microRNA-101 inhibits lung cancer invasion through the regulation of enhancer of zeste homolog 2

Cho,Hyun Min; Jeon,Hyo Sung; Lee,Soo Young; Jeong,Kang Jin; Park,Soon-Young; Lee,Hoi Young; Lee,Jung Uee; Kim,Ji hye; Kwon,Sun Jung; Choi,Eugene; Na,Moon Jun; Kang,Jaeku; Son,Ji Woong

doi:10.3892/etm.2011.284

microRNA-101 inhibits lung cancer invasion through the regulation of enhancer of zeste homolog 2

Authors:
- Hyun Min Cho
- Hyo Sung Jeon
- Soo Young Lee
- Kang Jin Jeong
- Soon-Young Park
- Hoi Young Lee
- Jung Uee Lee
- Ji hye Kim
- Sun Jung Kwon
- Eugene Choi
- Moon Jun Na
- Jaeku Kang
- Ji Woong Son
View Affiliations

Affiliations: Department of Thoracic Surgery, Konyang University Hospital, Daejeon 302-718, Republic of Korea, Department of Biochemistry, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea, Myunggok Research Institute for Medical Science, Konyang University, Daejeon 302-718, Republic of Korea, Department of Pharmacology, College of Medicine, Konyang University, Daejeon 302-718, Republic of Korea, Department of Hospital Pathology, The Catholic University of Korea, Daejeon St. Mary's Hospital, Daejeon 301-723, Republic of Korea, Department of Internal Medicine, Konyang University Hospital, Daejeon 302-718, Republic of Korea
Published online on: June 14, 2011 https://doi.org/10.3892/etm.2011.284
Pages: 963-967

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

microRNAs (miRNAs) may function as oncogenes or tumor-suppressor genes depending on the targets that are regulated. Enhancer of zeste homolog 2 (EZH2) is the target of miR-101 and a member of the polycomb repressive complex 2, which is involved in the methylation of histone H3 at lysine 27 (H3K27). Therefore, we aimed to ascertain whether or not the overexpression of miR-101 inhibits invasion of lung cancer through regulation of EZH2. In this study, the expression of miR-101 was down-regulated and the expression of EZH2 was up-regulated in lung cancer. Global methylation of H3K27 was higher in metastatic lung cancer than in early lung cancer lesions. Overexpression of miR-101 induced a marked reduction in EZH2 mRNA levels in several lung cancer cell lines. A reduction in the trimethyl H3K27 histone mark was detected at the CDH1 promoter in miR-101 precursor-transfected cells. Moreover, the expression of CDH1 and MMP-2 was reversed by miR-101 transfection. Therefore, the overexpression of miR-101 inhibits the invasiveness of lung cancer. miR-101 may be a potent tumor suppressor by altering chromatin structure through repression of EZH2 and may be a potential therapeutic tool for patients with lung cancer.

View Figures

View References

1.	Ambros V: The functions of animal microRNAs. Nature. 431:350–355. 2004. View Article : Google Scholar : PubMed/NCBI
2.	Kim VN and Nam JW: Genomics of microRNA. Trends Genet. 22:165–173. 2006. View Article : Google Scholar : PubMed/NCBI
3.	Lim LP, Lau NC, Garrett-Engele P, et al: Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 433:769–773. 2005. View Article : Google Scholar : PubMed/NCBI
4.	Bentwich I, Avniel A, Karov Y, et al: Identification of hundreds of conserved and nonconserved human microRNAs. Nat Genet. 37:766–770. 2005. View Article : Google Scholar : PubMed/NCBI
5.	Berezikov E, Guryev V, van de Belt J, Wienholds E, Plasterk RHA and Cuppen E: Phylogenetic shadowing and computational identification of human microRNA genes. Cell. 120:21–24. 2005. View Article : Google Scholar : PubMed/NCBI
6.	Cheng AM, Byrom MW, Shelton J and Ford LP: Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Res. 33:1290–1297. 2005. View Article : Google Scholar : PubMed/NCBI
7.	Xu P, Guo M and Hay BA: MicroRNAs and the regulation of cell death. Trends Genet. 20:617–624. 2004. View Article : Google Scholar
8.	Karp X and Ambros V: Encountering microRNAs in cell fate signaling. Science. 310:1288–1289. 2005. View Article : Google Scholar : PubMed/NCBI
9.	Chen C-Z, Li L, Lodish HF and Bartel DP: MicroRNAs modulate hematopoietic lineage differentiation. Science. 303:83–86. 2004. View Article : Google Scholar : PubMed/NCBI
10.	Varambally S, Cao Q, Mani R-S, et al: Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science. 322:1695–1699. 2008. View Article : Google Scholar : PubMed/NCBI
11.	Friedman JM, Liang G, Liu C-C, et al: The putative tumor suppressor microRNA-101 modulates the cancer epigenome by repressing the polycomb group protein EZH2. Cancer Res. 69:2623–2629. 2009. View Article : Google Scholar : PubMed/NCBI
12.	Anglim PP, Alonzo TA and Laird-Offringa IA: DNA methylation-based biomarkers for early detection of non-small cell lung cancer: an update. Mol Cancer. 7:812008. View Article : Google Scholar : PubMed/NCBI
13.	Barlesi F, Giaccone G, Gallegos-Ruiz MI, et al: Global histone modifications predict prognosis of resected non small-cell lung cancer. J Clin Oncol. 25:4358–4364. 2007. View Article : Google Scholar : PubMed/NCBI
14.	Ellinger J, Kahl P, von der Gathen J, et al: Global levels of histone modifications predict prostate cancer recurrence. Prostate. 70:61–69. 2010. View Article : Google Scholar : PubMed/NCBI
15.	Varambally S, Dhanasekaran SM, Zhou M, et al: The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 419:624–629. 2002. View Article : Google Scholar : PubMed/NCBI
16.	Collett K, Eide GE, Arnes J, et al: Expression of enhancer of zeste homologue 2 is significantly associated with increased tumor cell proliferation and is a marker of aggressive breast cancer. Clin Cancer Res. 12:1168–1174. 2006. View Article : Google Scholar : PubMed/NCBI
17.	Vleminckx K, Vakaet L, Mareel M, Fiers W and van Roy F: Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell. 66:107–119. 1991. View Article : Google Scholar : PubMed/NCBI
18.	Semb H and Christofori G: The tumor-suppressor function of E-cadherin. Am J Hum Genet. 63:1588–1593. 1998. View Article : Google Scholar : PubMed/NCBI
19.	Halbleib JM and Nelson WJ: Cadherins in development: cell adhesion, sorting, and tissue morphogenesis. Genes Dev. 20:3199–3214. 2006. View Article : Google Scholar : PubMed/NCBI
20.	Sulzer MA, Leers MP, van Noord JA, Bollen EC and Theunissen PH: Reduced E-cadherin expression is associated with increased lymph node metastasis and unfavorable prognosis in non-small cell lung cancer. Am J Respir Crit Care Med. 157:1319–1323. 1998. View Article : Google Scholar : PubMed/NCBI
21.	Liu D, Huang C, Kameyama K, et al: E-cadherin expression associated with differentiation and prognosis in patients with non-small cell lung cancer. Ann Thorac Surg. 71:949–955. 2001. View Article : Google Scholar : PubMed/NCBI
22.	Huang C, Liu D, Masuya D, et al: Clinical application of biological markers for treatments of resectable non-small cell lung cancers. Br J Cancer. 92:1231–1239. 2005. View Article : Google Scholar : PubMed/NCBI
23.	Liotta LA, Tryggvason K, Garbisa S, Hart I, Foltz CM and Shafie S: Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature. 284:67–68. 1980. View Article : Google Scholar : PubMed/NCBI
24.	Nelson AR, Fingleton B, Rothenberg ML and Matrisian LM: Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol. 18:11352000.PubMed/NCBI
25.	Chetty C, Lakka SS, Bhoopathi P and Rao JS: MMP-2 alters VEGF expression via αVβ3 integrin-mediated PI3K/AKT signaling in A549 lung cancer cells. Int J Cancer. 127:1081–1095. 2010.
26.	Leinonen T, Pirinen R, Bohm J, Johansson R and Kosma VM: Increased expression of matrix metalloproteinase-2 (MMP-2) predicts tumour recurrence and unfavourable outcome in non-small cell lung cancer. Histol Histopathol. 23:693–700. 2008.PubMed/NCBI
27.	Kim S-H, Choi HY, Lee J, et al: Elevated activities of MMP-2 in the non-tumorous lung tissues of curatively resected stage I NSCLC patients are associated with tumor recurrence and a poor survival. J Surg Oncol. 95:337–346. 2007. View Article : Google Scholar : PubMed/NCBI
28.	Hung W-C, Tseng W-L, Shiea J and Chang H-C: Skp2 overexpression increases the expression of MMP-2 and MMP-9 and invasion of lung cancer cells. Cancer Lett. 288:156–161. 2010. View Article : Google Scholar : PubMed/NCBI
29.	Polette M, Gilles C, de Bentzmann S, Gruenert D, Tournier J-M and Birembaut P: Association of fibroblastoid features with the invasive phenotype in human bronchial cancer cell lines. Clin Exp Metastasis. 16:105–112. 1998. View Article : Google Scholar : PubMed/NCBI
30.	Miyaki M, Tanaka K, Kikuchi-Yanoshita R, Muraoka M, Konishi M and Takeichi M: Increased cell-substratum adhesion, and decreased gelatinase secretion and cell growth, induced by E-cadherin transfection of human colon carcinoma cells. Oncogene. 11:2547–2552. 1995.
31.	Nawrocki-Raby B, Gilles C, Polette M, et al: E-cadherin mediates MMP down-regulation in highly invasive bronchial tumor cells. Am J Pathol. 163:653–661. 2003. View Article : Google Scholar : PubMed/NCBI
32.	Su H, Yang J-R, Xu T, et al: MicroRNA-101, down-regulated in hepatocellular carcinoma, promotes apoptosis and suppresses tumorigenicity. Cancer Res. 69:1135–1142. 2009. View Article : Google Scholar : PubMed/NCBI
33.	Li S, Fu H, Wang Y, et al: MicroRNA-101 regulates expression of the v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS) oncogene in human hepatocellular carcinoma. Hepatology. 49:1194–1202. 2009. View Article : Google Scholar
34.	Wang H-J, Ruan H-J, He X-J, et al: MicroRNA-101 is down-regulated in gastric cancer and involved in cell migration and invasion. Eur J Cancer. 46:2295–2303. 2010. View Article : Google Scholar : PubMed/NCBI
35.	Strillacci A, Griffoni C, Sansone P, et al: MiR-101 downregulation is involved in cyclooxygenase-2 overexpression in human colon cancer cells. Exp Cell Res. 315:1439–1447. 2009. View Article : Google Scholar : PubMed/NCBI