Prospective lncRNA-miRNA-mRNA regulatory network of long non-coding RNA LINC00968 in non-small cell lung cancer A549 cells: A miRNA microarray and bioinformatics investigation

Li,Dong-Yao; Chen,Wen-Jie; Luo,Lei; Wang,Yong-Kun; Shang,Jun; Zhang,Yu; Chen,Gang; Li,Shi-Kang

doi:10.3892/ijmm.2017.3187

Prospective lncRNA-miRNA-mRNA regulatory network of long non-coding RNA LINC00968 in non-small cell lung cancer A549 cells: A miRNA microarray and bioinformatics investigation

Authors:
- Dong-Yao Li
- Wen-Jie Chen
- Lei Luo
- Yong-Kun Wang
- Jun Shang
- Yu Zhang
- Gang Chen
- Shi-Kang Li
View Affiliations

Affiliations: Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China, Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
Published online on: October 12, 2017 https://doi.org/10.3892/ijmm.2017.3187
Pages: 1895-1906

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

Accumulating evidence suggests that the dysregulation of long non-coding RNAs (lncRNAs) serves vital roles in the incidence and progression of lung cancer. However, the molecular mechanisms of LINC00968, a recently identified lncRNA, remain unknown. The objective of present study was to investigate the role of a prospective lncRNA-miRNA‑mRNA network regulated by LINC00968 in non-small cell lung cancer cells. Following the transfection of lentiviruses carrying LINC00968 into A549 cells, the microRNA (miRNA) expression profile of the cells in response to the overexpression of LINC00968 was detected using an miRNA microarray. Five differentially expressed miRNAs (DEMs) with LINC00968 overexpression were obtained, including miR-9-3p, miR‑22-5p, miR-668-3p, miR‑3675-3p and miR-4536-3p. Five target prediction algorithms and three target validation algorithms were used to obtain 1,888 prospective target genes of the five DEMs. The result of Gene Ontology analysis suggested that these five DEMs were involved in complex cellular pathways, which included intracellular transport, organelle lumen and nucleotide binding. Furthermore, analysis of Kyoto Encyclopedia of Genes and Genomes pathways indicated that the five DEMs were important regulators in the adherens junction and focal adhesion. An lncRNA-miRNA-mRNA regulatory network and a protein-protein interaction network were then constructed. Eventually, a prospective lncRNA‑miRNA-mRNA regulatory network of LINC00968, three miRNAs (miR-9, miR-22 and miR-4536) and two genes (polo-like kinase 1 and exportin-1) was obtained following validation in the Cancer Genome Atlas database. These results may provide novel insights to support future research into lncRNA in lung cancer.

View Figures

View References

1	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	Torre LA, Siegel RL and Jemal A: Lung Cancer Statistics. Adv Exp Med Biol. 893:1–19. 2016. View Article : Google Scholar
3	Chen Z, Fillmore CM, Hammerman PS, Kim CF and Wong KK: Non-small-cell lung cancers: A heterogeneous set of diseases. Nat Rev Cancer. 14:535–546. 2014. View Article : Google Scholar : PubMed/NCBI
4	Zhou M, Li J, Li C, Guo L, Wang X, He Q, Fu Y and Zhang Z: Tertiary amine mediated targeted therapy against metastatic lung cancer. J Control Release. 241:81–93. 2016. View Article : Google Scholar : PubMed/NCBI
5	Khandelwal A, Bacolla A, Vasquez KM and Jain A: Long non-coding RNA: A new paradigm for lung cancer. Mol Carcinog. 54:1235–1251. 2015. View Article : Google Scholar : PubMed/NCBI
6	Castellano JJ, Navarro A, Viñolas N, Marrades RM, Moises J, Cordeiro A, Saco A, Muñoz C, Fuster D, Molins L, Ramirez J and Monzo M: LincRNA-p21 impacts prognosis in resected non-small cell lung cancer patients through angiogenesis regulation. J Thorac Oncol. 11:2173–2182. 2016. View Article : Google Scholar : PubMed/NCBI
7	Chang TH, Tsai MF, Gow CH, Wu SG, Liu YN, Chang YL, Yu SL, Tsai HC, Lin SW, Chen YW, et al: Upregulation of microRNA-137 expression by Slug promotes tumor invasion and metastasis of non-small cell lung cancer cells through suppression of TFAP2C. Cancer Lett. 402:190–202. 2017. View Article : Google Scholar : PubMed/NCBI
8	Bonasio R and Shiekhattar R: Regulation of transcription by long noncoding RNAs. Annu Rev Genet. 48:433–455. 2014. View Article : Google Scholar : PubMed/NCBI
9	Duval M, Cossart P and Lebreton A: Mammalian microRNAs and long noncoding RNAs in the host-bacterial pathogen crosstalk. Semin Cell Dev Biol. 65:11–19. 2016. View Article : Google Scholar : PubMed/NCBI
10	Yuan JH, Yang F, Wang F, Ma JZ, Guo YJ, Tao QF, Liu F, Pan W, Wang TT, Zhou CC, et al: A long noncoding RNA activated by TGF-β promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell. 25:666–681. 2014. View Article : Google Scholar : PubMed/NCBI
11	Shi X, Sun M, Wu Y, Yao Y, Liu H, Wu G, Yuan D and Song Y: Post-transcriptional regulation of long noncoding RNAs in cancer. Tumour Biol. 36:503–513. 2015. View Article : Google Scholar : PubMed/NCBI
12	Zhang H and Zhu JK: Emerging roles of RNA processing factors in regulating long non-coding RNAs. RNA Biol. 11:793–797. 2014. View Article : Google Scholar : PubMed/NCBI
13	Guz M, Rivero-Müller A, Okoń E, Stenzel-Bembenek A, Polberg K, Słomka M and Stepulak A: MicroRNAs-role in lung cancer. Dis Markers. 2014:2181692014. View Article : Google Scholar : PubMed/NCBI
14	Valinezhad Orang A, Safaralizadeh R and Kazemzadeh-Bavili M: Mechanisms of miRNA-Mediated Gene Regulation from Common Downregulation to mRNA-Specific Upregulation. Int J Genomics. 2014:9706072014. View Article : Google Scholar : PubMed/NCBI
15	Liang WC, Fu WM, Wong CW, Wang Y, Wang WM, Hu GX, Zhang L, Xiao LJ, Wan DC, Zhang JF, et al: The lncRNA H19 promotes epithelial to mesenchymal transition by functioning as miRNA sponges in colorectal cancer. Oncotarget. 6:22513–22525. 2015. View Article : Google Scholar : PubMed/NCBI
16	Liz J and Esteller M: lncRNAs and microRNAs with a role in cancer development. Biochim Biophys Acta. 1859:169–176. 2016. View Article : Google Scholar
17	Ye S, Yang L, Zhao X, Song W, Wang W and Zheng S: Bioinformatics method to predict two regulation mechanism: TF-miRNA-mRNA and lncRNA-miRNA-mRNA in pancreatic cancer. Cell Biochem Biophys. 70:1849–1858. 2014. View Article : Google Scholar : PubMed/NCBI
18	Zhang J, Fan D, Jian Z, Chen GG and Lai PB: Cancer specific long noncoding RNAs show differential expression patterns and competing endogenous RNA potential in hepatocellular carcinoma. PLoS One. 10:e01410422015. View Article : Google Scholar : PubMed/NCBI
19	Yang J, Lin J, Liu T, Chen T, Pan S, Huang W and Li S: Analysis of lncRNA expression profiles in non-small cell lung cancers (NSCLC) and their clinical subtypes. Lung Cancer. 85:110–115. 2014. View Article : Google Scholar : PubMed/NCBI
20	Kanehisa M, Sato Y, Kawashima M, Furumichi M and Tanabe M: KEGG as a reference resource for gene and protein annotation. Nucleic Acids Res. 44:D457–D462. 2016. View Article : Google Scholar :
21	Czerwinska U, Calzone L, Barillot E and Zinovyev A: DeDaL: Cytoscape 3 app for producing and morphing data-driven and structure-driven network layouts. BMC Syst Biol. 9:462015. View Article : Google Scholar : PubMed/NCBI
22	Vencken SF, Greene CM and McKiernan PJ: Non-coding RNA as lung disease biomarkers. Thorax. 70:501–503. 2015. View Article : Google Scholar : PubMed/NCBI
23	Song C, Zhang J, Liu Y, Pan H, Qi HP, Cao YG, Zhao JM, Li S, Guo J, Sun HL, et al: Construction and analysis of cardiac hypertrophy-associated lncRNA-mRNA network based on competitive endogenous RNA reveal functional lncRNAs in cardiac hypertrophy. Oncotarget. 7:10827–10840. 2016. View Article : Google Scholar : PubMed/NCBI
24	Lü MH, Tang B, Zeng S, Hu CJ, Xie R, Wu YY, Wang SM, He FT and Yang SM: Long noncoding RNA BC032469, a novel competing endogenous RNA, upregulates hTERT expression by sponging miR-1207-5p and promotes proliferation in gastric cancer. Oncogene. 35:3524–3534. 2016. View Article : Google Scholar
25	Frismantiene A, Kyriakakis E, Dasen B, Erne P, Resink TJ and Philippova M: Actin cytoskeleton regulates functional anchorage-migration switch during T-cadherin-induced phenotype modulation of vascular smooth muscle cells. Cell Adh Migr. 1–17. 2017. View Article : Google Scholar : PubMed/NCBI
26	Pluskota E, Bledzka KM, Bialkowska K, Szpak D, Soloviev DA, Jones SV, Verbovetskiy D and Plow EF: Kindlin-2 interacts with endothelial adherens junctions to support vascular barrier integrity. J Physiol. Aug 11–2017.Epub ahead of print. View Article : Google Scholar : PubMed/NCBI
27	Kleinschmidt EG and Schlaepfer DD: Focal adhesion kinase signaling in unexpected places. Curr Opin Cell Biol. 45:24–30. 2017. View Article : Google Scholar : PubMed/NCBI
28	Song S, Jacobson KN, McDermott KM, Reddy SP, Cress AE, Tang H, Dudek SM, Black SM, Garcia JG, Makino A, et al: ATP promotes cell survival via regulation of cytosolic [Ca²⁺] and Bcl-2/Bax ratio in lung cancer cells. Am J Physiol Cell Physiol. 310:C99–C114. 2016.
29	Galetti M, Petronini PG, Fumarola C, Cretella D, La Monica S, Bonelli M, Cavazzoni A, Saccani F, Caffarra C, Andreoli R, et al: Effect of ABCG2/BCRP expression on efflux and uptake of gefitinib in NSCLC cell lines. PLoS One. 10:e01417952015. View Article : Google Scholar : PubMed/NCBI
30	Holandino C, Teixeira CA, de Oliveira FA, Barbosa GM, Siqueira CM, Messeder DJ, de Aguiar FS, da Veiga VF, Girard-Dias W, Miranda K, et al: Direct electric current treatment modifies mitochondrial function and lipid body content in the A549 cancer cell line. Bioelectrochemistry. 111:83–92. 2016. View Article : Google Scholar : PubMed/NCBI
31	Kim BG, Kwon HY, Sohn EJ, Hwang S, Kwon OS and Kim SH: Activation of caspases and inhibition of ribosome biogenesis mediate antitumor activity of Chijongdan in A549 non-small lung cancer cells. BMC Complement Altern Med. 14:4202014. View Article : Google Scholar : PubMed/NCBI
32	Zhou C, Ye L, Jiang C, Bai J, Chi Y and Zhang H: Long noncoding RNA HOTAIR, a hypoxia-inducible factor-1α activated driver of malignancy, enhances hypoxic cancer cell proliferation, migration, and invasion in non-small cell lung cancer. Tumour Biol. 36:9179–9188. 2015. View Article : Google Scholar : PubMed/NCBI
33	Shao Y, Shen YQ, Li YL, Liang C, Zhang BJ, Lu SD, He YY, Wang P, Sun QL, Jin YX, et al: Direct repression of the oncogene CDK4 by the tumor suppressor miR-486-5p in non-small cell lung cancer. Oncotarget. 7:34011–34021. 2016. View Article : Google Scholar : PubMed/NCBI
34	Dong S, Khoo A, Wei J, Bowser RK, Weathington NM, Xiao S, Zhang L, Ma H, Zhao Y and Zhao J: Serum starvation regulates E-cadherin upregulation via activation of c-Src in non-small-cell lung cancer A549 cells. Am J Physiol Cell Physiol. 307:C893–C899. 2014. View Article : Google Scholar : PubMed/NCBI
35	Xu X, Kim JE, Sun PL, Yoo SB, Kim H, Jin Y and Chung JH: Immunohistochemical demonstration of alteration of β-catenin during tumor metastasis by different mechanisms according to histology in lung cancer. Exp Ther Med. 9:311–318. 2015. View Article : Google Scholar : PubMed/NCBI
36	Bennett DT, Reece TB, Foley LS, Sjoberg A, Meng X, Fullerton DA and Weyant MJ: C-terminal tensin-like protein mediates invasion of human lung cancer cells and is regulated by signal transducer and activator of transcription 3. J Thorac Cardiovasc Surg. 149:369–375. 2015. View Article : Google Scholar
37	Lin TY and Hsu HY: Ling Zhi-8 reduces lung cancer mobility and metastasis through disruption of focal adhesion and induction of MDM2-mediated Slug degradation. Cancer Lett. 375:340–348. 2016. View Article : Google Scholar : PubMed/NCBI
38	Colman MA, Pinali C, Trafford AW, Zhang H and Kitmitto A: A computational model of spatiotemporal cardiac intracellular calcium handling with realistic structure and spatial flux distribution from sarcoplasmic reticulum and t-tubule reconstructions. PLoS Comput Biol. 13:e10057142017. View Article : Google Scholar
39	Mukherjee R, Majumder P and Chakrabarti O: MGRN1 mediated ubiquitination of α-tubulin regulates microtubule dynamics and intracellular transport. Traffic. Sep 13–2017.Epub ahead of print. View Article : Google Scholar
40	Yang Q, Wang Y, Yang Q, Gao Y, Duan X, Fu Q, Chu C, Pan X, Cui X and Sun Y: Cuprous oxide nanoparticles trigger ER stress-induced apoptosis by regulating copper trafficking and overcoming resistance to sunitinib therapy in renal cancer. Biomaterials. 146:72–85. 2017. View Article : Google Scholar : PubMed/NCBI
41	Yuva-Aydemir Y, Simkin A, Gascon E and Gao FB: MicroRNA-9: Functional evolution of a conserved small regulatory RNA. RNA Biol. 8:557–564. 2011. View Article : Google Scholar : PubMed/NCBI
42	Chen X, Zhu L, Ma Z, Sun G, Luo X, Li M, Zhai S, Li P and Wang X: Oncogenic miR-9 is a target of erlotinib in NSCLCs. Sci Rep. 5:170312015. View Article : Google Scholar : PubMed/NCBI
43	Mitra R, Edmonds MD, Sun J, Zhao M, Yu H, Eischen CM and Zhao Z: Reproducible combinatorial regulatory networks elucidate novel oncogenic microRNAs in non-small cell lung cancer. RNA. 20:1356–1368. 2014. View Article : Google Scholar : PubMed/NCBI
44	Xu C, Zheng Y, Lian D, Ye S, Yang J and Zeng Z: Analysis of microRNA expression profile identifies novel biomarkers for non-small cell lung cancer. Tumori. 101:104–110. 2015. View Article : Google Scholar : PubMed/NCBI
45	Xin M, Qiao Z, Li J, Liu J, Song S, Zhao X, Miao P, Tang T, Wang L, Liu W, et al: miR-22 inhibits tumor growth and metastasis by targeting ATP citrate lyase: Evidence in osteosarcoma, prostate cancer, cervical cancer and lung cancer. Oncotarget. 7:44252–44265. 2016. View Article : Google Scholar : PubMed/NCBI
46	Wang XH, Lu Y, Liang JJ, Cao JX, Jin YQ, An GS, Ni JH, Jia HT and Li SY: MiR-509-3-5p causes aberrant mitosis and anti-proliferative effect by suppression of PLK1 in human lung cancer A549 cells. Biochem Biophys Res Commun. 478:676–682. 2016. View Article : Google Scholar : PubMed/NCBI
47	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
48	Chen Y, Camacho C, Silvers TR, Razak AR, Gabrail NY, Gerecitano JF, Kalir E, Pereira E, Evans BR, Ramus SJ, et al: Inhibition of the nuclear export receptor XPO1 as a therapeutic target for platinum resistant ovarian cancer. Clin Cancer Res. 23:1552–1563. 2016. View Article : Google Scholar
49	Kim J, McMillan E, Kim HS, Venkateswaran N, Makkar G, Rodriguez-Canales J, Villalobos P, Neggers JE, Mendiratta S, Wei S, et al: XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer. Nature. 538:114–117. 2016. View Article : Google Scholar : PubMed/NCBI