miRNA-223 is an anticancer gene in human non-small cell lung cancer through the PI3K/AKT pathway by targeting EGFR

Ma,Hui-Ping; Kong,Wei-Xiang; Li,Xiu-Ying; Li,Wei; Zhang,Yan; Wu,Yan

doi:10.3892/or.2019.6983

miRNA-223 is an anticancer gene in human non-small cell lung cancer through the PI3K/AKT pathway by targeting EGFR

Authors:
- Hui-Ping Ma
- Wei-Xiang Kong
- Xiu-Ying Li
- Wei Li
- Yan Zhang
- Yan Wu
View Affiliations

Affiliations: Department of Respiratory Medicine, Jining First People's Hospital, Jining, Shandong 272111, P.R. China, Department of Otorhinolaryngology, Jining First People's Hospital, Jining, Shandong 272111, P.R. China
Published online on: January 24, 2019 https://doi.org/10.3892/or.2019.6983
Pages: 1549-1559
Copyright: © Ma 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 present study aimed to further explore the molecular mechanisms of miRNA-223 in non-small cell lung cancer (NSCLC). Data prospectively collected from NSCLC patients and volunteers from March 2016 to MayMAP2016 at Tsinghua Changgung Hospital were analyzed. Cell proliferation was measured using MTT assay, while cell apoptosis and caspase-3/9 activity were measured using ﬂow cytometry and caspase-3/9 activity kit. Bax, EGFR, PI3K and p-Akt protein were also investigated using western blotting. The results revealed that the serum levels of miRNA-223 in NSCLC patients were downregulated. In an inMAPvitro model, overexpression of miRNA-223 induced apoptosis while reducing cell proliferation. In contrast, downregulation of the expression of miRNA-223 inhibited apoptosis whereas it increased cell proliferation. Meanwhile, overexpression of miRNA-223 suppressed the protein expression of EGFR, PI3K and p-Akt in NSCLC cells. An EGFR inhibitor promoted the anticancer effects of miRNA-223 in NSCLC cells through the EGFR/PI3K/AKT pathway. Meanwhile, a PI3K inhibitor increased the anticancer effects of miRNA-223 in NSCLC cells through the PI3K/AKT pathway. Thus, a new pathway has been identified in the present study, and application of miRNA-223 may induce the apoptosis of NSCLC through the PI3K/AKT pathway by EGFR.

View Figures

View References

1	Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A, Tjulandin S, Zhang K, et al: Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): A randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 15:569–579. 2014. View Article : Google Scholar : PubMed/NCBI
2	Denis F, Lethrosne C, Pourel N, Molinier O, Pointreau Y, Domont J, Bourgeois H, Senellart H, Trémolières P, Lizée T, et al: Randomized Trial Comparing a Web-Mediated Follow-up With Routine Surveillance in Lung Cancer Patients. J Natl Cancer Inst. 109:1092017. View Article : Google Scholar
3	Guo Y, Sun W, Gong T, Chai Y, Wang J, Hui B, Li Y, Song L and Gao Y: miR-30a radiosensitizes non-small cell lung cancer by targeting ATF1 that is involved in the phosphorylation of ATM. Oncol Rep. 37:1980–1988. 2017. View Article : Google Scholar : PubMed/NCBI
4	Li H, Zhou H, Luo J and Huang J: MicroRNA-17-5p inhibits proliferation and triggers apoptosis in non-small cell lung cancer by targeting transforming growth factor β receptor 2. Exp Ther Med. 13:2715–2722. 2017. View Article : Google Scholar : PubMed/NCBI
5	Ju L, Han M, Li X and Zhao C: MicroRNA signature of lung adenocarcinoma with EGFR exon 19 deletion. J Cancer. 8:1311–1318. 2017. View Article : Google Scholar : PubMed/NCBI
6	Li X, Liu Y, Shi W, Xu H, Hu H, Dong Z, Zhu G, Sun Y, Liu B, Gao H, et al: Droplet digital PCR improved the EGFR mutation diagnosis with pleural fluid samples in non-small-cell lung cancer patients. Clin Chim Acta. 471:177–184. 2017. View Article : Google Scholar : PubMed/NCBI
7	Ni J, Weng L, Liu Y, Sun Z, Bai C and Wang Y: Dynamic monitoring of EGFR mutations in circulating cell-free DNA for EGFR-mutant metastatic patients with lung cancer: Early detection of drug resistance and prognostic significance. Oncol Lett. 13:4549–4557. 2017. View Article : Google Scholar : PubMed/NCBI
8	Gao JW, Zhan P, Qiu XY, Jin JJ, Lv TF and Song Y: Erlotinib-based doublet targeted therapy versus erlotinib alone in previously treated advanced non-small-cell lung cancer: A meta-analysis from 24 randomized controlled trials. Oncotarget. 8:73258–73270. 2017.PubMed/NCBI
9	Zhou G, Zhang F, Guo Y, Huang J, Xie Y, Yue S, Chen M, Jiang H and Li M: miR-200c enhances sensitivity of drug-resistant non-small cell lung cancer to gefitinib by suppression of PI3K/Akt signaling pathway and inhibites cell migration via targeting ZEB1. Biomed Pharmacother. 85:113–119. 2017. View Article : Google Scholar : PubMed/NCBI
10	Liu XL, Zhang XT, Meng J, Zhang HF, Zhao Y, Li C, Sun Y, Mei QB, Zhang F and Zhang T: ING5 knockdown enhances migration and invasion of lung cancer cells by inducing EMT via EGFR/PI3K/Akt and IL-6/STAT3 signaling pathways. Oncotarget. 8:54265–54276. 2017.PubMed/NCBI
11	Tang Y, Wang Y, Chen Q, Qiu N, Zhao Y and You X: MiR-223 inhibited cell metastasis of human cervical cancer by modulating epithelial-mesenchymal transition. Int J Clin Exp Pathol. 8:11224–11229. 2015.PubMed/NCBI
12	Soria JC, Adjei AA, Bahleda R, Besse B, Ferte C, Planchard D, Zhou J, Ware J, Morrissey K, Shankar G, et al: A phase IB dose-escalation study of the safety and pharmacokinetics of pictilisib in combination with either paclitaxel and carboplatin (with or without bevacizumab) or pemetrexed and cisplatin (with or without bevacizumab) in patients with advanced non-small cell lung cancer. Eur J Cancer. 86:186–196. 2017. View Article : Google Scholar : PubMed/NCBI
13	Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, et al: ECOG-ACRIN: Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): An open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 18:1610–1623. 2017. View Article : Google Scholar : PubMed/NCBI
14	Melichar B, Adenis A, Lockhart AC, Bennouna J, Dees EC, Kayaleh O, Obermannova R, DeMichele A, Zatloukal P, Zhang B, et al: Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: A five-arm phase 2 study. Lancet Oncol. 16:395–405. 2015. View Article : Google Scholar : PubMed/NCBI
15	Schofield P, Ugalde A, Gough K, Reece J, Krishnasamy M, Carey M, Ball D and Aranda S: A tailored, supportive care intervention using systematic assessment designed for people with inoperable lung cancer: A randomised controlled trial. Psychooncology. 22:2445–2453. 2013. View Article : Google Scholar : PubMed/NCBI
16	Schuette W, Behringer D, Stoehlmacher J, Kollmeier J, Schmager S, Fischer von Weikersthal L, Schumann C and Buchmann J: CHAMP: A phase II study of panitumumab with pemetrexed and cisplatin versus pemetrexed and cisplatin in the treatment of patients with advanced-stage primary nonsquamous non-small-cell lung cancer with particular regard to the KRAS status. Clin Lung Cancer. 16:447–456. 2015. View Article : Google Scholar : PubMed/NCBI
17	Zhou W, Ye XL, Xu J, Cao MG, Fang ZY, Li LY, Guan GH, Liu Q, Qian YH and Xie D: The lncRNA H19 mediates breast cancer cell plasticity during EMT and MET plasticity by differentially sponging miR-200b/c and let-7b. Sci Signal. 10:102017. View Article : Google Scholar
18	Daly C, Castanaro C, Zhang W, Zhang Q, Wei Y, Ni M, Young TM, Zhang L, Burova E and Thurston G: FGFR3-TACC3 fusion proteins act as naturally occurring drivers of tumor resistance by functionally substituting for EGFR/ERK signaling. Oncogene. 36:471–481. 2017. View Article : Google Scholar : PubMed/NCBI
19	Kim JY, Welsh EA, Fang B, Bai Y, Kinose F, Eschrich SA, Koomen JM and Haura EB: Phosphoproteomics reveals MAPK inhibitors enhance MET- and EGFR-driven AKT signaling in KRAS-mutant lung cancer. Mol Cancer Res. 14:1019–1029. 2016. View Article : Google Scholar : PubMed/NCBI
20	Pan H, Jiang T, Cheng N, Wang Q, Ren S, Li X, Zhao C, Zhang L, Cai W and Zhou C: Long non-coding RNA BC087858 induces non-T790M mutation acquired resistance to EGFR-TKIs by activating PI3K/AKT and MEK/ERK pathways and EMT in non-small-cell lung cancer. Oncotarget. 7:49948–49960. 2016. View Article : Google Scholar : PubMed/NCBI
21	Torres AF, Nogueira C, Magalhaes J, Costa IS, Aragao A, Gomes Neto A, Martins F and Tavora F: Expression of EGFR and molecules downstream to PI3K/Akt, Raf-1-MEK-1-MAP (Erk1/2), and JAK (STAT3) pathways in invasive lung adenocarcinomas resected at a single institution. Anal Cell Pathol (Amst) 2014. 3529252014.
22	Li H, Schmid-Bindert G, Wang D, Zhao Y, Yang X, Su B and Zhou C: Blocking the PI3K/AKT and MEK/ERK signaling pathways can overcome gefitinib-resistance in non-small cell lung cancer cell lines. Adv Med Sci. 56:275–284. 2011. View Article : Google Scholar : PubMed/NCBI
23	Wang Q, Zhao DY, Xu H, Zhou H, Yang QY, Liu F and Zhou GP: Down-regulation of microRNA-223 promotes degranulation via the PI3K/Akt pathway by targeting IGF-1R in mast cells. PLoS One. 10:e01235752015. View Article : Google Scholar : PubMed/NCBI