Long non‑coding RNA FEZF1‑AS1 facilitates non‑small cell lung cancer progression via the ITGA11/miR‑516b‑5p axis

Song,Heng; Li,Hui; Ding,Xiaosong; Li,Minglei; Shen,Haitao; Li,Yuehong; Zhang,Xianghong; Xing,Lingxiao

doi:10.3892/ijo.2020.5142

Long non‑coding RNA FEZF1‑AS1 facilitates non‑small cell lung cancer progression via the ITGA11/miR‑516b‑5p axis

Authors:
- Heng Song
- Hui Li
- Xiaosong Ding
- Minglei Li
- Haitao Shen
- Yuehong Li
- Xianghong Zhang
- Lingxiao Xing
View Affiliations

Affiliations: Department of Pathology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China, Department of Pathology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
Published online on: October 29, 2020 https://doi.org/10.3892/ijo.2020.5142
Pages: 1333-1347
Copyright: © Song 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

Long non‑coding RNAs (lncRNAs) have emerged as key players in the development and progression of cancer. FEZ family zinc finger 1 antisense RNA 1 (FEZF1‑AS1) is a novel lncRNA that is involved in the development of cancer and acts as a potential biomarker for cancer. However, the clinical significance and molecular mechanism of FEZF1‑AS1 in non‑small cell lung cancer (NSCLC) remains uncertain. In the present study, FEZF1‑AS1 was selected using Arraystar Human lncRNA microarray and was identified to be upregulated in NSCLC tissues and negatively associated with the overall survival of patients with NSCLC. Loss‑of‑function assays revealed that FEZF1‑AS1 inhibition decreased cell proliferation and migration, and arrested cells at the G2/M cell cycle phase. Mechanistically, FEZF1‑AS1 expression was influenced by N6‑methyladenosine (m6A) modification. Since FEZF1‑AS1 was mainly located in the cytoplasmic fraction of NSCLC cells, it was hypothesized that it may be involved in competing endogenous RNA regulatory network to impact the prognosis of NSCLC. Via integrating Arraystar Human mRNA microarray data and miRNA bioinformatics analysis, it was revealed that ITGA11 expression was decreased with loss of FEZF1‑AS1 and increased with gain of FEZF1‑AS1 expression, and microRNA (miR)‑516b‑5p inhibited the expression levels of both FEZF1‑AS and ITGA11. RNA‑binding protein immunoprecipitation and RNA pulldown assays further demonstrated that FEZF1‑AS1 could bind to miR‑516b‑5p and that ITGA11 was a direct target of miR‑516b‑5p by luciferase reporter assay. Overall, the present findings demonstrated that FEZF1‑AS1 was upregulated and acted as an oncogene in NSCLC by regulating the ITGA11/miR‑516b‑5p axis, suggesting that FEZF1‑AS1 may be a potential prognostic biomarker and therapeutic target for NSCLC.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2020. CA Cancer J Clin. 70:7–30. 2020. View Article : Google Scholar : PubMed/NCBI
2	Bade BC and Dela Cruz CS: Lung cancer 2020: Epidemiology, etiology, and prevention. Clin Chest Med. 41:1–24. 2020. View Article : Google Scholar : PubMed/NCBI
3	Velcheti V, Schalper KA, Carvajal DE, Anagnostou VK, Syrigos KN, Sznol M, Herbst RS, Gettinger SN, Chen L and Rimm DL: Programmed death ligand-1 expression in non-small cell lung cancer. Lab Invest. 94:107–116. 2014. View Article : Google Scholar
4	Iyer MK, Niknafs YS, Malik R, Singhal U, Sahu A, Hosono Y, Barrette TR, Prensner JR, Evans JR, Zhao S, et al: The landscape of long noncoding RNAs in the human transcriptome. Nat Genet. 47:199–208. 2015. View Article : Google Scholar : PubMed/NCBI
5	Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, et al: Landscape of transcription in human cells. Nature. 489:101–108. 2012. View Article : Google Scholar : PubMed/NCBI
6	Wang KC and Chang HY: Molecular mechanisms of long noncoding RNAs. Mol Cell. 43:904–914. 2011. View Article : Google Scholar : PubMed/NCBI
7	Ulitsky I and Bartel DP: lincRNAs: Genomics, evolution, and mechanisms. Cell. 154:26–46. 2013. View Article : Google Scholar : PubMed/NCBI
8	Rinn JL and Chang HY: Genome regulation by long noncoding RNAs. Annu Rev Biochem. 81:145–166. 2012. View Article : Google Scholar : PubMed/NCBI
9	Ponting CP, Oliver PL and Reik W: Evolution and functions of long noncoding RNAs. Cell. 136:629–641. 2009. View Article : Google Scholar : PubMed/NCBI
10	Du Z, Sun T, Hacisuleyman E, Fei T, Wang X, Brown M, Rinn JL, Lee MG, Chen Y, Kantoff PW and Liu XS: Integrative analyses reveal a long noncoding RNA-mediated sponge regulatory network in prostate cancer. Nat Commun. 7:109822016. View Article : Google Scholar : PubMed/NCBI
11	Yang Y, Chen L, Gu J, Zhang H, Yuan J, Lian Q, Lv G, Wang S, Wu Y, Yang YT, et al: Recurrently deregulated lncRNAs in hepatocellular carcinoma. Nat Commun. 8:144212017. View Article : Google Scholar : PubMed/NCBI
12	Seiler J, Breinig M, Caudron-Herger M, Polycarpou-Schwarz M, Boutros M and Diederichs S: The lncRNA veluct strongly regulates viability of lung cancer cells despite its extremely low abundance. Nucleic Acids Res. 45:5458–5469. 2017. View Article : Google Scholar : PubMed/NCBI
13	Park SM, Choi EY, Bae DH, Sohn HA, Kim SY and Kim YJ: The LncRNA EPEL promotes lung cancer cell proliferation through E2F target activation. Cell Physiol Biochem. 45:1270–1283. 2018. View Article : Google Scholar : PubMed/NCBI
14	Chen N, Guo D, Xu Q, Yang M, Wang D, Peng M, Ding Y, Wang S and Zhou J: Long non-coding RNA FEZF1-AS1 facilitates cell proliferation and migration in colorectal carcinoma. Oncotarget. 7:11271–11283. 2016. View Article : Google Scholar : PubMed/NCBI
15	Wu X, Zhang P, Zhu H, Li S, Chen X and Shi L: Long noncoding RNA FEZF1-AS1 indicates a poor prognosis of gastric cancer and promotes tumorigenesis via activation of Wnt signaling pathway. Biomed Pharmacother. 96:1103–1108. 2017. View Article : Google Scholar : PubMed/NCBI
16	Liu Z, Zhao P, Han Y and Lu S: LincRNA FEZF1-AS1 is associated with prognosis in lung adenocarcinoma and promotes cell proliferation, migration and invasion. Oncol Res. 27:39–45. 2018. View Article : Google Scholar : PubMed/NCBI
17	He R, Zhang FH and Shen N: LncRNA FEZF1-AS1 enhances epithelial-mesenchymal transition (EMT) through suppressing E-cadherin and regulating WNT pathway in non-small cell lung cancer (NSCLC). Biomed Pharmacother. 95:331–338. 2017. View Article : Google Scholar : PubMed/NCBI
18	Zhou C, Xu J, Lin J, Lin R, Chen K, Kong J and Shui X: Long noncoding RNA FEZF1-AS1 promotes osteosarcoma progression by regulating the miR-4443/NUPR1 axis. Oncol Res. 26:1335–1343. 2018.PubMed/NCBI
19	Ye H, Zhou Q, Zheng S, Li G, Lin Q, Ye L, Wang Y, Wei L, Zhao X, Li W, et al: FEZF1-AS1/miR-107/ZNF312B axis facilitates progression and Warburg effect in pancreatic ductal adenocarcinoma. Cell Death Dis. 9:342018. View Article : Google Scholar : PubMed/NCBI
20	Li QY, Chen L, Hu N and Zhao H: Long non-coding RNA FEZF1-AS1 promotes cell growth in multiple myeloma via miR-610/Akt3 axis. Biomed Pharmacother. 103:1727–1732. 2018. View Article : Google Scholar : PubMed/NCBI
21	Goldstraw P, Chansky K, Crowley J, Rami-Porta R, Asamura H, Eberhardt WE, Nicholson AG, Groome P, Mitchell A, Bolejack V, et al: The IASLC lung cancer staging project: Proposals for revision of the TNM stage groupings in the forthcoming (Eighth) Edition of the TNM classification for lung cancer. J Thorac Oncol. 11:39–51. 2016. View Article : Google Scholar : PubMed/NCBI
22	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
23	Zhou Y, Zeng P, Li YH, Zhang Z and Cui Q: SRAMP: Prediction of mammalian N6-methyladenosine (m6A) sites based on sequence-derived features. Nucleic Acids Res. 44:e912016. View Article : Google Scholar : PubMed/NCBI
24	Backlund PS Jr, Carotti D and Cantoni GL: Effects of the S-adenosylhomocysteine hydrolase inhibitors 3-deazaadenosine and 3-deazaaristeromycin on RNA methylation and synthesis. Eur J Biochem. 160:245–251. 1986. View Article : Google Scholar : PubMed/NCBI
25	Wang K, Long B, Zhou LY, Liu F, Zhou QY, Liu CY, Fan YY and Li PF: CARL lncRNA inhibits anoxia-induced mitochondrial fission and apoptosis in cardiomyocytes by impairing miR-539-dependent PHB2 downregulation. Nat Commun. 5:35962014. View Article : Google Scholar : PubMed/NCBI
26	Wang Y, Ding X, Liu B, Li M, Chang Y, Shen H, Xie SM, Xing L and Li Y: ETV4 overexpression promotes progression of non-small cell lung cancer by upregulating PXN and MMP1 transcriptionally. Mol Carcinog. 59:73–86. 2020. View Article : Google Scholar
27	Fu Y, Dominissini D, Rechavi G and He C: Gene expression regulation mediated through reversible m⁶A RNA methylation. Nat Rev Genet. 15:293–306. 2014. View Article : Google Scholar : PubMed/NCBI
28	Cheloufi S, Dos Santos CO, Chong MM and Hannon GJ: A dicer-independent miRNA biogenesis pathway that requires Ago catalysis. Nature. 465:584–589. 2010. View Article : Google Scholar : PubMed/NCBI
29	Mao Z, Wu F and Shan Y: Identification of key genes and miRNAs associated with carotid atherosclerosis based on mRNA-seq data. Medicine (Baltimore). 97:e98322018. View Article : Google Scholar
30	Li Z, Jia J, Gou J, Tong A, Liu X, Zhao X and Yi T: Mmu-miR-126a-3p plays a role in murine embryo implantation by regulating Itga11. Reprod Biomed Online. 31:384–393. 2015. View Article : Google Scholar : PubMed/NCBI
31	Huang TC, Renuse S, Pinto S, Kumar P, Yang Y, Chaerkady R, Godsey B, Mendell JT, Halushka MK, Civin CI, et al: Identification of miR-145 targets through an integrated omics analysis. Mol Biosyst. 11:197–207. 2015. View Article : Google Scholar :
32	Zhang HH and Li AH: Long non-coding RNA FEZF1-AS1 is up-regulated and associated with poor prognosis in patients with cervical cancer. Eur Rev Med Pharmacol Sci. 22:3357–3362. 2018.PubMed/NCBI
33	Zhang Z, Sun L, Zhang Y, Lu G, Li Y and Wei Z: Long non-coding RNA FEZF1-AS1 promotes breast cancer stemness and tumorigenesis via targeting miR-30a/Nanog axis. J Cell Physiol. 233:8630–8638. 2018. View Article : Google Scholar : PubMed/NCBI
34	Zhao BS, Roundtree IA and He C: Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol. 18:31–42. 2017. View Article : Google Scholar
35	Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M, et al: Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 485:201–206. 2012. View Article : Google Scholar : PubMed/NCBI
36	Alarcon CR, Goodarzi H, Lee H, Liu X, Tavazoie S and Tavazoie SF: HNRNPA2B1 is a mediator of m(6)A-dependent nuclear RNA processing events. Cell. 162:1299–1308. 2015. View Article : Google Scholar : PubMed/NCBI
37	Guo F, Li Y, Liu Y, Wang J, Li Y and Li G: Inhibition of metastasis-associated lung adenocarcinoma transcript 1 in CaSki human cervical cancer cells suppresses cell proliferation and invasion. Acta Biochim Biophys Sin (Shanghai). 42:224–229. 2010. View Article : Google Scholar
38	Patil DP, Chen CK, Pickering BF, Chow A, Jackson C, Guttman M and Jaffrey SR: m(6)A RNA methylation promotes XIST-mediated transcriptional repression. Nature. 537:369–373. 2016. View Article : Google Scholar : PubMed/NCBI
39	Takada Y, Ye X and Simon S: The integrins. Genome Biol. 8:2152007. View Article : Google Scholar : PubMed/NCBI
40	Hegde S and Raghavan S: A skin-depth analysis of integrins: Role of the integrin network in health and disease. Cell Commun Adhes. 20:155–169. 2013. View Article : Google Scholar : PubMed/NCBI
41	Tiger CF, Fougerousse F, Grundström G, Velling T and Gullberg D: alpha11beta1 integrin is a receptor for interstitial collagens involved in cell migration and collagen reorganization on mesenchymal nonmuscle cells. Dev Biol. 237:116–129. 2001. View Article : Google Scholar : PubMed/NCBI
42	Chai J, Modak C, Ouyang Y, Wu SY and Jamal MM: CCN1 induces ß-catenin translocation in esophageal squamous cell carcinoma through integrin a11. ISRN Gastroenterol. 2012:2072352012. View Article : Google Scholar
43	Parajuli H, Teh MT, Abrahamsen S, Christoffersen I, Neppelberg E, Lybak S, Osman T, Johannessen AC, Gullberg D, Skarstein K and Costea DE: Integrin a11 is overexpressed by tumour stroma of head and neck squamous cell carcinoma and correlates positively with alpha smooth muscle actin expression. J Oral Pathol Med. 46:267–275. 2017. View Article : Google Scholar
44	Reigstad I, Smeland HY, Skogstrand T, Sortland K, Schmid MC, Reed RK and Stuhr L: Stromal integrin a11ß1 affects RM11 prostate and 4T1 breast xenograft tumors differently. PLoS One. 11:e01516632016. View Article : Google Scholar
45	Zhu CQ, Popova SN, Brown ER, Barsyte-Lovejoy D, Navab R, Shih W, Li M, Lu M, Jurisica I, Penn LZ, et al: Integrin alpha 11 regulates IGF2 expression in fibroblasts to enhance tumorigenicity of human non-small-cell lung cancer cells. Proc Natl Acad Sci USA. 104:11754–11759. 2007. View Article : Google Scholar : PubMed/NCBI
46	Wu P, Wang Y, Wu Y, Jia Z, Song Y and Liang N: Expression and prognostic analyses of ITGA11, ITGB4 and ITGB8 in human non-small cell lung cancer. PeerJ. 7:e82992019. View Article : Google Scholar :
47	Qi L, Gao C, Feng F, Zhang T, Yao Y, Wang X, Liu C, Li J, Li J and Sun C: MicroRNAs associated with lung squamous cell carcinoma: New prognostic biomarkers and therapeutic targets. J Cell Biochem. 120:18956–18966. 2019. View Article : Google Scholar : PubMed/NCBI