Decreased expression of miR-204 in plasma is associated with a poor prognosis in patients with non-small cell lung cancer

Guo,Weigang; Zhang,Yongxing; Zhang,Yi; Shi,Yu; Xi,Junjie; Fan,Hong; Xu,Songtao

doi:10.3892/ijmm.2015.2388

Decreased expression of miR-204 in plasma is associated with a poor prognosis in patients with non-small cell lung cancer

Authors:
- Weigang Guo
- Yongxing Zhang
- Yi Zhang
- Yu Shi
- Junjie Xi
- Hong Fan
- Songtao Xu
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Affiliations: Department of Thoracic Surgery, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
Published online on: October 22, 2015 https://doi.org/10.3892/ijmm.2015.2388
Pages: 1720-1726

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Abstract

In order to identify novel non-invasive biomarkers with high accuracy for the screening of non-small cell lung cancer (NSCLC), we investigated the predictive power of 4 microRNAs (miR-146, miR-204, miR-106a and miR-124) in plasma samples obtained from patients with NSCLC and healthy controls (n=50; training phase) by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). We found that the levels of miR-204 in the patients with NSCLC were significantly dysregulated compared with the healthy controls, and thus this miRNA was selected for further validation. For the validation phase, RT-qPCR was performed on plasma samples from patients with NSCLC and healthy controls (n=176) in order to examine the expression levels of the candidate miRNA, miR-204. The results revealed that the plasma levels of miR-204 were significantly downregulated in the patients with NSCLC compared with the healthy controls (p<0.001). The value of the area under the receiver operating characteristic (ROC) curve obtained for miR-204 was 0.809 (sensitivity, 76%; specificity, 82%), which was higher than the values obtained for carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9). The expression of miR-204 in plasma significantly correlated with the tumor stage (p=0.009) and distant metastasis (p=0.048). A log-rank test revealed that lower plasma levels of miR-204 were associated with a shorter overall survival and disease-free survival (p=0.006 and 0.0065, respectively). Both univariate and multivariate Cox regression analyses indicated that a lower miR-204 expression level in plasma was a prognostic factor with a relative risk of death of 1.936 and 1.712, respectively. On the whole, our results suggest that the decreased expression of miR-204 in plasma is a promising biomarker for the detection of NSCLC and the prediction of poor survival in patients with the disease.

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1	Jemal A, Siegel R, Ward E, Hao Y, Xu J and Thun MJ: Cancer statistics, 2009. CA Cancer J Clin. 59:225–249. 2009. View Article : Google Scholar : PubMed/NCBI
2	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
3	Wu YL and Zhou Q: Clinical trials and biomarker research on lung cancer in China. Expert Opin Ther Targets. 16(Suppl 1): S45–S50. 2012. View Article : Google Scholar : PubMed/NCBI
4	Dykxhoorn DM: MicroRNAs and metastasis: little RNAs go a long way. Cancer Res. 70:6401–6406. 2010. View Article : Google Scholar : PubMed/NCBI
5	Garzon R, Fabbri M, Cimmino A, Calin GA and Croce CM: MicroRNA expression and function in cancer. Trends Mol Med. 12:580–587. 2006. View Article : Google Scholar : PubMed/NCBI
6	Zhang B, Pan X, Cobb GP and Anderson TA: microRNAs as oncogenes and tumor suppressors. Dev Biol. 302:1–12. 2007. View Article : Google Scholar
7	Li W, Wang Y, Zhang Q, Tang L, Liu X, Dai Y, Xiao L, Huang S, Chen L, Guo Z, Lu J and Yuan K: MicroRNA-486 as a biomarker for early diagnosis and recurrence of non-small cell lung cancer. PLoS One. 10:e01342202015. View Article : Google Scholar : PubMed/NCBI
8	Mavridis K, Gueugnon F, Petit-Courty A, Courty Y, Barascu A, Guyetant S and Scorilas A: The oncomiR miR-197 is a novel prognostic indicator for non-small cell lung cancer patients. Br J Cancer. 112:1527–1535. 2015. View Article : Google Scholar : PubMed/NCBI
9	Tejero R, Navarro A, Campayo M, Viñolas N, Marrades RM, Cordeiro A, Ruíz-Martínez M, Santasusagna S, Molins L, Ramirez J and Monzó M: miR-141 and miR-200c as markers of overall survival in early stage non-small cell lung cancer adenocarcinoma. PLoS One. 9:e1018992014. View Article : Google Scholar : PubMed/NCBI
10	Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O'Briant KC, Allen A, et al: Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA. 105:10513–10518. 2008. View Article : Google Scholar : PubMed/NCBI
11	Patnaik SK, Mallick R and Yendamuri S: Detection of microRNAs in dried serum blots. Anal Biochem. 407:147–149. 2010. View Article : Google Scholar : PubMed/NCBI
12	Yang X, Zeng Z, Hou Y, Yuan T, Gao C, Jia W, Yi X and Liu M: MicroRNA-92a as a potential biomarker in diagnosis of colorectal cancer: a systematic review and meta-analysis. PLoS One. 9:e887452014. View Article : Google Scholar : PubMed/NCBI
13	Shen J, Hruby GW, McKiernan JM, Gurvich I, Lipsky MJ, Benson MC and Santella RM: Dysregulation of circulating microRNAs and prediction of aggressive prostate cancer. Prostate. 72:1469–1477. 2012. View Article : Google Scholar : PubMed/NCBI
14	Ng EK, Li R, Shin VY, Jin HC, Leung CP, Ma ES, Pang R, Chua D, Chu KM, Law WL, et al: Circulating microRNAs as specific biomarkers for breast cancer detection. PLoS One. 8:e531412013. View Article : Google Scholar : PubMed/NCBI
15	Gorur A, Balci Fidanci S, Dogruer Unal N, Ayaz L, Akbayir S, Yildirim Yaroglu H, Dirlik M, Serin MS and Tamer L: Determination of plasma microRNA for early detection of gastric cancer. Mol Biol Rep. 40:2091–2096. 2013. View Article : Google Scholar
16	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
17	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
18	Munari E, Marchionni L, Chitre A, Hayashi M, Martignoni G, Brunelli M, Gobbo S, Argani P, Allaf M, Hoque MO and Netto GJ: Clear cell papillary renal cell carcinoma: micro-RNA expression profiling and comparison with clear cell renal cell carcinoma and papillary renal cell carcinoma. Hum Pathol. 45:1130–1138. 2014. View Article : Google Scholar : PubMed/NCBI
19	Shi L, Zhang B, Sun X, Lu S, Liu Z, Liu Y, Li H, Wang L, Wang X and Zhao C: MiR-204 inhibits human NSCLC metastasis through suppression of NUAK1. Br J Cancer. 111:2316–2327. 2014. View Article : Google Scholar : PubMed/NCBI
20	Imam JS, Plyler JR, Bansal H, Prajapati S, Bansal S, Rebeles J, Chen HI, Chang YF, Panneerdoss S, Zoghi B, et al: Genomic loss of tumor suppressor miRNA-204 promotes cancer cell migration and invasion by activating AKT/mTOR/Rac1 signaling and actin reorganization. PLoS One. 7:e523972012. View Article : Google Scholar
21	Yin Y, Zhang B, Wang W, Fei B, Quan C, Zhang J, Song M, Bian Z, Wang Q, Ni S, et al: miR-204-5p inhibits proliferation and invasion and enhances chemotherapeutic sensitivity of colorectal cancer cells by downregulating RAB22A. Clin Cancer Res. 20:6187–6199. 2014. View Article : Google Scholar : PubMed/NCBI
22	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
23	Li G, Luna C, Qiu J, Epstein DL and Gonzalez P: Role of miR-204 in the regulation of apoptosis, endoplasmic reticulum stress response, and inflammation in human trabecular meshwork cells. Invest Ophthalmol Vis Sci. 52:2999–3007. 2011. View Article : Google Scholar : 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
25	Niklinski J, Furman M, Laudanski J and Kozlowski M: Prognostic value of pretreatment CEA, SCC-Ag and CA 19-9 levels in sera of patients with non-small cell lung cancer. Eur J Cancer Prev. 1:401–406. 1992. View Article : Google Scholar : PubMed/NCBI
26	Ruopp MD, Perkins NJ, Whitcomb BW and Schisterman EF: Youden Index and optimal cut-point estimated from observations affected by a lower limit of detection. Biom J. 50:419–430. 2008. View Article : Google Scholar : PubMed/NCBI
27	Schwarzenbach H, Nishida N, Calin GA and Pantel K: Clinical relevance of circulating cell-free microRNAs in cancer. Nat Rev Clin Oncol. 11:145–156. 2014. View Article : Google Scholar : PubMed/NCBI
28	Kang K, Peng X, Luo J and Gou D: Identification of circulating miRNA biomarkers based on global quantitative real-time PCR profiling. J Anim Sci Biotechnol. 3:42012. View Article : Google Scholar : PubMed/NCBI
29	Wang J, Zhang KY, Liu SM and Sen S: Tumor-associated circulating microRNAs as biomarkers of cancer. Molecules. 19:1912–1938. 2014. View Article : Google Scholar : PubMed/NCBI
30	Cortez MA, Bueso-Ramos C, Ferdin J, Lopez-Berestein G, Sood AK and Calin GA: MicroRNAs in body fluids - the mix of hormones and biomarkers. Nat Rev Clin Oncol. 8:467–477. 2011. View Article : Google Scholar : PubMed/NCBI
31	Jia W, Wu Y, Zhang Q, Gao G, Zhang C and Xiang Y: Identification of four serum microRNAs from a genome-wide serum microRNA expression profile as potential non-invasive biomarkers for endometrioid endometrial cancer. Oncol Lett. 6:261–267. 2013.PubMed/NCBI
32	Wang Y, Li W, Zang X, Chen N, Liu T, Tsonis PA and Huang Y: MicroRNA-204-5p regulates epithelial-to-mesenchymal transition during human posterior capsule opacification by targeting SMAD4. Invest Ophthalmol Vis Sci. 54:323–332. 2013. View Article : Google Scholar
33	Zhou X, Li L, Su J and Zhang G: Decreased miR-204 in H pylori- associated gastric cancer promotes cancer cell proliferation and invasion by targeting SOX4. PLoS One. 9:e1014572014. View Article : Google Scholar
34	Xia Y, Zhu Y, Ma T, Pan C, Wang J, He Z, Li Z, Qi X and Chen Y: miR-204 functions as a tumor suppressor by regulating SIX1 in NSCLC. FEBS Lett. 588:3703–3712. 2014. View Article : Google Scholar : PubMed/NCBI
35	Ma L, Deng X, Wu M, Zhang G and Huang J: Down-regulation of miRNA-204 by LMP-1 enhances CDC42 activity and facilitates invasion of EBV-associated nasopharyngeal carcinoma cells. FEBS Lett. 588:1562–1570. 2014. View Article : Google Scholar : PubMed/NCBI
36	Bao W, Wang HH, Tian FJ, He XY, Qiu MT, Wang JY, Zhang HJ, Wang LH and Wan XP: A TrkB-STAT3-miR-204-5p regulatory circuitry controls proliferation and invasion of endometrial carcinoma cells. Mol Cancer. 12:1552013. View Article : Google Scholar : PubMed/NCBI
37	Ryan J, Tivnan A, Fay J, Bryan K, Meehan M, Creevey L, Lynch J, Bray IM, O'Meara A, Tracey L, et al: MicroRNA-204 increases sensitivity of neuroblastoma cells to cisplatin and is associated with a favourable clinical outcome. Br J Cancer. 107:967–976. 2012. View Article : Google Scholar : PubMed/NCBI
38	Sacconi A, Biagioni F, Canu V, Mori F, Di Benedetto A, Lorenzon L, Ercolani C, Di Agostino S, Cambria AM, Germoni S, et al: miR-204 targets Bcl-2 expression and enhances responsiveness of gastric cancer. Cell Death Dis. 3:e4232012. View Article : Google Scholar : PubMed/NCBI