MicroRNA-186 suppresses cell proliferation and metastasis through targeting MAP3K2 in non-small cell lung cancer

Huang,Tonghai; She,Kelin; Peng,Guilin; Wang,Wei; Huang,Jun; Li,Jingpei; Wang,Zheng; He,Jianxing

doi:10.3892/ijo.2016.3637

MicroRNA-186 suppresses cell proliferation and metastasis through targeting MAP3K2 in non-small cell lung cancer

Authors:
- Tonghai Huang
- Kelin She
- Guilin Peng
- Wei Wang
- Jun Huang
- Jingpei Li
- Zheng Wang
- Jianxing He
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Affiliations: Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, P.R. China, Department of Thoracic Surgery, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, P.R. China
Published online on: July 29, 2016 https://doi.org/10.3892/ijo.2016.3637
Pages: 1437-1444

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Abstract

MicroRNAs are a class of small endogenous non-coding RNAs that play crucial roles in the initiation and progression of human cancers. miR-186 was found decreased in various human malignancies and function as a tumor suppressor. However, the regulating mechanism of miR-186 in growth and metastasis of human non-small cell lung cancer (NSCLC) is still poorly understood. We investigated the role of miR-186 in the growth and metastasis of human NSCLC. In the present study, we found that miR-186 was significantly decreased in lung cancer tissues and cells. Furthermore, overexpression of miR-186 suppressed lung cancer cell proliferation, migration and invasion, and induced cell apoptosis. Moreover, we found that confirmed mitogen-activated protein kinase kinase kinase 2 (MAP3K2) protein was increased in lung cancer tissues and confirmed that MAP3K2 is a target gene of miR-186. In addition, knockdown of MAP3K2 by RNA interference inhibited lung cancer cell proliferation, migration and invasion, and promoted cell apoptosis in vitro. Furthermore, we observed tthat the overexpression of MAP3K2 partially reversed the inhibitory effect of miR-186 on the proliferation and metastasis of A549 and HCC827 cell lines. Taken together, our data indicated that miR-186 regulates lung cancer growth and metastasis through suppressing MAP3K2 expression, at least partly. Therefore, miR-186-MAP3K2 may represent a new and useful potential clinical treatment and diagnosis target for NSCLC.

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1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
2	Smith RA, Manassaram-Baptiste D, Brooks D, Doroshenk M, Fedewa S, Saslow D, Brawley OW and Wender R: Cancer screening in the United States, 2015: A review of current American cancer society guidelines and current issues in cancer screening. CA Cancer J Clin. 65:30–54. 2015. View Article : Google Scholar : PubMed/NCBI
3	Novaes FT, Cataneo DC, Ruiz RL Jr, Defaveri J, Michelin OC and Cataneo AJ: Lung cancer: histology, staging, treatment and survival. J Bras Pneumol. 34:595–600. 2008. View Article : Google Scholar : PubMed/NCBI
4	Youlden DR, Cramb SM and Baade PD: The International Epidemiology of lung cancer: Geographical distribution and secular trends. J Thorac Oncol. 3:819–831. 2008. View Article : Google Scholar : PubMed/NCBI
5	Johnson JL, Pillai S and Chellappan SP: Genetic and biochemical alterations in non-small cell lung cancer. Biochem Res Int. 2012:9404052012. View Article : Google Scholar : PubMed/NCBI
6	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
7	Ginsberg RJ and Rubinstein LV: Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg. 60:615–622; discussion 622–613. 1995. View Article : Google Scholar : PubMed/NCBI
8	Timmerman R, Paulus R, Galvin J, Michalski J, Straube W, Bradley J, Fakiris A, Bezjak A, Videtic G, Johnstone D, et al: Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA. 303:1070–1076. 2010. View Article : Google Scholar : PubMed/NCBI
9	Chi A, Liao Z, Nguyen NP, Xu J, Stea B and Komaki R: Systemic review of the patterns of failure following stereotactic body radiation therapy in early-stage non-small-cell lung cancer: clinical implications. Radiother Oncol. 94:1–11. 2010. View Article : Google Scholar : PubMed/NCBI
10	Martini N, Bains MS, Burt ME, Zakowski MF, McCormack P, Rusch VW and Ginsberg RJ: Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg. 109:120–129. 1995. View Article : Google Scholar : PubMed/NCBI
11	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
12	Bartel DP and Chen CZ: Micromanagers of gene expression: The potentially widespread influence of metazoan microRNAs. Nat Rev Genet. 5:396–400. 2004. View Article : Google Scholar : PubMed/NCBI
13	Chen CZ, Li L, Lodish HF and Bartel DP: MicroRNAs modulate hematopoietic lineage differentiation. Science. 303:83–86. 2004. View Article : Google Scholar
14	Kim VN: MicroRNA biogenesis: Coordinated cropping and dicing. Nat Rev Mol Cell Biol. 6:376–385. 2005. View Article : Google Scholar : PubMed/NCBI
15	Zhang S, Lu Z, Unruh AK, Ivan C, Baggerly KA, Calin GA, Li Z, Bast RC Jr and Le XF: Clinically relevant microRNAs in ovarian cancer. Mol Cancer Res. 13:393–401. 2015. View Article : Google Scholar :
16	Zhao N, Sun H, Sun B, Zhu D, Zhao X, Wang Y, Gu Q, Dong X, Liu F, Zhang Y, et al: miR-27a-3p suppresses tumor metastasis and VM by down-regulating VE-cadherin expression and inhibiting EMT: An essential role for Twist-1 in HCC. Sci Rep. 6:230912016. View Article : Google Scholar : PubMed/NCBI
17	Gomes BC, Santos B, Rueff J and Rodrigues AS: Methods for studying MicroRNA expression and their targets in formalin-fixed, paraffin-embedded (FFPE) breast cancer tissues. Methods Mol Biol. 1395:189–205. 2016. View Article : Google Scholar : PubMed/NCBI
18	Kim G, An HJ, Lee MJ, Song JY, Jeong JY, Lee JH and Jeong HC: Hsa-miR-1246 and hsa-miR-1290 are associated with stemness and invasiveness of non-small cell lung cancer. Lung Cancer. 91:15–22. 2016. View Article : Google Scholar
19	Zhang Y, Li M, Wang H, Fisher WE, Lin PH, Yao Q and Chen C: Profiling of 95 microRNAs in pancreatic cancer cell lines and surgical specimens by real-time PCR analysis. World J Surg. 33:698–709. 2009. View Article : Google Scholar
20	Myatt SS, Wang J, Monteiro LJ, Christian M, Ho KK, Fusi L, Dina RE, Brosens JJ, Ghaem-Maghami S and Lam EW: Definition of microRNAs that repress expression of the tumor suppressor gene FOXO1 in endometrial cancer. Cancer Res. 70:367–377. 2010. View Article : Google Scholar
21	Erdmann K, Kaulke K, Thomae C, Huebner D, Sergon M, Froehner M, Wirth MP and Fuessel S: Elevated expression of prostate cancer-associated genes is linked to down-regulation of microRNAs. BMC Cancer. 14:82. 2014. View Article : Google Scholar : PubMed/NCBI
22	Cai J, Wu J, Zhang H, Fang L, Huang Y, Yang Y, Zhu X, Li R and Li M: miR-186 downregulation correlates with poor survival in lung adenocarcinoma, where it interferes with cell-cycle regulation. Cancer Res. 73:756–766. 2013. View Article : Google Scholar
23	Cui G, Cui M, Li Y, Liang Y, Li W, Guo H and Zhao S: MiR-186 targets ROCK1 to suppress the growth and metastasis of NSCLC cells. Tumour Biol. 35:8933–8937. 2014. View Article : Google Scholar : PubMed/NCBI
24	Ruan WD, Wang P, Feng S, Xue Y and Zhang B: MicroRNA-497 inhibits cell proliferation, migration, and invasion by targeting AMOT in human osteosarcoma cells. Onco Targets Ther. 9:303–313. 2016. View Article : Google Scholar : PubMed/NCBI
25	Wang J, Liu G, Li Q, Wang F, Xie F, Zhai R, Guo Y, Chen T, Zhang N, Ni W, et al: Mucin1 promotes the migration and invasion of hepatocellular carcinoma cells via JNK-mediated phosphorylation of Smad2 at the C-terminal and linker regions. Oncotarget. 6:19264–19278. 2015. View Article : Google Scholar : PubMed/NCBI
26	Tian L, Fang YX, Xue JL and Chen JZ: Four microRNAs promote prostate cell proliferation with regulation of PTEN and its downstream signals in vitro. PLoS One. 8:e758852013. View Article : Google Scholar : PubMed/NCBI
27	Brennecke J, Hipfner DR, Stark A, Russell RB and Cohen SM: bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell. 113:25–36. 2003. View Article : Google Scholar : PubMed/NCBI
28	Hauser B, Zhao Y, Pang X, Ling Z, Myers E, Wang P, Califano J and Gu X: Functions of MiRNA-128 on the regulation of head and neck squamous cell carcinoma growth and apoptosis. PLoS One. 10:e01163212015. View Article : Google Scholar : PubMed/NCBI
29	Lv SQ, Kim YH, Giulio F, Shalaby T, Nobusawa S, Yang H, Zhou Z, Grotzer M and Ohgaki H: Genetic alterations in microRNAs in medulloblastomas. Brain Pathol. 22:230–239. 2012. View Article : Google Scholar
30	Su B, Cheng J, Yang J and Guo Z: MEKK2 is required for T-cell receptor signals in JNK activation and interleukin-2 gene expression. J Biol Chem. 276:14784–14790. 2001. View Article : Google Scholar : PubMed/NCBI
31	Chayama K, Papst PJ, Garrington TP, Pratt JC, Ishizuka T, Webb S, Ganiatsas S, Zon LI, Sun W, Johnson GL, et al: Role of MEKK2-MEK5 in the regulation of TNF-alpha gene expression and MEKK2-MKK7 in the activation of c-Jun N-terminal kinase in mast cells. Proc Natl Acad Sci USA. 98:4599–4604. 2001. View Article : Google Scholar : PubMed/NCBI
32	Schaefer BC, Ware MF, Marrack P, Fanger GR, Kappler JW, Johnson GL and Monks CR: Live cell fluorescence imaging of T cell MEKK2: Redistribution and activation in response to antigen stimulation of the T cell receptor. Immunity. 11:411–421. 1999. View Article : Google Scholar : PubMed/NCBI
33	Sun W, Wei X, Kesavan K, Garrington TP, Fan R, Mei J, Anderson SM, Gelfand EW and Johnson GL: MEK kinase 2 and the adaptor protein Lad regulate extracellular signal-regulated kinase 5 activation by epidermal growth factor via Src. Mol Cell Biol. 23:2298–2308. 2003. View Article : Google Scholar : PubMed/NCBI
34	Cazares LH1, Troyer D, Mendrinos S, Lance RA, Nyalwidhe JO, Beydoun HA, Clements MA, Drake RR and Semmes OJ: Imaging mass spectrometry of a specific fragment of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 2 discriminates cancer from uninvolved prostate tissue. Clin Cancer Res. 15:5541–5551. 2009. View Article : Google Scholar : PubMed/NCBI
35	Zhang W, Kong G, Zhang J, Wang T, Ye L and Zhang X: MicroRNA-520b inhibits growth of hepatoma cells by targeting MEKK2 and cyclin D1. PLoS One. 7:e314502012. View Article : Google Scholar : PubMed/NCBI