E74‑like ETS transcription factor 5 facilitates cell proliferation through regulating the expression of adenomatous polyposis coli 2 in non‑small cell lung cancer

Wen,Jing; Wen,Jing; Qin,Genggeng; Qin,Genggeng; Jiang,Zhaojing; Jiang,Zhaojing; Lin,Zixun; Lin,Zixun; Zhou,Ruixin; Zhou,Ruixin; Dai,Hui; Dai,Hui; Xu,Zhanfa; Xu,Zhanfa; Chen,Weiguo; Chen,Weiguo; Song,Qiancheng; Song,Qiancheng

doi:10.3892/ijmm.2023.5278

E74‑like ETS transcription factor 5 facilitates cell proliferation through regulating the expression of adenomatous polyposis coli 2 in non‑small cell lung cancer

Authors:
- Jing Wen
- Genggeng Qin
- Zhaojing Jiang
- Zixun Lin
- Ruixin Zhou
- Hui Dai
- Zhanfa Xu
- Weiguo Chen
- Qiancheng Song
View Affiliations

Affiliations: Department of Radiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, Hospital Office, Ganzhou Hospital‑Nanfang Hospital, Southern Medical University, Ganzhou, Jiangxi 341000, P.R. China
Published online on: July 11, 2023 https://doi.org/10.3892/ijmm.2023.5278
Article Number: 75
Copyright: © Wen 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

E74‑like ETS transcription factor 5 (ELF5) is known to regulate the specification and differentiation of epithelial cells in the embryonic lung. However, the pathological function of ELF5 in lung cancer has yet to be fully elucidated. In the present study, the expression of ELF5 was found to be significantly higher in lung adenocarcinoma compared with that in corresponding adjacent normal tissues. Subsequently, cell and animal experiments were performed to investigate the role of ELF5 in lung adenocarcinoma cells. The results indicated that the overexpression of ELF5 increased the proliferation of lung adenocarcinoma cells, whereas, by contrast, a reduction in the expression of ELF5 led to a decrease in their proliferation. Mechanistically, the hypothesis is advanced that ELF5 can promote lung cancer cell proliferation through inhibiting adenomatous polyposis coli 2 and increasing the expression of cyclin D1, which is a critical downstream target of the Wnt pathway. Taken together, these findings support the notion that ELF5 exerts an essential role in the proliferation of lung adenocarcinoma cells and may be a therapeutic target for the treatment of lung adenocarcinoma.

View Figures

View References

1	Metzger DE, Stahlman MT and Shannon JM: Misexpression of ELF5 disrupts lung branching and inhibits epithelial differentiation. Dev Biol. 320:149–160. 2008. View Article : Google Scholar : PubMed/NCBI
2	Metzger DE, Xu Y and Shannon JM: Elf5 is an epithelium-specific, fibroblast growth factor-sensitive transcription factor in the embryonic lung. Dev Dyn. 236:1175–1192. 2007. View Article : Google Scholar : PubMed/NCBI
3	Yao B, Zhao J, Li Y, Li H, Hu Z, Pan P, Zhang Y, Du E, Liu R and Xu Y: Elf5 inhibits TGF-β-driven epithelial-mesenchymal transition in prostate cancer by repressing SMAD3 activation. Prostate. 75:872–882. 2015. View Article : Google Scholar : PubMed/NCBI
4	Li K, Guo Y, Yang X, Zhang Z, Zhang C and Xu Y: ELF5-mediated AR activation regulates prostate cancer progression. Sci Rep. 7:427592017. View Article : Google Scholar : PubMed/NCBI
5	Wu B, Cao X, Liang X, Zhang X, Zhang W, Sun G and Wang D: Epigenetic regulation of Elf5 is associated with epithelial-mesenchymal transition in urothelial cancer. PLoS One. 10:e01175102015. View Article : Google Scholar :
6	Yan H, Qiu L, Xie X, Yang H, Liu Y, Lin X and Huang H: ELF5 in epithelial ovarian carcinoma tissues and biological behavior in ovarian carcinoma cells. Oncol Rep. 37:1412–1418. 2017. View Article : Google Scholar : PubMed/NCBI
7	Hu Y, Yan Y, Xu Y, Yang H, Fang L, Liu Y, Li X, Li Q and Yan H: Expression and clinical significance of WWOX, Elf5, Snail1 and EMT related factors in epithelial ovarian cancer. Oncol Lett. 19:1281–1290. 2020.
8	Singh S, Kumar S, Srivastava RK, Nandi A, Thacker G, Muralil H, Kim S, Baldeon M, Tobias J, Blanco MA, et al: Loss of ELF5-FBXW7 stabilizes IFNGR1 to promote the growth and metastasis of triple-negative breast cancer through interferon-γ signalling. Nat Cell Biol. 22:591–602. 2020. View Article : Google Scholar : PubMed/NCBI
9	Piggin CL, Roden DL, Law AMK, Molloy MP, Krisp C, Swarbrick A, Naylor MJ, Kalyuga M, Kaplan W, Oakes SR, et al: ELF5 modulates the estrogen receptor cistrome in breast cancer. PLoS Genet. 16:e10085312020. View Article : Google Scholar :
10	Yao F, Wang X, Cui ZK, Lan H, Ai X, Song Q, Chen Z, Yang J, Wu B and Bai X: ETS2 promotes epithelial-to-mesenchymal transition in renal fibrosis by targeting JUNB transcription. Lab Invest. 100:438–453. 2020. View Article : Google Scholar
11	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
12	Takasaki Y, Deng JS and Tan EM: A nuclear antigen associated with cell proliferation and blast transformation. J Exp Med. 154:1899–1909. 1981. View Article : Google Scholar : PubMed/NCBI
13	Juríková M, Danihel Ľ, Polák Š and Varga I: Ki67, PCNA, and MCM proteins: Markers of proliferation in the diagnosis of breast cancer. Acta Histochem. 118:544–552. 2016. View Article : Google Scholar : PubMed/NCBI
14	Castro-Mondragon JA, Riudavets-Puig R, Rauluseviciute I, Lemma RB, Turchi L, Blanc-Mathieu R, Lucas J, Boddie P, Khan A, Manosalva Pérez N, et al: JASPAR 2022: The 9th release of the open-access database of transcription factor binding profiles. Nucleic Acids Res. 50(D1): D165–D173. 2022. View Article : Google Scholar :
15	Barta JA, Powell CA and Wisnivesky JP: Global epidemiology of lung cancer. Ann Glob Health. 85:82019. View Article : Google Scholar : PubMed/NCBI
16	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
17	Zhou J, Chehab R, Tkalcevic J, Naylor MJ, Harris J, Wilson TJ, Tsao S, Tellis I, Zavarsek S, Xu D, et al: Elf5 is essential for early embryogenesis and mammary gland development during pregnancy and lactation. EMBO J. 24:635–644. 2005. View Article : Google Scholar :
18	Oakes SR, Naylor MJ, Asselin-Labat ML, Blazek KD, Gardiner-Garden M, Hilton HN, Kazlauskas M, Pritchard MA, Chodosh LA, Pfeffer PL, et al: The Ets transcription factor Elf5 specifies mammary alveolar cell fate. Gene Dev. 22:581–586. 2008. View Article : Google Scholar : PubMed/NCBI
19	Kalyuga M, Gallego-Ortega D, Lee HJ, Roden DL, Cowley MJ, Caldon CE, Stone A, Allerdice SL, Valdes-Mora F, Launchbury R, et al: ELF5 suppresses estrogen sensitivity and underpins the acquisition of antiestrogen resistance in luminal breast cancer. PLoS Biol. 10:e10014612012. View Article : Google Scholar
20	Luk IY, Reehorst CM and Mariadason JM: ELF3, ELF5, EHF and SPDEF transcription factors in tissue homeostasis and cancer. Molecules. 23:21912018. View Article : Google Scholar : PubMed/NCBI
21	Bonner AE, Lemon WJ, Devereux TR, Lubet RA and You M: Molecular profiling of mouse lung tumors: Association with tumor progression, lung development, and human lung adenocarcinomas. Oncogene. 23:1166–1176. 2004. View Article : Google Scholar
22	Miura K, Bowman ED, Simon R, Peng AC, Robles AI, Jones RT, Katagiri T, He P, Mizukami H, Charboneau L, et al: Laser capture microdissection and microarray expression analysis of lung adenocarcinoma reveals tobacco smoking- and prognosis-related molecular profiles. Cancer Res. 62:3244–3250. 2002.PubMed/NCBI
23	Zhang K, Wang J, Yang L, Yuan YC, Tong TR, Wu J, Yun X, Bonner M, Pangeni R, Liu Z, et al: Targeting histone methyltransferase G9a inhibits growth and Wnt signaling pathway by epigenetically regulating HP1α and APC2 gene expression in non-small cell lung cancer. Mol Cancer. 17:1532018. View Article : Google Scholar
24	Croy HE, Fuller CN, Giannotti J, Robinson P, Foley AVA, Yamulla RJ, Cosgriff S, Greaves BD, von Kleeck RA, An HH, et al: The Poly(ADP-ribose) polymerase enzyme tankyrase antagonizes activity of the β-catenin destruction complex through ADP-ribosylation of axin and APC2. J Biol Chem. 291:12747–12760. 2016. View Article : Google Scholar : PubMed/NCBI
25	Dai B, Kong DL, Tian J, Liu TW, Zhou H and Wang ZF: microRNA-1205 promotes cell growth by targeting APC2 in lung adenocarcinoma. Eur Rev Med Pharmacol Sci. 23:1125–1133. 2019.PubMed/NCBI
26	Dong Y, Wu B, Wang X, Lu F, Li Q and Zhao Q: High miR-3648 expression and low APC2 expression are associated with shorter survival and tumor progression in NSCLC. Histol Histopathol. 37:355–364. 2022.
27	Ge YX, Wang CH, Hu FY, Pan LX, Min J, Niu KY, Zhang L, Li J and Xu T: New advances of TMEM88 in cancer initiation and progression, with special emphasis on Wnt signaling pathway. J Cell Physiol. 233:79–87. 2018. View Article : Google Scholar
28	Rimerman RA, Gellert-Randleman A and Diehl JA: Wnt1 and MEK1 cooperate to promote cyclin D1 accumulation and cellular transformation. J Biol Chem. 275:14736–14742. 2000. View Article : Google Scholar
29	Varma S, Cao Y, Tagne JB, Lakshminarayanan M, Li J, Friedman TB, Morell RJ, Warburton D, Kotton DN and Ramirez MI: The transcription factors Grainyhead-like 2 and NK2-homeobox 1 form a regulatory loop that coordinates lung epithelial cell morphogenesis and differentiation. J Biol Chem. 287:37282–37295. 2012. View Article : Google Scholar : PubMed/NCBI
30	Kersbergen A, Best SA, Dworkin S, Ah-Cann C, de Vries ME, Asselin-Labat ML, Ritchie ME, Jane SM and Sutherland KD: Lung morphogenesis is orchestrated through Grainyhead-like 2 (Grhl2) transcriptional programs. Dev Biol. 443:1–9. 2018. View Article : Google Scholar : PubMed/NCBI
31	Gao X, Bali AS, Randell SH and Hogan BLM: GRHL2 coordinates regeneration of a polarized mucociliary epithelium from basal stem cells. J Cell Biol. 211:669–682. 2015. View Article : Google Scholar :
32	Pan X, Zhang R, Xie C, Gan M, Yao S, Yao YB, Jin J, Han T, Huang Y, Gong Y, et al: GRHL2 suppresses tumor metastasis via regulation of transcriptional activity of RhoG in non-small cell lung cancer. Am J Transl Res. 9:4217–4226. 2017.PubMed/NCBI
33	Werner S, Frey S, Riethdorf S, Schulze C, Alawi M, Kling L, Vafaizadeh V, Sauter G, Terracciano L, Schumacher U, et al: Dual roles of the transcription factor grainyhead-like 2 (GRHL2) in breast cancer. J Biol Chem. 288:22993–23008. 2013. View Article : Google Scholar : PubMed/NCBI
34	He J, Feng C, Zhu H, Wu S, Jin P and Xu T: Grainyhead-like 2 as a double-edged sword in development and cancer. Am J Transl Res. 12:310–331. 2020.PubMed/NCBI