Clinical significance of high expression of miR-452-5p in lung squamous cell carcinoma

Gan,Xiao‑Ning; Gan,Ting‑Qing; He,Rong‑Quan; Luo,Jie; Tang,Rui‑Xue; Wang,Han‑Lin; Zhou,Hong; Qing,Hui; Ma,Jie; Hu,Xiao‑Hua; Chen,Gang

doi:10.3892/ol.2018.8088

Clinical significance of high expression of miR-452-5p in lung squamous cell carcinoma

Authors:
- Xiao‑Ning Gan
- Ting‑Qing Gan
- Rong‑Quan He
- Jie Luo
- Rui‑Xue Tang
- Han‑Lin Wang
- Hong Zhou
- Hui Qing
- Jie Ma
- Xiao‑Hua Hu
- Gang Chen
View Affiliations

Affiliations: Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China, Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
Published online on: February 20, 2018 https://doi.org/10.3892/ol.2018.8088
Pages: 6418-6430
Copyright: © Gan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The role of microRNA (miRNA)-452-5p in lung squamous cell carcinoma (LUSC) remains unclear. Therefore, the present systematic study was performed to investigate the clinical significance and the rudimentary mechanism of the function of miR‑452‑5p in LUSC. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized to confirm the expression level and clinical value of miR‑452‑5p in LUSC. Using online databases and bioinformatic software, gene ontology (GO), pathway and protein‑protein interaction (PPI) analyses of miR‑452‑5p target genes were performed to examine the molecular mechanism of miR‑452‑5p. The association between the expression of miR‑452‑5p and that of its hub genes was verified using TCGA. Based on TCGA data on 387 clinical specimens, the expression of miR‑452‑5p in LUSC was significantly increased compared with adjacent lung tissues (7.1525±1.39063 vs. 6.0885±0.35298; P<0.001). The expression levels of miR‑452‑5p were significantly correlated with age (P=0.001) and tumor‑node metastasis stage (P=0.028). Furthermore, the increased expression of miR‑452‑5p in LUSC compared with non‑cancerous tissue [standard mean deviation (SMD), 0.372; 95% confidence interval (CI), 0.020‑0.724; z=2.07; P=0.038] was validated by a meta‑analysis of 720 clinical samples. The GO and pathway analyses revealed that miR‑452‑5p target genes were mainly enriched in the ʻregulation of transcription’, ʻnucleoplasm’, ʻprotein binding’ and ʻcell cycle’ pathways. A total of 10 hub genes were identified by PPI analysis, and 5 hub genes (SMAD4, SMAD2, CDKN1B, YWHAE and YWHAB) were significantly enriched in the ʻcell cycle’ pathway. The expression of CDKN1B was negatively correlated with miR‑452‑5p (P=0.003). It was concluded that miR‑452‑5p may serve an essential role in the occurrence and progression of LUSC by targeting CDKN1B, which is involved in the cell cycle.

View Figures

View References

1	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
2	McGuire S: World cancer report 2014. Geneva, Switzerland: World health organization, international agency for research on cancer, WHO Press, 2015. Adv Nutr. 7:418–419. 2016. View Article : Google Scholar : PubMed/NCBI
3	Hu M, Hu Y, He J and Li B: Prognostic value of basic fibroblast growth factor (bFGF) in lung cancer: A systematic review with meta-analysis. PLoS One. 11:e01473742016. View Article : Google Scholar : PubMed/NCBI
4	Schmidt B, Beyer J, Dietrich D, Bork I, Liebenberg V and Fleischhacker M: Quantification of cell-free mSHOX2 Plasma DNA for therapy monitoring in advanced stage non-small cell (NSCLC) and small-cell lung cancer (SCLC) patients. PLoS One. 10:e01181952015. View Article : Google Scholar : PubMed/NCBI
5	Takahashi A, Ishii G, Neri S, Yoshida T, Hashimoto H, Suzuki S, Umemura S, Matsumoto S, Yoh K, Niho S, et al: Podoplanin-expressing cancer-associated fibroblasts inhibit small cell lung cancer growth. Oncotarget. 6:9531–9541. 2015. View Article : Google Scholar : PubMed/NCBI
6	Meza R, Meernik C, Jeon J and Cote ML: Lung cancer incidence trends by gender, race and histology in the United States, 1973–2010. PLoS One. 10:e01213232015. View Article : Google Scholar : PubMed/NCBI
7	Sun Y, Han Y, Wang X, Wang W, Wang X, Wen M, Xia J, Xing H, Li X and Zhang Z: Correlation of EGFR Del 19 with Fn14/JAK/STAT signaling molecules in non-small cell lung cancer. Oncol Rep. 36:1030–1040. 2016. View Article : Google Scholar : PubMed/NCBI
8	Lee CK, Brown C, Gralla RJ, Hirsh V, Thongprasert S, Tsai CM, Tan EH, Ho JC, Chu da T, Zaatar A, et al: Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: A meta-analysis. J Natl Cancer Inst. 105:595–605. 2013. View Article : Google Scholar : PubMed/NCBI
9	Drilon A, Rekhtman N, Ladanyi M and Paik P: Squamous-cell carcinomas of the lung: Emerging biology, controversies, and the promise of targeted therapy. Lancet Oncol. 13:e418–e426. 2012. View Article : Google Scholar : PubMed/NCBI
10	Xu C, Li S, Chen T, Hu H, Ding C, Xu Z, Chen J, Liu Z, Lei Z, Zhang HT, et al: miR-296-5p suppresses cell viability by directly targeting PLK1 in non-small cell lung cancer. Oncol Rep. 35:497–503. 2016. View Article : Google Scholar : PubMed/NCBI
11	Liu Y, Miao L, Ni R, Zhang H, Li L, Wang X, Li X and Wang J: microRNA-520a-3p inhibits proliferation and cancer stem cell phenotype by targeting HOXD8 in non-small cell lung cancer. Oncol Rep. 36:3529–3535. 2016. View Article : Google Scholar : PubMed/NCBI
12	Wang D, Ma J, Ji X, Xu F and Wei Y: miR-141 regulation of EIF4E expression affects docetaxel chemoresistance of non-small cell lung cancer. Oncol Rep. 37:608–616. 2017. View Article : Google Scholar : PubMed/NCBI
13	Zhou L, Di Q, Sun B, Wang X, Li M and Shi J: MicroRNA-194 restrains the cell progression of non-small cell lung cancer by targeting human nuclear distribution protein C. Oncol Rep. 35:3435–3444. 2016. View Article : Google Scholar : PubMed/NCBI
14	Chen X, Wei L and Zhao S: miR-338 inhibits the metastasis of lung cancer by targeting integrin β3. Oncol Rep. 36:1467–1474. 2016. View Article : Google Scholar : PubMed/NCBI
15	Wu X, Liu T, Fang O, Dong W, Zhang F, Leach L, Hu X and Luo Z: MicroRNA-708-5p acts as a therapeutic agent against metastatic lung cancer. Oncotarget. 7:2417–2432. 2016.PubMed/NCBI
16	Li D, Du X, Liu A and Li P: Suppression of nucleosome-binding protein 1 by miR-326 impedes cell proliferation and invasion in non-small cell lung cancer cells. Oncol Rep. 35:1117–1124. 2016. View Article : Google Scholar : PubMed/NCBI
17	Taylor MA, Wappett M, Delpuech O, Brown H and Chresta CM: Enhanced MAPK signaling drives ETS1-mediated induction of miR-29b leading to downregulation of TET1 and changes in epigenetic modifications in a subset of lung SCC. Oncogene. 35:4345–4357. 2016. View Article : Google Scholar : PubMed/NCBI
18	Olbromski M, Grzegrzolka J, Jankowska-Konsur A, Witkiewicz W, Podhorska-Okolow M and Dziegiel P: MicroRNAs modulate the expression of the SOX18 transcript in lung squamous cell carcinoma. Oncol Rep. 36:2884–2892. 2016. View Article : Google Scholar : PubMed/NCBI
19	Altuvia Y, Landgraf P, Lithwick G, Elefant N, Pfeffer S, Aravin A, Brownstein MJ, Tuschl T and Margalit H: Clustering and conservation patterns of human microRNAs. Nucleic Acids Res. 33:2697–2706. 2005. View Article : Google Scholar : PubMed/NCBI
20	Bentwich I, Avniel A, Karov Y, Aharonov R, Gilad S, Barad O, Barzilai A, Einat P, Einav U, Meiri E, et al: Identification of hundreds of conserved and nonconserved human microRNAs. Nat Genet. 37:766–770. 2005. View Article : Google Scholar : PubMed/NCBI
21	Veerla S, Lindgren D, Kvist A, Frigyesi A, Staaf J, Persson H, Liedberg F, Chebil G, Gudjonsson S, Borg A, et al: MiRNA expression in urothelial carcinomas: Important roles of miR-10a, miR-222, miR-125b, miR-7 and miR-452 for tumor stage and metastasis, and frequent homozygous losses of miR-31. Int J Cancer. 124:2236–2242. 2009. View Article : Google Scholar : PubMed/NCBI
22	Liu SG, Qin XG, Zhao BS, Qi B, Yao WJ, Wang TY, Li HC and Wu XN: Differential expression of miRNAs in esophageal cancer tissue. Oncol Lett. 5:1639–1642. 2013. View Article : Google Scholar : PubMed/NCBI
23	Zheng Q, Sheng Q, Jiang C, Shu J, Chen J, Nie Z, Lv Z and Zhang Y: MicroRNA-452 promotes tumorigenesis in hepatocellular carcinoma by targeting cyclin-dependent kinase inhibitor 1B. Mol Cell Biochem. 389:187–195. 2014. View Article : Google Scholar : PubMed/NCBI
24	Hu Q, Gong JP, Li J, Zhong SL, Chen WX, Zhang JY, Ma TF, Ji H, Lv MM, Zhao JH and Tang JH: Down-regulation of miRNA-452 is associated with adriamycin-resistance in breast cancer cells. Asian Pac J Cancer Prev. 15:5137–5142. 2014. View Article : Google Scholar : PubMed/NCBI
25	Kristensen H, Haldrup C, Strand S, Mundbjerg K, Mortensen MM, Thorsen K, Ostenfeld MS, Wild PJ, Arsov C, Goering W, et al: Hypermethylation of the GABRE~miR-452~miR-224 promoter in prostate cancer predicts biochemical recurrence after radical prostatectomy. Clin Cancer Res. 20:2169–2181. 2014. View Article : Google Scholar : PubMed/NCBI
26	Liu L, Chen K, Wu J, Shi L, Hu B, Cheng S, Li M and Song L: Downregulation of miR-452 promotes stem-like traits and tumorigenicity of gliomas. Clin Cancer Res. 19:3429–3438. 2013. View Article : Google Scholar : PubMed/NCBI
27	Zhang Y, Han L, Pang J, Wang Y, Feng F and Jiang Q: Expression of microRNA-452 via adenoviral vector inhibits non-small cell lung cancer cells proliferation and metastasis. Tumour Biol. 37:8259–8270. 2016. View Article : Google Scholar : PubMed/NCBI
28	He Z, Xia Y, Pan C, Ma T, Liu B, Wang J, Chen L and Chen Y: Up-regulation of MiR-452 inhibits metastasis of non-small cell lung cancer by regulating BMI1. Cell Physiol Biochem. 37:387–398. 2015. View Article : Google Scholar : PubMed/NCBI
29	He Z, Xia Y, Liu B, Qi X, Li Z, Wang J, Chen L and Chen Y: Down-regulation of miR-452 is associated with poor prognosis in the non-small-cell lung cancer. J Thorac Dis. 8:894–900. 2016. View Article : Google Scholar : PubMed/NCBI
30	Merico D, Isserlin R, Stueker O, Emili A and Bader GD: Enrichment map: A network-based method for gene-set enrichment visualization and interpretation. PLoS One. 5:e139842010. View Article : Google Scholar : PubMed/NCBI
31	Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B and Ideker T: Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 13:2498–2504. 2003. View Article : Google Scholar : PubMed/NCBI
32	Shannon PT, Grimes M, Kutlu B, Bot JJ and Galas DJ: RCytoscape: Tools for exploratory network analysis. BMC Bioinformatics. 14:2172013. View Article : Google Scholar : PubMed/NCBI
33	Beckers A, Van Peer G, Carter DR, Mets E, Althoff K, Cheung BB, Schulte JH, Mestdagh P, Vandesompele J, Marshall GM, et al: MYCN-targeting miRNAs are predominantly downregulated during MYCN-driven neuroblastoma tumor formation. Oncotarget. 6:5204–5216. 2015. View Article : Google Scholar : PubMed/NCBI
34	Wang J, Chu ES, Chen HY, Man K, Go MY, Huang XR, Lan HY, Sung JJ and Yu J: microRNA-29b prevents liver fibrosis by attenuating hepatic stellate cell activation and inducing apoptosis through targeting PI3K/AKT pathway. Oncotarget. 6:7325–7338. 2015.PubMed/NCBI
35	Zou ZJ, Fan L, Wang L, Xu J, Zhang R, Tian T, Li JY and Xu W: miR-26a and miR-214 down-regulate expression of the PTEN gene in chronic lymphocytic leukemia, but not PTEN mutation or promoter methylation. Oncotarget. 6:1276–1285. 2015. View Article : Google Scholar : PubMed/NCBI
36	Li J, Guan J, Long X, Wang Y and Xiang X: mir-1-mediated paracrine effect of cancer-associated fibroblasts on lung cancer cell proliferation and chemoresistance. Oncol Rep. 35:3523–3531. 2016. View Article : Google Scholar : PubMed/NCBI
37	Peng J, Liu HZ, Zhong J, Deng ZF, Tie CR, Rao Q, Xu W, You T, Li J, Cai CB, et al: MicroRNA-187 is an independent prognostic factor in lung cancer and promotes lung cancer cell invasion via targeting of PTRF. Oncol Rep. 36:2609–2618. 2016. View Article : Google Scholar : PubMed/NCBI
38	Fukazawa T, Guo M, Ishida N, Yamatsuji T, Takaoka M, Yokota E, Haisa M, Miyake N, Ikeda T, Okui T, et al: SOX2 suppresses CDKN1A to sustain growth of lung squamous cell carcinoma. Sci Rep. 6:201132016. View Article : Google Scholar : PubMed/NCBI
39	Cannell IG, Merrick KA, Morandell S, Zhu CQ, Braun CJ, Grant RA, Cameron ER, Tsao MS, Hemann MT and Yaffe MB: A pleiotropic RNA-binding protein controls distinct cell cycle checkpoints to drive resistance of p53-defective tumors to chemotherapy. Cancer Cell. 28:623–637. 2015. View Article : Google Scholar : PubMed/NCBI