miR‑497 inhibits the proliferation and migration of A549 non‑small‑cell lung cancer cells by targeting FGFR1

Huang,Qibin; Li,Hongtao; Dai,Xiaofeng; Zhao,Di; Guan,Bingfeng; Xia,Wen

doi:10.3892/mmr.2019.10611

miR‑497 inhibits the proliferation and migration of A549 non‑small‑cell lung cancer cells by targeting FGFR1

Authors:
- Qibin Huang
- Hongtao Li
- Xiaofeng Dai
- Di Zhao
- Bingfeng Guan
- Wen Xia
View Affiliations

Affiliations: Department of Cardiothoracic Surgery, Jingzhou First People's Hospital, Jingzhou, Hubei 434000, P.R. China, Department of Oncology, Jingzhou First People's Hospital, Jingzhou, Hubei 434000, P.R. China, Department of Anesthesiology, Jingzhou First People's Hospital, Jingzhou, Hubei 434000, P.R. China
Published online on: August 23, 2019 https://doi.org/10.3892/mmr.2019.10611
Pages: 3959-3967

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

Fibroblast growth factor receptor 1 (FGFR1) signaling has been reported to contribute to the carcinogenic progression of various cancer types. Previous studies have demonstrated that FGFR1 expression is increased in non‑small cell lung cancer (NSCLC) and promotes cancer cell metastasis. However, the molecular mechanisms underlying increased FGFR1 expression in NSCLC remains largely unknown. In the current study, microRNA (miR)‑497 levels were observed to be inversely correlated with FGFR1 expression in tumor samples from patients with NSCLC. In the NSCLC cell line A549, miR‑497 overexpression inhibited cell proliferation and migration. Increased expression of miR‑497 led to a reduction in FGFR1 expression, at the mRNA and protein levels. In addition, transfection of miR‑497 mimics inactivated the protein kinase B (AKT) and c‑Jun N‑terminal kinase (JNK) signaling pathways, as reduced matrix metallopeptidase 26 expression; all of which are regulated by FGFR1. Using TargetScan software, FGFR1 was also identified as a predicted target gene of miR‑497, and a dual luciferase reporter assay confirmed that miR‑497 directly regulated FGFR1. Transfection of a recombinant FGFR1 overexpression vector reversed miR‑497 mimic‑induced arrest of cell growth and migration in A549 cells. In conclusion, the results of the present study identified miR‑497 as a potential tumor suppressor gene in NSCLC that may function via repressing FGFR1 expression, and AKT and JNK signaling.

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	Marshall AL and Christiani DC: Genetic susceptibility to lung cancer-light at the end of the tunnel? Carcinogenesis. 34:487–502. 2013. View Article : Google Scholar : PubMed/NCBI
3	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
4	Wistuba II, Gelovani JG, Jacoby JJ, Davis SE and Herbst RS: Methodological and practical challenges for personalized cancer therapies. Nat Rev Clin Oncol. 8:135–141. 2011. View Article : Google Scholar : PubMed/NCBI
5	Tiong KH, Mah LY and Leong CO: Functional roles of fibroblast growth factor receptors (FGFRs) signaling in human cancers. Apoptosis. 18:1447–1468. 2013. View Article : Google Scholar : PubMed/NCBI
6	Monaco SE, Rodriguez EF, Mahaffey AL and Dacic S: FGFR1 amplification in squamous cell carcinoma of the lung with correlation of primary and metastatic tumor status. Am J Clin Pathol. 145:55–61. 2016. View Article : Google Scholar : PubMed/NCBI
7	Young RJ, Lim AM, Angel C, Collins M, Deb S, Corry J, Wiesenfeld D, Kleid S, Sigston E, Lyons B, et al: Frequency of fibroblast growth factor receptor 1 gene amplification in oral tongue squamous cell carcinomas and associations with clinical features and patient outcome. Oral Oncol. 49:576–581. 2013. View Article : Google Scholar : PubMed/NCBI
8	Ishizuka T, Tanabe C, Sakamoto H, Aoyagi K, Maekawa M, Matsukura N, Tokunaga A, Tajiri T, Yoshida T, Terada M and Sasaki H: Gene amplification profiling of esophageal squamous cell carcinomas by DNA array CGH. Biochem Biophys Res Commun. 296:152–155. 2002. View Article : Google Scholar : PubMed/NCBI
9	Gru AA and Allred DC: FGFR1 amplification and the progression of non-invasive to invasive breast cancer. Breast Cancer Res. 14:1162012. View Article : Google Scholar : PubMed/NCBI
10	Kim HR, Kim DJ, Kang DR, Lee JG, Lim SM, Lee CY, Rha SY, Bae MK, Lee YJ, Kim SH, et al: Fibroblast growth factor receptor 1 gene amplification is associated with poor survival and cigarette smoking dosage in patients with resected squamous cell lung cancer. J Clin Oncol. 31:731–737. 2013. View Article : Google Scholar : PubMed/NCBI
11	Wang Y, Cai Y, Ji J, Liu Z, Zhao C, Zhao Y, Wei T, Shen X, Zhang X, Li X and Liang G: Discovery and identification of new non-ATP competitive FGFR1 inhibitors with therapeutic potential on non-small-cell lung cancer. Cancer Lett. 344:82–89. 2014. View Article : Google Scholar : PubMed/NCBI
12	Pu D, Liu J, Li Z, Zhu J and Hou M: Fibroblast growth factor receptor 1 (FGFR1), partly related to vascular endothelial growth factor receptor 2 (VEGFR2) and microvessel density, is an independent prognostic factor for non-small cell lung cancer. Med Sci Monit. 23:247–257. 2017. View Article : Google Scholar : PubMed/NCBI
13	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
14	Kawahara Y: Human diseases caused by germline and somatic abnormalities in microRNA and microRNA-related genes. Congenit Anom (Kyoto). 54:12–21. 2014. View Article : Google Scholar : PubMed/NCBI
15	Iorio MV and Croce CM: MicroRNAs in cancer: Small molecules with a huge impact. J Clin Oncol. 27:5848–5856. 2009. View Article : Google Scholar : PubMed/NCBI
16	Kasinski AL and Slack FJ: miRNA-34 prevents cancer initiation and progression in a therapeutically resistant K-ras and p53-induced mouse model of lung adenocarcinoma. Cancer Res. 72:5576–5587. 2012. View Article : Google Scholar : PubMed/NCBI
17	Fortunato O, Boeri M, Moro M, Verri C, Mensah M, Conte D, Caleca L, Roz L, Pastorino U and Sozzi G: Mir-660 is downregulated in lung cancer patients and its replacement inhibits lung tumorigenesis by targeting MDM2-p53 interaction. Cell Death Dis. 5:e15642014. View Article : Google Scholar : PubMed/NCBI
18	Peng Y, Dai Y, Hitchcock C, Yang X, Kassis ES, Liu L, Luo Z, Sun HL, Cui R, Wei H, et al: Insulin growth factor signaling is regulated by microRNA-486, an underexpressed microRNA in lung cancer. Proc Natl Acad Sci USA. 110:15043–15048. 2013. View Article : Google Scholar : PubMed/NCBI
19	Wang J, Li J, Wang X, Zheng C and Ma W: Downregulation of microRNA-214 and overexpression of FGFR-1 contribute to hepatocellular carcinoma metastasis. Biochem Biophys Res Commun. 439:47–53. 2013. View Article : Google Scholar : PubMed/NCBI
20	Jiang H, Qu L, Wang Y, Cong J, Wang W and Yang X: miR-99a promotes proliferation targeting FGFR3 in human epithelial ovarian cancer cells. Biomed Pharmacother. 68:163–169. 2014. View Article : Google Scholar : PubMed/NCBI
21	Nishijima N, Seike M, Soeno C, Chiba M, Miyanaga A, Noro R, Sugano T, Matsumoto M, Kubota K and Gemma A: miR-200/ZEB axis regulates sensitivity to nintedanib in non-small cell lung cancer cells. Int J Oncol. 48:937–944. 2016. View Article : Google Scholar : PubMed/NCBI
22	Chen QY, Jiao DM, Yan L, Wu YQ, Hu HZ, Song J, Yan J, Wu LJ, Xu LQ and Shi JG: Comprehensive gene and microRNA expression profiling reveals miR-206 inhibits MET in lung cancer metastasis. Mol Biosyst. 11:2290–2302. 2015. View Article : Google Scholar : PubMed/NCBI
23	Wang R, Chen XF and Shu YQ: Prediction of non-small cell lung cancer metastasis-associated microRNAs using bioinformatics. Am J Cancer Res. 5:32–51. 2014.PubMed/NCBI
24	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 : PubMed/NCBI
25	Hu F, Liu H, Xie X, Mei J and Wang M: Activated cdc42-associated kinase is up-regulated in non-small-cell lung cancer and necessary for FGFR-mediated AKT activation. Mol Carcinog. 55:853–863. 2016. View Article : Google Scholar : PubMed/NCBI
26	Jung SY, Yi JY, Kim MH, Song KH, Kang SM, Ahn J, Hwang SG, Nam KY and Song JY: IM-412 inhibits the invasion of human breast carcinoma cells by blocking FGFR-mediated signaling. Oncol Rep. 34:2731–2737. 2015. View Article : Google Scholar : PubMed/NCBI
27	Zhao D, Lu Y, Yang C, Zhou X and Xu Z: Activation of FGF receptor signaling promotes invasion of non-small-cell lung cancer. Tumour Biol. 36:3637–3642. 2015. View Article : Google Scholar : PubMed/NCBI
28	Theelen WS, Mittempergher L, Willems SM, Bosma AJ, Peters DD, van der Noort V, Japenga EJ, Peeters T, Koole K, Šuštić T, et al: FGFR1, 2 and 3 protein overexpression and molecular aberrations of FGFR3 in early stage non-small cell lung cancer. J Pathol Clin Res. 2:223–233. 2016. View Article : Google Scholar : PubMed/NCBI
29	Göke A, Franzen A, Menon R, Goltz D, Kirsten R, Boehm D, Vogel W, Scheble V, Ellinger J, Gerigk U, et al: Rationale for treatment of metastatic squamous cell carcinoma of the lung using fibroblast growth factor receptor inhibitors. Chest. 142:1020–1026. 2012. View Article : Google Scholar : PubMed/NCBI
30	Tran TN, Selinger CI, Kohonen-Corish MR, McCaughan BC, Kennedy CW, O'Toole SA and Cooper WA: Fibroblast growth factor receptor 1 (FGFR1) copy number is an independent prognostic factor in non-small cell lung cancer. Lung Cancer. 81:462–467. 2013. View Article : Google Scholar : PubMed/NCBI
31	Dutt A, Ramos AH, Hammerman PS, Mermel C, Cho J, Sharifnia T, Chande A, Tanaka KE, Stransky N, Greulich H, et al: Inhibitor-sensitive FGFR1 amplification in human non-small cell lung cancer. PLoS One. 6:e203512011. View Article : Google Scholar : PubMed/NCBI
32	Wynes MW, Hinz TK, Gao D, Martini M, Marek LA, Ware KE, Edwards MG, Böhm D, Perner S, Helfrich BA, et al: FGFR1 mRNA and protein expression, not gene copy number, predict FGFR TKI sensitivity across all lung cancer histologies. Clin Cancer Res. 20:3299–3309. 2014. View Article : Google Scholar : PubMed/NCBI
33	Yang J, Zhao H, Xin Y and Fan L: MicroRNA-198 inhibits proliferation and induces apoptosis of lung cancer cells via targeting FGFR1. J Cell Biochem. 115:987–995. 2014. View Article : Google Scholar : PubMed/NCBI
34	Huang C, Ma R, Yue J, Li N, Li Z and Qi D: MiR-497 suppresses YAP1 and inhibits tumor growth in non-small cell lung cancer. Cell Physiol Biochem. 37:342–352. 2015. View Article : Google Scholar : PubMed/NCBI
35	Zhao WY, Wang Y, An ZJ, Shi CG, Zhu GA, Wang B, Lu MY, Pan CK and Chen P: Downregulation of miR-497 promotes tumor growth and angiogenesis by targeting HDGF in non-small cell lung cancer. Biochem Biophys Res Commun. 435:466–471. 2013. View Article : Google Scholar : PubMed/NCBI
36	Gu A, Lu J, Wang W, Shi C, Han B and Yao M: Role of miR-497 in VEGF-A-mediated cancer cell growth and invasion in non-small cell lung cancer. Int J Biochem Cell Biol. 70:118–125. 2016. View Article : Google Scholar : PubMed/NCBI
37	Han Z, Zhang Y, Yang Q, Liu B, Wu J, Zhang Y, Yang C and Jiang Y: miR-497 and miR-34a retard lung cancer growth by co-inhibiting cyclin E1 (CCNE1). Oncotarget. 6:13149–13163. 2015. View Article : Google Scholar : PubMed/NCBI
38	Yin Q, Han Y, Zhu D, Li Z, Shan S, Jin W, Lu Q and Ren T: miR-145 and miR-497 suppress TGF-β-induced epithelial-mesenchymal transition of non-small cell lung cancer by targeting MTDH. Cancer Cell Int. 18:1052018. View Article : Google Scholar : PubMed/NCBI