miR-339-5p inhibits metastasis of non-small cell lung cancer by regulating the epithelial-to-mesenchymal transition

Li,Yun; Zhang,Xuelin; Yang,Zhen; Li,Yanan; Han,Baiyu; Chen,Liang  An

doi:10.3892/ol.2017.7608

miR-339-5p inhibits metastasis of non-small cell lung cancer by regulating the epithelial-to-mesenchymal transition

Authors:
- Yun Li
- Xuelin Zhang
- Zhen Yang
- Yanan Li
- Baiyu Han
- Liang An Chen
View Affiliations

Affiliations: Department of Respiratory Medicine, Chinese People's Liberation Army (PLA) General Hospital and Chinese PLA Medical School, Beijing 100853, P.R. China, Department of Internal Medicine, Beijing Aerospace General Hospital, Beijing 100076, P.R. China, Department of Endocrinology and Metabolism, The 264th Hospital of PLA, Taiyaun, Shanxi 030000, P.R. China
Published online on: December 13, 2017 https://doi.org/10.3892/ol.2017.7608
Pages: 2508-2514

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

Metastasis is a common event in cancer pathology, and represents the primary cause of cancer‑associated mortality. Metastasis, which is the process in which cancer cells at the primary tumor site spread to a different location in the body and form a new tumor, is regulated by multiple factors and includes a number of steps and stages. In our previous study, it was demonstrated miR‑339‑5p inhibits cell migration and invasion in vitro and is associated with the tumor‑node‑metastasis stage and the lymph node metastasis status of non‑small cell lung cancer. In the present study, expression of miR‑339‑5p was first determined in the tissues and peripheral blood of patients with non‑small cell lung cancer (NSCLC) and in NSCLC cell lines. It was then demonstrated that miR‑339‑5p inhibits A549 and H1299 cell invasion. The underlying molecular events of miR‑339‑5p action in NSCLC were also explored. By luciferase assay and western blot analysis, B‑cell CLL/lymphoma 6 (BCL6) was verified as the direct target gene of miR‑339‑5p. miR‑339‑5p may inhibit lung cancer cell invasion and migration by regulating the epithelial‑to‑mesenchymal transition via BCL6 in vitro. It was also demonstrated that the relative expression of miR‑339‑5p in the peripheral blood is associated with cancer metastasis in patients with non‑small cell lung cancer.

View Figures

View References

1	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clinc. 64:9–29. 2014. View Article : Google Scholar
2	Steeq PS: Tumor metastasis: Mechanistic insights and clinical challenges. Nat Med. 12:895–904. 2006. View Article : Google Scholar : PubMed/NCBI
3	Fidler IJ: The pathogenesis of cancer metastasis: The ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 3:453–458. 2003. View Article : Google Scholar : PubMed/NCBI
4	Croce CM and Calin GA: miRNAs, cancer, and stem cell division. Cell. 122:6–7. 2005. View Article : Google Scholar : PubMed/NCBI
5	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
6	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
7	Mendell JT: MicroRNAs: Critical regulators of development, cellular physiology and malignancy. Cell Cycle. 4:1179–1184. 2005. View Article : Google Scholar : PubMed/NCBI
8	Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, Stephens RM, Okamoto A, Yokota J, Tanaka T, et al: Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell. 9:189–198. 2006. View Article : Google Scholar : PubMed/NCBI
9	Gibborns DL, Lin W, Creiqhton CJ, Rizvi ZH, Gregory PA, Goodall GJ, Thilaganathan N, Du L, Zhang Y, Pertsemlidis A and Kurie JM: Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expression. Genes Dev. 23:2140–2151. 2009. View Article : Google Scholar : PubMed/NCBI
10	Ceppi P, Mudduluru G, Kumarswamy R, Rapa I, Scagliotti GV, Papotti M and Allgayer H: Loss of miR-200c expression induces an aggressive, invasive, and chemoresistant phenotype in non-small cell lung cancer. Mol Cancer Res. 8:1207–1216. 2010. View Article : Google Scholar : PubMed/NCBI
11	Li Y, Zhao W, Bao P, Li C, Ma XQ, Li Y and Chen LA: miR-339-5p inhibits cell migration and invasion in vitro and may be associated with the tumor-node-metastasis staging and lymph node metastasis of non-small cell lung cancer. Oncology Lett. 8:719–725. 2014.
12	Kang Y and Massagué J: Epithelial-mesenchymal transitions: Twist in development and metastasis. Cell. 118:277–279. 2004. View Article : Google Scholar : PubMed/NCBI
13	Sobin LH, Gospodrowicz MK and Wittekind C: International Union against Cancer: TNM Classification of Malignant Tumours. 7th edition. Wiley-Blackwell; New York, NY: 2011
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 : PubMed/NCBI
15	Zhang X, Zhu J, Xing R, Tie Y, Fu H, Zheng X and Yu B: miR-513a-3p sensitizes human lung adenocarcinoma cells to chemotherapy by targeting GSTP1. Lung Cancer. 77:488–494. 2012. View Article : Google Scholar : PubMed/NCBI
16	Fan Z, Cui H, Xu X, Lin Z, Zhang X, Kang L, Han B, Meng J, Yan Z, Yan X and Jiao S: miR-125a suppresses tumor growth, invasion and metastasis in cervical cancer by targeting STAT3. Oncotarget. 6:25266–25280. 2015. View Article : Google Scholar : PubMed/NCBI
17	Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S and Allgayer H: MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene. 27:2128–2136. 2008. View Article : Google Scholar : PubMed/NCBI
18	Bourguignon LY, Spevak CC, Wong G, Xia W and Gilad E: Hyaluronan-CD44 interaction with protein kinase C(epsilon) promotes oncogenic signaling by the stem cell marker Nanog and the production of microRNA-2, leading to down-regulation of the tumor suppressor protein PDCD4, anti-apoptosis, and chemotherapy resistance in breast tumor cells. J Biol Chem. 284:26533–26546. 2009. View Article : Google Scholar : PubMed/NCBI
19	Li N, Fu H, Tie Y, Hu Z, Kong W, Wu Y and Zheng X: miR-34a inhibits migration and invasion by down-regulation of c-Met expression in human hepatocellular carcinoma cells. Cancer Lett. 275:44–53. 2009. View Article : Google Scholar : PubMed/NCBI
20	Valastyan S, Reinhardt F, Benaich N, Calogrias D, Szász AM, Wang ZC, Brock JE, Richardson AL and Weinberg RA: A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis. Cell. 137:1032–1046. 2009. View Article : Google Scholar : PubMed/NCBI
21	Yang K, Handorean AM and Iczkowski KA: MicroRNAs 373 and 520c are downregulated in prostate cancer, suppress CD44 translation and enhance invasion of prostate cancer cells in vitro. Int J Clin Exp Pathol. 2:361–369. 2009.PubMed/NCBI
22	Rhoads K, Arderiu G, Charboneau A, Hansen SL, Hoffman W and Boudreau N: A role for Hox A5 in regulating angiogenesis and vascular patterning. Lymphat Res Biol. 3:240–252. 2005. View Article : Google Scholar : PubMed/NCBI
23	Chen Y and Gorski DH: Regulation of angiogenesis through a microRNA (miR-130a) that down-regulates antiangiogenic homeobox genes GAX and HOXA5. Blood. 111:1217–1226. 2008. View Article : Google Scholar : PubMed/NCBI
24	Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E, Liu S, Alder H, Costinean S, Fernandez-Cymering C, et al: MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci USA. 104:15805–15810. 2007. View Article : Google Scholar : PubMed/NCBI
25	Bracken CP, Gregory PA, Khew-Goodall Y and Goodall GJ: The role of microRNAs in metastasis and epithelial-mesenchymal transition. Cell Mol Life Sci. 66:1682–1699. 2009. View Article : Google Scholar : PubMed/NCBI
26	Gregory PA, Bracken CP, Bert AG and Goodall GJ: MicroRNAs as regulators of epithelial-mesenchymal transition. Cell Cycle. 7:3112–3118. 2008. View Article : Google Scholar : PubMed/NCBI
27	Polyak K and Weinberg RA: Transitions between epithelial and mesenchymal states: Acquisition of malignant and stem cell traits. Nat Rev Cancer. 9:265–273. 2009. View Article : Google Scholar : PubMed/NCBI
28	Ma L and Weinberg RA: Micromanagers of malignancy: Role of microRNAs in regulating metastasis. Trends Genet. 24:448–456. 2008. View Article : Google Scholar : PubMed/NCBI
29	Park SM, Gaur AB, Lengvel E and Peter ME: The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 22:894–907. 2008. View Article : Google Scholar : PubMed/NCBI
30	Hurteau GJ, Carlson JA, Spivack SD and Brock GJ: Overexpression of the microRNA hsa-miR-200c leads to reduced expression of transcription factor 8 and increased expression of E-cadherin. Cancer Res. 67:7972–7976. 2007. View Article : Google Scholar : PubMed/NCBI
31	Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y and Goodall GJ: The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 10:593–601. 2008. View Article : Google Scholar : PubMed/NCBI
32	Chang CC, Ye BH, Chaganti RS and Dalla-Favera R: BCL-6, a POZ/zinc-finger protein, is a sequence-specific transcriptional repressor. Proc Natl Acad Sci USA. 93:6947–6952. 1996. View Article : Google Scholar : PubMed/NCBI
33	Polo JM, Dell'Oso T, Ranuncolo SM, Cerchietti L, Beck D, Da Silva GF, Prive GG, Licht JD and Melnick A: Specific peptide interference reveals BCL6 transcriptional and oncogenic mechanisms in B-cell lymphoma cells. Nat Med. 10:1329–1335. 2004. View Article : Google Scholar : PubMed/NCBI
34	Phan RT, Saito M, Basso K, Niu H and Dalla-Favera R: BCL6 interacts with the transcription factor Miz-1 to suppress the cyclin-dependent kinase inhibitor p21 and cell cycle arrest in germinal center B cells. Nat Immunol. 6:1054–1060. 2005. View Article : Google Scholar : PubMed/NCBI
35	Jardin F, Ruminy P, Bastard C and Tilly H: The BCL6 proto-oncogene: A leading role during germinal center development and lymphomagenesis. Pathol Biol (Paris). 55:73–83. 2007. View Article : Google Scholar : PubMed/NCBI
36	Wu ZS, Wu Q, Wang CQ, Wang XN, Wang Y, Zhao JJ, Mao SS, Zhang GH, Zhang N and Xu XC: miR-339-5p inhibits breast cancer cell migration and invasion in vitro and may be a potential biomarker for breast cancer prognosis. BMC Cancer. 10:5422010. View Article : Google Scholar : PubMed/NCBI
37	Zhao X, Duan Z, Liu X, Wang B, Wang X, He J, Yao Z and Yang J: MicroRNA-127 is downregulated by Tudor-SN protein and contributes to metastasis and proliferation in breast cancer cell line MDA-MB-231. Anat Rec (Hoboken). 296:1842–1849. 2013. View Article : Google Scholar : PubMed/NCBI
38	Pinto AE, André S, Silva G, Vieira S, Santos AC, Dias S and Soares J: BCL-6 oncoprotein in breast cancer: Loss of expression in disease progression. Pathobiology. 76:235–242. 2009. View Article : Google Scholar : PubMed/NCBI
39	Hirata Y, Ogasawara N, Sasaki M, Mizushima T, Shimura T, Mizoshita T, Mori Y, Kubota E, Wada T, Tanida S, et al: BCL6 degradation caused by the interaction with the C-terminus of pro-HB-EGF induces cyclin D2 expression in gastric cancers. Br J Cancer. 100:1320–1329. 2009. View Article : Google Scholar : PubMed/NCBI