Knockdown of EIF5A2 inhibits the malignant potential of non-small cell lung cancer cells

Chen,Cheng; Zhang,Bojia; Wu,Shanshan; Song,Yongxiang; Li,Jian

doi:10.3892/ol.2018.7832

Knockdown of EIF5A2 inhibits the malignant potential of non-small cell lung cancer cells

Authors:
- Cheng Chen
- Bojia Zhang
- Shanshan Wu
- Yongxiang Song
- Jian Li
View Affiliations

Affiliations: Department of Thoracic Surgery, Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou 563000, P.R. China, Department of Infectious Disease, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China, Department of Nursing, Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou 563000, P.R. China
Published online on: January 22, 2018 https://doi.org/10.3892/ol.2018.7832
Pages: 4541-4549

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

Eukaryotic translation initiation factor 5A2 (EIF5A2) has been demonstrated to be upregulated in numerous types of human cancer and is associated with cancer progression. However, the expression and role of EIF5A2 in non‑small cell lung cancer (NSCLC) remains unclear. In the present study, the role of EIF5A2 in NSCLC was investigated, in addition to the underlying molecular mechanisms by which EIF5A2 acts. Relative EIF5A2 expression levels were determined in NSCLC cells and compared with levels in non‑cancerous lung tissues. Short interfering (si)RNA targeted against EIF5A2 was used to knock down EIF5A2 levels in NSCLC cells. Cell proliferation, apoptosis rate, migration ability and invasion ability were determined in untreated and siRNA‑treated NSCLC cells, in addition to the relative protein expression levels of various tumorigenic proteins and E‑cadherin. EIF5A2 expression was significantly higher in NSCLC tissues compared with adjacent normal tissues. Knockdown of EIF5A2 in the NSCLC cells significantly inhibited cell proliferation and induced apoptosis. Furthermore, EIF5A2 silencing suppressed cell migratory and invasive capacities in vitro. Silencing of EIF5A2 in the NSCLC cells resulted in the downregulation of the tumorigenic proteins, apoptosis regulator Bcl‑2 and myc proto‑oncogene protein, and upregulation of E‑cadherin, suggesting that EIF5A2 promotes proliferation and metastasis through these proteins. EIF5A2 may therefore serve as a novel therapeutic target for the treatment of NSCLC.

View Figures

View References

1	D'Addario G, Früh M, Reck M, Baumann P, Klepetko W and Felip E; ESMO Guidelines Working Group, : Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 21 Suppl 5:v116–v119. 2010. View Article : Google Scholar : PubMed/NCBI
2	Rosell R, Felip E, Taron M, Majo J, Mendez P, Sanchez-Ronco M, Queralt C, Sanchez JJ and Maestre J: Gene expression as a predictive marker of outcome in stage IIB-IIIA-IIIB non-small cell lung cancer after induction gemcitabine-based chemotherapy followed by resectional surgery. Clin Cancer Res. 10:4215s–4219s. 2004. View Article : Google Scholar : PubMed/NCBI
3	Thiery JP and Sleeman JP: Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 7:131–142. 2006. View Article : Google Scholar : PubMed/NCBI
4	Thiery JP: Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2:442–454. 2002. View Article : Google Scholar : PubMed/NCBI
5	Mathews MB and Hershey JW: The translation factor eIF5A and human cancer. Biochim Biophys Acta. 1849:836–844. 2015. View Article : Google Scholar : PubMed/NCBI
6	Ishfaq M, Maeta K, Maeda S, Natsume T, Ito A and Yoshida M: The role of acetylation in the subcellular localization of an oncogenic isoform of translation factor eIF5A. Biosci Biotechnol Biochem. 76:2165–2167. 2012. View Article : Google Scholar : PubMed/NCBI
7	Tong Y, Park I, Hong BS, Nedyalkova L, Tempel W and Park HW: Crystal structure of human eIF5A1: Insight into functional similarity of human eIF5A1 and eIF5A2. Proteins. 75:1040–1045. 2009. View Article : Google Scholar : PubMed/NCBI
8	Fujimura K, Wright T, Strnadel J, Kaushal S, Metildi C, Lowy AM, Bouvet M, Kelber JA and Klemke RL: A hypusine-eIF5A-PEAK1 switch regulates the pathogenesis of pancreatic cancer. Cancer Res. 74:6671–6681. 2014. View Article : Google Scholar : PubMed/NCBI
9	Clement PM, Henderson CA, Jenkins ZA, Smit-McBride Z, Wolff EC, Hershey JW, Park MH and Johansson HE: Identification and characterization of eukaryotic initiation factor 5A-2. Eur J Biochem. 270:4254–4263. 2003. View Article : Google Scholar : PubMed/NCBI
10	Jenkins ZA, Hååg PG and Johansson HE: Human eIF5A2 on chromosome 3q25-q27 is a phylogenetically conserved vertebrate variant of eukaryotic translation initiation factor 5A with tissue-specific expression. Genomics. 71:101–109. 2001. View Article : Google Scholar : PubMed/NCBI
11	Xu GD, Shi XB, Sun LB, Zhou QY, Zheng DW, Shi HS, Che YL, Wang ZS and Shao GF: Down-regulation of eIF5A-2 prevents epithelial-mesenchymal transition in non-small-cell lung cancer cells. J Zhejiang Univ Sci B. 14:460–467. 2013. View Article : Google Scholar : PubMed/NCBI
12	He LR, Zhao HY, Li BK, Liu YH, Liu MZ, Guan XY, Bian XW, Zeng YX and Xie D: Overexpression of eIF5A-2 is an adverse prognostic marker of survival in stage I non-small cell lung cancer patients. Int J Cancer. 129:143–150. 2011. View Article : Google Scholar : PubMed/NCBI
13	Xu G, Yu H, Shi X, Zhou Q, Zheng D, Shi H, Li N, Zhang X and Shao G: Cisplatin sensitivity is enhanced in non-small cell lung cancer cells by regulating epithelial-mesenchymal transition through inhibition of eukaryotic translation initiation factor 5A2. BMC Pulm Med. 14:1742014. View Article : Google Scholar : PubMed/NCBI
14	Wei YX, Chen G, You L and Zhao YP: Expression of eukaryotic translation initiation factor 5A2 in pancreatic adenocarcinoma and its correlation with the prognosis. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 35:634–638. 2013.(In Chinese). PubMed/NCBI
15	Khosravi S, Wong RP, Ardekani GS, Zhang G, Martinka M, Ong CJ and Li G: Role of EIF5A2, a downstream target of Akt, in promoting melanoma cell invasion. Br J Cancer. 110:399–408. 2014. View Article : Google Scholar : PubMed/NCBI
16	Li S, Ma Y, Xie C, Wu Z, Kang Z, Fang Z, Su B and Guan M: EphA6 promotes angiogenesis and prostate cancer metastasis and is associated with human prostate cancer progression. Oncotarget. 6:22587–22597. 2015.PubMed/NCBI
17	Li Y, Fu L, Li JB, Qin Y, Zeng TT, Zhou J, Zeng ZL, Chen J, Cao TT, Ban X, et al: Increased expression of EIF5A2, via hypoxia or gene amplification, contributes to metastasis and angiogenesis of esophageal squamous cell carcinoma. Gastroenterology. 146:1701–1713.e9. 2014. View Article : Google Scholar : PubMed/NCBI
18	Liu Y, Liu R, Fu P, Du F, Hong Y, Yao M, Zhang X and Zheng S: N1-Guanyl-1,7-diaminoheptane sensitizes estrogen receptor negative breast cancer cells to doxorubicin by preventing epithelial-mesenchymal transition through inhibition of eukaryotic translation initiation factor 5A2 activation. Cell Physiol Biochem. 36:2494–2503. 2015. View Article : Google Scholar : PubMed/NCBI
19	Meng QB, Kang WM, Yu JC, Liu YQ, Ma ZQ, Zhou L, Cui QC and Zhou WX: Overexpression of eukaryotic translation initiation factor 5A2 (EIF5A2) correlates with cell aggressiveness and poor survival in gastric cancer. PLoS One. 10:e01192292015. View Article : Google Scholar : PubMed/NCBI
20	Wei JH, Cao JZ, Zhang D, Liao B, Zhong WM, Lu J, Zhao HW, Zhang JX, Tong ZT, Fan S, et al: EIF5A2 predicts outcome in localised invasive bladder cancer and promotes bladder cancer cell aggressiveness in vitro and in vivo. Br J Cancer. 110:1767–1777. 2014. View Article : Google Scholar : PubMed/NCBI
21	Xu X, Liu H, Zhang H, Dai W, Guo C, Xie C, Wei S, He S and Xu X: Sonic hedgehog-GLI family zinc finger 1 signaling pathway promotes the growth and migration of pancreatic cancer cells by regulating the transcription of eukaryotic translation initiation factor 5A2. Pancreas. 44:1252–1258. 2015. View Article : Google Scholar : PubMed/NCBI
22	Zhu W, Cai MY, Tong ZT, Dong SS, Mai SJ, Liao YJ, Bian XW, Lin MC, Kung HF, Zeng YX, et al: Overexpression of EIF5A2 promotes colorectal carcinoma cell aggressiveness by upregulating MTA1 through C-myc to induce epithelial-mesenchymaltransition. Gut. 61:562–575. 2012. View Article : Google Scholar : PubMed/NCBI
23	Shek FH, Fatima S and Lee NP: Implications of the use of eukaryotic translation initiation factor 5A (eIF5A) for prognosis and treatment of hepatocellular carcinoma. Int J Hepatol. 2012:7609282012. View Article : Google Scholar : PubMed/NCBI
24	Tang DJ, Dong SS, Ma NF, Xie D, Chen L, Fu L, Lau SH, Li Y, Li Y and Guan XY: Overexpression of eukaryotic initiation factor 5A2 enhances cell motility and promotes tumor metastasis in hepatocellular carcinoma. Hepatology. 51:1255–1263. 2010. View Article : Google Scholar : PubMed/NCBI
25	Chen Z, Yu T, Zhou B, Wei J, Fang Y, Lu J, Guo L, Chen W, Liu ZP and Luo J: Mg(II)-Catechin nanoparticles delivering siRNA targeting EIF5A2 inhibit bladder cancer cell growth in vitro and in vivo. Biomaterials. 81:125–134. 2016. View Article : Google Scholar : PubMed/NCBI
26	Bao Y, Lu Y, Wang X, Feng W, Sun X, Guo H, Tang C, Zhang X, Shi Q and Yu H: Eukaryotic translation initiation factor 5A2 (eIF5A2) regulates chemoresistance in colorectal cancer through epithelial mesenchymal transition. Cancer Cell Int. 15:1092015. View Article : Google Scholar : PubMed/NCBI
27	Tian SB, Yu JC, Liu YQ, Kang WM, Ma ZQ, Ye X and Yan C: MiR-30b suppresses tumor migration and invasion by targeting EIF5A2 in gastric cancer. World J Gastroenterol. 21:9337–9347. 2015. View Article : Google Scholar : PubMed/NCBI
28	Tsang FH, Au V, Lu WJ, Shek FH, Liu AM, Luk JM, Fan ST, Poon RT and Lee NP: Prognostic marker microRNA-125b inhibits tumorigenic properties of hepatocellular carcinoma cells via suppressing tumorigenic molecule eIF5A2. Dig Dis Sci. 59:2477–2487. 2014. View Article : Google Scholar : PubMed/NCBI
29	Chen QY, Zheng Y, Jiao DM, Chen FY, Hu HZ, Wu YQ, Song J, Yan J, Wu LJ and Lv GY: Curcumin inhibits lung cancer cell migration and invasion through Rac1-dependent signaling pathway. J Nutr Biochem. 25:177–185. 2014. View Article : Google Scholar : PubMed/NCBI
30	Coultas L and Strasser A: The role of the Bcl-2 protein family in cancer. Semin Cancer Biol. 13:115–123. 2003. View Article : Google Scholar : PubMed/NCBI
31	Khaleghian M, Shakoori A, Razavi AE and Azimi C: Relationship of amplification and expression of the C-MYC gene with survival among gastric cancer patients. Asian Pac J Cancer Prev. 16:7061–7069. 2015. View Article : Google Scholar : PubMed/NCBI
32	Wang FW, Cai MY, Mai SJ, Chen JW, Bai HY, Li Y, Liao YJ, Li CP, Tian XP, Kung HF, et al: Ablation of EIF5A2 induces tumor vasculature remodeling and improves tumor response to chemotherapy via regulation of matrix metalloproteinase 2 expression. Oncotarget. 5:6716–6733. 2014.PubMed/NCBI
33	Lou B, Fan J, Wang K, Chen W, Zhou X, Zhang J, Lin S, Lv F and Chen Y: N1-guanyl-1,7-diaminoheptane (GC7) enhances the therapeutic efficacy of doxorubicin by inhibiting activation of eukaryotic translation initiation factor 5A2 (eIF5A2) and preventing the epithelial-mesenchymal transition in hepatocellular carcinoma cells. Exp Cell Res. 319:2708–2717. 2013. View Article : Google Scholar : PubMed/NCBI
34	Yang J, Yu H, Shen M, Wei W, Xia L and Zhao P: N1-guanyl-1,7-diaminoheptane sensitizes bladder cancer cells to doxorubicin by preventing epithelial-mesenchymal transition through inhibition of eukaryotic translation initiation factor 5A2 activation. Cancer Sci. 105:219–227. 2014. View Article : Google Scholar : PubMed/NCBI
35	Yang H, Li XD, Zhou Y, Ban X, Zeng TT, Li L, Zhang BZ, Yun J, Xie D, Guan XY and Li Y: Stemness and chemotherapeutic drug resistance induced by EIF5A2 overexpression in esophageal squamous cell carcinoma. Oncotarget. 6:26079–26089. 2015.PubMed/NCBI