MicroRNA-204 inhibits the proliferation, migration and invasion of human lung cancer cells by targeting PCNA-1 and inhibits tumor growth in vivo

Li,Ping; Wang,Qingan; Wang,Haining

doi:10.3892/ijmm.2018.4044

MicroRNA-204 inhibits the proliferation, migration and invasion of human lung cancer cells by targeting PCNA-1 and inhibits tumor growth in vivo

Authors:
- Ping Li
- Qingan Wang
- Haining Wang
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Affiliations: Department of Thoracic Surgery, Shengli Oilfield Central Hospital, Dongying, Shandong 257034, P.R. China
Published online on: December 31, 2018 https://doi.org/10.3892/ijmm.2018.4044
Pages: 1149-1156
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Lung cancer accounts for ~20% of the total cancer‑associated mortalities worldwide. Lung cancer is often diagnosed at advanced stages and is therefore difficult to treat. The biomarkers for diagnosis of lung cancer are limited and unreliable. In addition, the lack of availability of efficient chemotherapeutic agents and targets has resulted in limitations in the successful treatment of lung cancer. Previously, microRNAs (miRNA/miR) have been implicated in the onset and development of several types of cancer. The expression of miRNAs is often dysregulated in cancer cells; therefore, they are considered important therapeutic targets and agents. The present study examined the expression of miR‑204 in 4 different lung cancer cell lines and 1 normal cell line. The results revealed that miR‑204 was significantly downregulated (4‑8‑fold) in all the cancer cell lines (P<0.05). Overexpression of miR‑204 in A549 lung cancer cells inhibited the proliferative, migratory and invasive capabilities of the lung cancer cells. Furthermore, miR‑204 overexpression also induced apoptosis in the A549 lung cancer cells. Bioinformatics analysis revealed proliferating cell nuclear antigen 1 (PCNA‑1) to be a potential target of miR‑204. The reverse transcription quantitative polymerase chain reaction analysis revealed that PCNA‑1 was significantly upregulated (up to 5‑fold) in the lung cancer cells (P<0.05), and the overexpression of miR‑204 caused the downregulation of PCNA‑1 in A549 lung cancer cells. Silencing of PCNA‑1 in A549 cells exerted similar effects to that of miR‑204 overexpression on the proliferative, migratory and invasive capabilities of A549 lung cancer cells. Additionally, the suppression of miR‑204 in A549 cells transfected with Si‑PCNA‑1 did not rescue the effects of PCNA‑1 silencing on cell proliferation, migration or invasion. Conversely, the overexpression of PCNA‑1 in A549 cells transfected with miR‑204 mimics promoted the proliferation, migration and invasion of lung cancer cells. Furthermore, overexpression of miR‑204 in xenograft tumors significantly inhibited their growth. Taken together, these results indicated that miR‑204 regulates the proliferative, migratory and invasive capabilities of lung cancer cells by targeting PCNA‑1.

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1	Cheng TY, Cramb SM, Baade PD, Youlden DR, Nwogu C and Reid ME: The international epidemiology of lung cancer: Latest trends, disparities, and tumor characteristics. J Thorac Oncol. 11:1653–1671. 2016. View Article : Google Scholar : PubMed/NCBI
2	Torre LA, Siegel RL and Jemal A: Lung cancer statistics. Adv Exp Med Biol. 893:1–19. 2016. View Article : Google Scholar
3	Alberg AJ and Samet JM: Epidemiology of lung cancer. Chest. 123:21S–49S. 2003. View Article : Google Scholar : PubMed/NCBI
4	Bourguignon LY, Wong G and Shiina M: Up-regulation of histone methyltransferase, DOT1L, by matrix hyaluronan promotes microRNA-10 expression leading to tumor cell invasion and chemoresistance in cancer stem cells from head and neck squamous cell carcinoma. J Biol Chem. 291:10571–10585. 2016. View Article : Google Scholar : PubMed/NCBI
5	Ambros V: The functions of animal microRNAs. Nature. 431:350–355. 2004. View Article : Google Scholar : PubMed/NCBI
6	Bartel DP: MicroRNAs: Target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
7	Esquela-Kerscher A and Slack FJ: Oncomirs-microRNAs with a role in cancer. Nat Rev Cancer. 6:259–269. 2006. View Article : Google Scholar : PubMed/NCBI
8	Schetter AJ, Leung SY, Sohn JJ, Zanetti KA, Bowman ED, Yanaihara N, Yuen ST, Chan TL, Kwong DL, Au GK, et al: MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA. 299:425–436. 2008. View Article : Google Scholar : PubMed/NCBI
9	Li W, Jin X, Zhang Q, Zhang G, Deng X and Ma L: Decreased expression of miR-204 is associated with poor prognosis in patients with breast cancer. Int J Clin Exp Pathol. 7:3287–3292. 2014.PubMed/NCBI
10	Ding M, Lin B, Li T, Liu Y, Li Y, Zhou X, Miao M, Gu J, Pan H, Yang F, et al: A dual yet opposite growth-regulating function of miR-204 and its target XRN1 in prostate adenocarcinoma cells and neuroendocrine-like prostate cancer cells. Oncotarget. 6:7686–7700. 2015. View Article : Google Scholar : PubMed/NCBI
11	Guo W, Zhang Y, Zhang Y, Shi Y, Xi J, Fan H and Xu S: Decreased expression of miR-204 in plasma is associated with a poor prognosis in patients with non-small cell lung cancer. Int J Mol Med. 36:1720–1726. 2015. View Article : Google Scholar : PubMed/NCBI
12	Wu X, Zeng Y, Wu S, Zhong J, Wang Y and Xu J: MiR-204, down regulated in retinoblastoma, regulates proliferation and invasion of human retinoblastoma cells by targeting CyclinD2 and MMP-9. FEBS Lett. 589:645–650. 2015. View Article : Google Scholar : PubMed/NCBI
13	Chen X, Liu XS, Liu HY, Lu YY and Li Y: Reduced expression of serum miR-204 predicts poor prognosis of gastric cancer. Genet Mol Res. 15:2016.
14	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
15	Zhao C, Wang W, Yu W, Jou D, Wang Y, Ma H, Xiao H, Qin H, Zhang C, Lü J, et al: A novel small molecule STAT3 inhibitor, LY5, inhibits cell viability, colony formation, and migration of colon and liver cancer cells. Oncotarget. 7:12917–12926. 2016.PubMed/NCBI
16	National Research Council: Guide for the Care and Use of Laboratory Animals. National Academies Press; Washington, DC: 1985
17	Wang Y, Zhao W and Fu Q: miR-335 suppresses migration and invasion by targeting ROCK1 in osteosarcoma cells. Mol Cell Biochem. 384:105–111. 2013. View Article : Google Scholar : PubMed/NCBI
18	Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, et al: Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 373:123–135. 2015. View Article : Google Scholar : PubMed/NCBI
19	Pérol M, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, Park K, Kowalyszyn RD, Pikiel J, Lewanski CR, et al: Quality of life results from the phase 3 REVEL randomized clinical trial of ramucirumab-plus-docetaxel versus placebo-plus-docetaxel in advanced/metastatic non-small cell lung cancer patients with progression after platinum-based chemotherapy. Lung Cancer. 93:95–103. 2016. View Article : Google Scholar : PubMed/NCBI
20	Lynam-Lennon N, Maher SG and Reynolds JV: The roles of microRNA in cancer and apoptosis. Biol Rev Camb Philos Soc. 84:55–71. 2009. View Article : Google Scholar
21	Slack FJ and Weidhaas JB: MicroRNA in cancer prognosis. N Engl J Med. 2720–2722. 2008. View Article : Google Scholar : PubMed/NCBI
22	Han Z, Zhang Y, Sun Y, Chen J, Chang C, Wang X and Yeh S: ERβ-mediated alteration of circATP2B1 and miR-204-3p signaling promotes invasion of clear cell renal cell carcinoma. Cancer Res. 2018.
23	Chung TK, Lau TS, Cheung TH, Yim SF, Lo KW, Siu NS, Chan LK, Yu MY, Kwong J, Doran G, et al: Dysregulation of microRNA-204 mediates migration and invasion of endometrial cancer by regulating FOXC1. Int J Cancer. 130:1036–1045. 2012. View Article : Google Scholar
24	Butrym A, Rybka J, Baczyńska D, Tukiendorf A, Kuliczkowski K and Mazur G: Low expression of microRNA-204 (miR-204) is associated with poor clinical outcome of acute myeloid leukemia (AML) patients. J Exp Clin Cancer Res. 34:682015. View Article : Google Scholar : PubMed/NCBI
25	Zhang B, Yin Y, Hu Y, Zhang J, Bian Z, Song M, Hua D and Huang Z: MicroRNA-204-5p inhibits gastric cancer cell proliferation by downregulating USP47 and RAB22A. Med Oncol. 32:3312015. View Article : Google Scholar
26	Shi Y, Huang J, Zhou J, Liu Y, Fu X, Li Y, Yin G and Wen J: MicroRNA-204 inhibits proliferation, migration, invasion and epithelial-mesenchymal transition in osteosarcoma cells via targeting Sirtuin 1. Oncol Rep. 34:399–406. 2015. View Article : Google Scholar : PubMed/NCBI
27	Moldovan GL, Pfander B and Jentsch S: PCNA, the maestro of the replication fork. Cell. 129:665–679. 2007. View Article : Google Scholar : PubMed/NCBI
28	Stoimenov I and Helleday T: PCNA on the crossroad of cancer. Biochem Soc Trans. 37:605–613. 2009. View Article : Google Scholar : PubMed/NCBI
29	Witko-Sarsat V, Mocek J, Bouayad D, Tamassia N, Ribeil JA, Candalh C, Davezac N, Reuter N, Mouthon L, Hermine O, et al: Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival. J Exp Med. 207:2631–2645. 2010. View Article : Google Scholar : PubMed/NCBI
30	Rosental B, Brusilovsky M, Hadad U, Oz D, Appel MY, Afergan F, Yossef R, Rosenberg LA, Aharoni A, Cerwenka A, et al: Proliferating cell nuclear antigen is a novel inhibitory ligand for the natural cytotoxicity receptor NKp44. J Immunol. 187:5693–5702. 2011. View Article : Google Scholar : PubMed/NCBI
31	Nadauld LD, Garcia S, Natsoulis G, Bell JM, Miotke L, Hopmans ES, Xu H, Pai RK, Palm C, Regan JF, et al: Metastatic tumor evolution and organoid modeling implicate TGFBR2 as a cancer driver in diffuse gastric cancer. Genome Biol. 15:4282014. View Article : Google Scholar : PubMed/NCBI
32	Wang SC: PCNA: A silent housekeeper or a potential therapeutic target? Trends Pharmacol Sci. 35:178–186. 2014. View Article : Google Scholar : PubMed/NCBI
33	Wang Y, Chen T, Huang H, Jiang Y, Yang L, Lin Z, He H, Liu T, Wu B, Chen J, et al: miR-363-3p inhibits tumor growth by targeting PCNA in lung adenocarcinoma. Oncotarget. 8:20133–20144. 2017.PubMed/NCBI
34	Urruticoechea A, Smith IE and Dowsett M: Proliferation marker Ki-67 in early breast cancer. J Clin Oncol. 23:7212–7220. 2005. View Article : Google Scholar : PubMed/NCBI