contributes to pancreatic cancer development. Carcinogenesis. 2011;32:1183–9.PubMedCrossRef
23.
Ke G, Liang L, Yang JM, Huang X, Han D, Huang S, et al. MiR-181a confers resistance of cervical cancer to radiation therapy through targeting the pro-apoptotic PRKCD gene. Oncogene. 2013;32:3019–27.PubMedCrossRef
24.
Momen-Heravi F, Bala S, Kodys K, Szabo G. Exosomes derived from alcohol-treated hepatocytes horizontally transfer liver specific miRNA-122 and sensitize monocytes to LPS. Sci Rep. 2015;5:9991.PubMedPubMedCentralCrossRef
25.
Thery C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. 2006;Chapter 3:Unit 3.22.PubMed
26.
Yang HJ, Youn H, Seong KM, Jin YW, Kim J, Youn B. Phosphorylation of ribosomal protein S3 and antiapoptotic TRAF2 protein mediates radioresistance in non-small cell lung cancer cells. J Biol Chem. 2013;288:2965–75.PubMedPubMedCentralCrossRef
27.
Skladanowski A, Bozko P, Sabisz M. DNA structure and integrity checkpoints during the cell cycle and their role in drug targeting and sensitivity of tumor cells to anticancer treatment. Chem Rev. 2009;109:2951–73.PubMedCrossRef
28.
29.
Zheng M, Morgan-Lappe SE, Yang J, Bockbrader KM, Pamarthy D, Thomas D, et al. Growth inhibition and radiosensitization of glioblastoma and lung cancer cells by small interfering RNA silencing of tumor necrosis factor receptor-associated factor 2. Cancer Res. 2008;68:7570–8.PubMedPubMedCentralCrossRef
30.
Xu T, Liao Z, O'Reilly MS, Levy LB, Welsh JW, Wang LE, et al. Serum inflammatory miRNAs predict radiation esophagitis in patients receiving definitive radiochemotherapy for non-small cell lung cancer. Radiother Oncol. 2014;113:379–84.PubMedCrossRef
31.
Liu A, Shao C, Jin G, Liu R, Hao J, Song B, et al. miR-208-induced epithelial to mesenchymal transition of pancreatic cancer cells promotes cell metastasis and invasion. Cell Biochem Biophys. 2014;69:341–6.PubMedCrossRef
32.
Li H, Zheng D, Zhang B, Liu L, Ou J, Chen W, et al. Mir-208 promotes cell proliferation by repressing SOX6 expression in human esophageal squamous cell carcinoma. J Transl Med. 2014;12:196.PubMedPubMedCentralCrossRef
33.
Grueter CE, van Rooij E, Johnson BA, DeLeon SM, Sutherland LB, Qi X, et al. A cardiac microRNA governs systemic energy homeostasis by regulation of MED13. Cell. 2012;149:671–83.PubMedPubMedCentralCrossRef
34.
Oliveira-Carvalho V, Carvalho VO, Bocchi EA. The emerging role of miR-208a in the heart. DNA Cell Biol. 2013;32:8–12.PubMedCrossRef
35.
Shyu KG, Wang BW, Cheng WP, Lo HM. MicroRNA-208a Increases Myocardial Endoglin Expression and Myocardial Fibrosis in Acute Myocardial Infarction. Can J Cardiol. 2015;31:679–90.PubMedCrossRef
36.
Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D. p21 is a universal inhibitor of cyclin kinases. Nature. 1993;366:701–4.PubMedCrossRef
37.
Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999;13:1501–12.PubMedCrossRef
38.
Tian H, Wittmack EK, Jorgensen TJ. p21WAF1/CIP1 antisense therapy radiosensitizes human colon cancer by converting growth arrest to apoptosis. Cancer Res. 2000;60:679–84.PubMed
39.
Zhao R, Chen M, Jiang Z, Zhao F, Xi B, Zhang X, et al. Platycodin-D Induced Autophagy in Non-Small Cell Lung Cancer Cells via PI3K/Akt/mTOR and MAPK Signaling Pathways. J Cancer Educ. 2015;6:623–31.CrossRef
40.
Gridelli C, Maione P, Rossi A. The potential role of mTOR inhibitors in non-small cell lung cancer. Oncologist. 2008;13:139–47.PubMedCrossRef
41.
Mao K, Kobayashi S, Jaffer ZM, Huang Y, Volden P, Chernoff J, et al. Regulation of Akt/PKB activity by P21-activated kinase in cardiomyocytes. J Mol Cell Cardiol. 2008;44:429–34.PubMedPubMedCentralCrossRef
42.
Chen B, Xu X, Luo J, Wang H, Zhou S. Rapamycin Enhances the Anti-Cancer Effect of Dasatinib by Suppressing Src/PI3K/mTOR Pathway in NSCLC Cells. PLoS One. 2015;10:e0129663.PubMedPubMedCentralCrossRef
43.
44.
Hornick NI, Huan J, Doron B, Goloviznina NA, Lapidus J, Chang BH, et al. Serum Exosome MicroRNA as a Minimally-Invasive Early Biomarker of AML. Sci Rep. 2015;5:11295.PubMedPubMedCentralCrossRef
45.
Zhou W, Fong MY, Min Y, Somlo G, Liu L, Palomares MR, et al. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell. 2014;25:501–15.PubMedPubMedCentralCrossRef
46.
Schwarzenbach H. The clinical relevance of circulating, exosomal miRNAs as biomarkers for cancer. Expert Rev Mol Diagn. 2015;15:1159–69.PubMedCrossRef
47.
Squadrito ML, Baer C, Burdet F, Maderna C, Gilfillan GD, Lyle R, et al. Endogenous RNAs modulate microRNA sorting to exosomes and transfer to acceptor cells. Cell Rep. 2014;8:1432–46.PubMedCrossRef
Metadata
Title
Radiation-induced miR-208a increases the proliferation and radioresistance by targeting p21 in human lung cancer cells
Authors
Yiting Tang
Yayun Cui
Zengpeng Li
Zhuqing Jiao
Yong Zhang
Yan He
Guangxia Chen
Qunyan Zhou
Wenjie Wang
Xifa Zhou
Judong Luo
Shuyu Zhang
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2016
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-016-0285-3

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