Identification of the tumor‑suppressive function of circular RNA FOXO3 in non‑small cell lung cancer through sponging miR‑155

Zhang,Yanni; Zhao,Hui; Zhang,Lichuan

doi:10.3892/mmr.2018.8830

Identification of the tumor‑suppressive function of circular RNA FOXO3 in non‑small cell lung cancer through sponging miR‑155

Authors:
- Yanni Zhang
- Hui Zhao
- Lichuan Zhang
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Affiliations: Department of Emergency Respiratory, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China, Health Checkup Center, The Second Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
Published online on: March 29, 2018 https://doi.org/10.3892/mmr.2018.8830
Pages: 7692-7700
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Circular RNAs (circRNAs) are a class of endogenous noncoding RNAs that have been demonstrated to be potential regulators in the development and progression of various types of human cancer. However, little is known about their roles in cancer initiation and progression, particular in non‑small cell lung cancer (NSCLC). In the present study, the expression level of circRNA‑forkhead box O3 class (FOXO3) in NSCLC specimens was determined and its functional role was investigated in NSCLC cells. By performing Taq‑man based RT‑qPCR, it was identified that circRNA‑FOXO3 was downregulated in NSCLC tissues and cell lines. Receiver operating curve analysis indicated that circRNA‑FOXO3 had a relatively higher diagnostic accuracy. The functional relevance was further examined by biological assays. circRNA‑FOXO3 significantly promoted the ability of cell proliferation, migration and invasion of NSCLC cells. The linear isomer of circRNA‑FOXO3, FOXO3 gene, was identified as a downstream target. RNA immunoprecipitation indicated that circRNA‑FOXO3 sequestering miR‑155, which further promoted linear FOXO3 expression. In addition, gain and loss functional assays indicated that circRNA‑FOXO3 served an anti‑oncogenic role through sequestering miR‑155 and enhancing FOXO3 expression. These results suggest that circRNA‑FOXO3 is a tumor‑suppressor in NSCLC and may serve as a promising therapeutic target. Therefore, restoration of circRNA‑FOXO3 expression could be a future approach to develop a novel treatment strategy.

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1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar : PubMed/NCBI
2	Pastorino U: Lung cancer screening. Br J Cancer. 102:1681–1686. 2010. View Article : Google Scholar : PubMed/NCBI
3	Liang D and Wilusz JE: Short intronic repeat sequences facilitate circular RNA production. Genes Dev. 28:2233–2247. 2014. View Article : Google Scholar : PubMed/NCBI
4	Chen LL and Yang L: Regulation of circRNA biogenesis. RNA Biol. 12:381–388. 2015. View Article : Google Scholar : PubMed/NCBI
5	Lasda E and Parker R: Circular RNAs: Diversity of form and function. RNA. 20:1829–1842. 2014. View Article : Google Scholar : PubMed/NCBI
6	Ivanov A, Memczak S, Wyler E, Torti F, Porath HT, Orejuela MR, Piechotta M, Levanon EY, Landthaler M, Dieterich C and Rajewsky N: Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals. Cell Rep. 10:170–177. 2015. View Article : Google Scholar : PubMed/NCBI
7	Xia W, Qiu M, Chen R, Wang S, Leng X, Wang J, Xu Y, Hu J, Dong G, Xu PL and Yin R: Circular RNA has_circ_0067934 is upregulated in esophageal squamous cell carcinoma and promoted proliferation. Sci Rep. 6:355762016. View Article : Google Scholar : PubMed/NCBI
8	Zhou B and Yu JW: A novel identified circular RNA, circRNA_010567, promotes myocardial fibrosis via suppressing miR-141 by targeting TGF-β1. Biochem Biophys Res Commun. 487:769–775. 2017. View Article : Google Scholar : PubMed/NCBI
9	Zhang XO, Wang HB, Zhang Y, Lu X, Chen LL and Yang L: Complementary sequence-mediated exon circularization. Cell. 159:134–147. 2014. View Article : Google Scholar : PubMed/NCBI
10	Myatt SS and Lam EW: The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer. 7:847–859. 2007. View Article : Google Scholar : PubMed/NCBI
11	Cho EC, Kuo ML, Liu X, Yang L, Hsieh YC, Wang J, Cheng Y and Yen Y: Tumor suppressor FOXO3 regulates ribonucleotide reductase subunit RRM2B and impacts on survival of cancer patients. Oncotarget. 5:4834–4844. 2014. View Article : Google Scholar : PubMed/NCBI
12	Du WW, Yang W, Liu E, Yang Z, Dhaliwal P and Yang BB: Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucleic Acids Res. 44:2846–2858. 2016. View Article : Google Scholar : PubMed/NCBI
13	Afonso-Grunz F and Müller S: Principles of miRNA-mRNA interactions: Beyond sequence complementarity. Cell Mol Life Sci. 72:3127–3141. 2015. View Article : Google Scholar : PubMed/NCBI
14	Katoh M and Katoh M: Human FOX gene family (Review). Int J Oncol. 25:1495–1500. 2004.PubMed/NCBI
15	Nanavaty P, Alvarez MS and Alberts WM: Lung cancer screening: Advantages, controversies, and applications. Cancer Control. 21:9–14. 2014. View Article : Google Scholar : PubMed/NCBI
16	Sanger HL, Klotz G, Riesner D, Gross HJ and Kleinschmidt AK: Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures. Proc Natl Acad Sci USA. 73:3852–3856. 1976. View Article : Google Scholar : PubMed/NCBI
17	Guo JU, Agarwal V, Guo H and Bartel DP: Expanded identification and characterization of mammalian circular RNAs. Genome Biol. 15:4092014. View Article : Google Scholar : PubMed/NCBI
18	Osaki M, Okada F and Ochiya T: miRNA therapy targeting cancer stem cells: A new paradigm for cancer treatment and prevention of tumor recurrence. Ther Deliv. 6:323–337. 2015. View Article : Google Scholar : PubMed/NCBI
19	Huang YS, Jie N, Zou KJ and Weng Y: Expression profile of circular RNAs in human gastric cancer tissues. Mol Med Rep. 16:2469–2476. 2017. View Article : Google Scholar : PubMed/NCBI
20	Du WW, Fang L, Yang W, Wu N, Awan FM, Yang Z and Yang BB: Induction of tumor apoptosis through a circular RNA enhancing Foxo3 activity. Cell Death Differ. 24:357–370. 2017. View Article : Google Scholar : PubMed/NCBI
21	Bartel DP: MicroRNAs: Target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
22	Melo SA, Sugimoto H, O'Connell JT, Kato N, Villanueva A, Vidal A, Qiu L, Vitkin E, Perelman LT, Melo CA, et al: Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell. 26:707–721. 2014. View Article : Google Scholar : PubMed/NCBI
23	Xu H, Guo S, Li W and Yu P: The circular RNA Cdr1as, via miR-7 and its targets, regulates insulin transcription and secretion in islet cells. Sci Rep. 5:124532015. View Article : Google Scholar : PubMed/NCBI
24	Sun S, Sun P, Wang C and Sun T: Downregulation of microRNA-155 accelerates cell growth and invasion by targeting c-myc in human gastric carcinoma cells. Oncol Rep. 32:951–956. 2014. View Article : Google Scholar : PubMed/NCBI
25	Yu F, Jia X, Du F, Wang J, Wang Y, Ai W and Fan D: miR-155-deficient bone marrow promotes tumor metastasis. Mol Cancer Res. 11:923–936. 2013. View Article : Google Scholar : PubMed/NCBI
26	Wang Y, Li J, Tong L, Zhang J, Zhai A, Xu K, Wei L and Chu M: The prognostic value of miR-21 and miR-155 in non-small-cell lung cancer: A meta-analysis. Jpn J Clin Oncol. 43:813–820. 2013. View Article : Google Scholar : PubMed/NCBI
27	Yang M, Shen H, Qiu C, Ni Y, Wang L, Dong W, Liao Y and Du J: High expression of miR-21 and miR-155 predicts recurrence and unfavourable survival in non-small cell lung cancer. Eur J Cancer. 49:604–615. 2013. View Article : Google Scholar : PubMed/NCBI