Mir-200 Explained

mir-200
Width:	220px
Symbol:	mir-200
Rfam:	RF00982
Mirbase Family:	MIPF0000019
Rna Type:	microRNA
Tax Domain:	Eukaryota Chordata;
Entrezgene:	406983
Hgncid:	31578
Omim:	612090

In molecular biology, the miR-200 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by binding and cleaving mRNAs or inhibiting translation. The miR-200 family contains miR-200a, miR-200b, miR-200c, miR-141, and miR-429. There is growing evidence to suggest that miR-200 microRNAs are involved in cancer metastasis.^[1]

Genomic location

The five members of miR-200 are found in two clusters. In humans, miR-200a, miR-200b, and miR-429 are located on chromosome 1 and miR-200c and miR-141 are on chromosome 12. In mice, the two clusters are on chromosomes 4 and 6.^[1]

Expression and epigenetic regulation

Members of the miR-200 family are highly enriched in epithelial tissues.^[2] While the mir-200 family is highly expressed in normal epithelial cells, it is not expressed in normal fibroblast cells that are of mesenchymal origin. The expression in mesenchymal cells is repressed by epigenetic marks and each cluster is repressed by a different mark. While the promoter of the cluster on chromosome 1 is occupied by polycomb specific mark H3K27me3, the promoter of the cluster on chromosome 12 is repressed by DNA methylation.^[3] DNA methylation of the mir-200c/mir-141 promoter occurs aberrantly in certain aggressive carcinoma cells that are of epithelial origin, but have undergone epithelial to mesenchymal transition and have the mir-200 family silenced.^[4]

Association with tumour progression

The miR-200 family is believed to play an essential role in tumor suppression by inhibiting epithelial-mesenchymal transition (EMT), the initiating step of metastasis (Korpal). EMT occurs as part of embryonic development, and shares many similarities with cancer progression. During EMT, cells lose adhesion and increase in motility. This is characterized by repression of E-cadherin expression, which also occurs during the initial stages of metastasis.

By contrast, miR-200 has been shown to promote the last step of metastasis in which migrating cancer cells undergo MET during their colonization at distant tissues. In a series of mouse mammary isogenic cancer cell lines, the miR-200 family is highly expressed only in the cells that are able to form metastases (4T1 cells) but not in other cells which are unable to colonize (4TO7 cells). Overexpression of miR-200c in non-metastatic 4TO7 cells readily enables MET and colonization of the liver and lung.^[5]

MiR-200 targets the E-cadherin transcriptional repressors ZEB1 and ZEB2. Knockdown of miR-141 and miR-200b has been shown to reduce E-cadherin expression thus increasing cell motility and inducing EMT.^{[6] [7]} Consistent with these findings, overexpression of miR-200b resulted in a decrease of endometriotic cell motility and invasive growth, associated with ZEB1 and ZEB2 downregulation and E-cadherin upregulation.^[8] Note that family members of miR-200 may have different functions due to differences in their seed regions: miR-200bc share the same seed region, while miR-200a has one nucleotide change.^[9]

Cancer

The role of miR-200 in EMT and tumor progression has been linked to several cancers including:

• Bladder cancer^{[10] [11]}
• Breast cancer^{[12] [13]}
• Melanoma^[14]
• Ovarian cancer^[15]
• Pancreatic cancer^[16]
• Prostate cancer^[17]
• Stomach cancer^[18]
• Lung cancer^[19]
• Colorectal cancer: MiR-200a regulates epithelial to mesenchymal transition-related gene expression and determines prognosis in colorectal cancer patients.^[20]

Further reading

• Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y, Goodall GJ . The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. . Nat Cell Biol . 10 . 5 . 593–601 . 2008 . 18376396 . 10.1038/ncb1722. free .
• Iliopoulos D, Lindahl-Allen M, Polytarchou C, Hirsch HA, Tsichlis PN, Struhl K . Loss of miR-200 inhibition of Suz12 leads to polycomb-mediated repression required for the formation and maintenance of cancer stem cells. . Mol Cell . 39 . 5 . 761–72 . 2010 . 20832727 . 2938080 . 10.1016/j.molcel.2010.08.013.
• Brabletz S, Brabletz T . The ZEB/miR-200 feedback loop--a motor of cellular plasticity in development and cancer? . EMBO Rep . 11 . 9 . 670–7 . 2010 . 20706219 . 2933868 . 10.1038/embor.2010.117.
• 10.4161/cbt.10.3.12548 . Mongroo PS, Rustgi AK . The role of the miR-200 family in epithelial-mesenchymal transition. . Cancer Biol Ther . 10 . 3 . 219–22. 2010 . 20592490. 3040834 .
• Lin Z, Wang X, Fewell C, Cameron J, Yin Q, Flemington EK . Differential expression of the miR-200 family microRNAs in epithelial and B cells and regulation of Epstein-Barr virus reactivation by the miR-200 family member miR-429. . J Virol . 84 . 15 . 7892–7 . 2010 . 20484493 . 2897641 . 10.1128/JVI.00379-10.
• Teleman AA . miR-200 de-FOGs insulin signaling. . Cell Metab . 11 . 1 . 8–9 . 2010 . 20085731 . 10.1016/j.cmet.2009.12.004. free .
• Hyun S, Lee JH, Jin H, Nam J, Namkoong B, Lee G, Chung J, Kim VN . Conserved MicroRNA miR-8/miR-200 and its target USH/FOG2 control growth by regulating PI3K. . Cell . 139 . 6 . 1096–108 . 2009 . 20005803 . 10.1016/j.cell.2009.11.020. free .
• Bendoraite A, Knouf EC, Garg KS, Parkin RK, Kroh EM, O'Briant KC, Ventura AP, Godwin AK, Karlan BY, Drescher CW, Urban N, Knudsen BS, Tewari M . Regulation of miR-200 family microRNAs and ZEB transcription factors in ovarian cancer: evidence supporting a mesothelial-to-epithelial transition. . Gynecol Oncol . 116 . 1 . 117–25 . 2010 . 19854497 . 2867670 . 10.1016/j.ygyno.2009.08.009.
• Spaderna S, Brabletz T, Opitz OG . The miR-200 family: central player for gain and loss of the epithelial phenotype. . Gastroenterology . 136 . 5 . 1835–7 . 2009 . 19324106 . 10.1053/j.gastro.2009.03.009. free .
• Peter ME . Let-7 and miR-200 microRNAs: guardians against pluripotency and cancer progression. . Cell Cycle . 8 . 6 . 843–52 . 2009 . 19221491 . 10.4161/cc.8.6.7907 . 2688687.
• 10.4161/rna.5.3.6558 . Korpal M, Kang Y . The emerging role of miR-200 family of microRNAs in epithelial-mesenchymal transition and cancer metastasis. . RNA Biol . 5 . 3 . 115–9 . 2008. 19182522. 3532896 .
• Paterson EL, Kolesnikoff N, Gregory PA, Bert AG, Khew-Goodall Y, Goodall GJ . The microRNA-200 family regulates epithelial to mesenchymal transition. . ScientificWorldJournal . 8 . 901–4 . 2008 . 18836656 . 10.1100/tsw.2008.115. 5848679 . free .
• Bracken CP, Gregory PA, Kolesnikoff N, Bert AG, Wang J, Shannon MF, Goodall GJ . A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. . Cancer Res . 68 . 19 . 7846–54 . 2008 . 18829540 . 10.1158/0008-5472.CAN-08-1942. free .
• Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S, Brabletz T . A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. . EMBO Rep . 9 . 6 . 582–9 . 2008 . 18483486 . 2396950 . 10.1038/embor.2008.74.

Notes and References

1. Korpal M, Lee ES, Hu G, Kang Y . The miR-200 family inhibits epithelial-mesenchymal transition (EMT) and promotes mesenchymal-epithelial transition (MET) by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2 . J. Biol. Chem. . 283 . 22 . 14910–4 . May 2008 . 18411277 . 10.1074/jbc.C800074200 . 3258899. free .
2. Lu J, Getz G, Miska EA, etal . MicroRNA expression profiles classify human cancers . Nature . 435 . 7043 . 834–8 . June 2005 . 15944708 . 10.1038/nature03702 . 2005Natur.435..834L . 4423938 .
3. Vrba . L . Garbe . JC . Stampfer . MR . Futscher . BW . 2011 . Epigenetic regulation of normal human mammary cell type-specific miRNAs. . Genome Research . 21 . 12 . 2026–37 . 10.1101/gr.123935.111 . 21873453 . 3227093.
4. Vrba . L . Jensen . TJ . Garbe . JC . Heimark . RL . Cress . AE . Dickinson . S . Stampfer . MR . Futscher . BW . 2010 . Role for DNA methylation in the regulation of miR-200c and miR-141 expression in normal and cancer cells. . PLOS ONE . 5 . 1 . e8697 . 10.1371/journal.pone.0008697 . 20084174 . 2805718. 2010PLoSO...5.8697V . free .
5. 10.1158/0008-5472.CAN-10-1346 . Dykxhoorn DM . 2010 . MicroRNAs and metastasis: little RNAs go a long way . Cancer Res . 70 . 16. 6401–6406 . 20663901 . 2922433 .
6. Gregory PA, Bert AG, Paterson EL, etal . The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1 . Nat. Cell Biol. . 10 . 5 . 593–601 . May 2008 . 18376396 . 10.1038/ncb1722 . free .
7. Park SM, Gaur AB, Lengyel E, 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 . 7 . 894–907 . April 2008 . 18381893 . 2279201 . 10.1101/gad.1640608 .
8. Eggers . Julia . microRNA miR-200b affects proliferation, invasiveness and stemness of endometriotic cells by targeting ZEB1, ZEB2 and KLF4. . Reproductive Biomedicine Online . 2016 . 32 . 4 . 434–45 . 10.1016/j.rbmo.2015.12.013 . 26854065 . free .
9. Uhlmann . S . Zhang . JD . Schwäger . A . Mannsperger . H . Riazalhosseini . Y . Burmester . S . Ward . A . Korf . U . Wiemann . S . Sahin . O . miR-200bc/429 cluster targets PLCgamma1 and differentially regulates proliferation and EGF-driven invasion than miR-200a/141 in breast cancer. . Oncogene . 29 July 2010 . 29 . 30 . 4297–306 . 10.1038/onc.2010.201 . 20514023. free .
10. Adam L, Zhong M, Choi W, etal . miR-200 expression regulates epithelial-to-mesenchymal transition in bladder cancer cells and reverses resistance to epidermal growth factor receptor therapy . Clin. Cancer Res. . 15 . 16 . 5060–72 . August 2009 . 19671845 . 10.1158/1078-0432.CCR-08-2245 . 5938624 .
11. Wiklund ED, Bramsen JB, Hulf T, etal . Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer . Int J Cancer . 128. 6. 1327–34. May 2010 . 20473948 . 10.1002/ijc.25461 . free .
12. Tryndyak VP, Beland FA, Pogribny IP . E-cadherin transcriptional down-regulation by epigenetic and microRNA-200 family alterations is related to mesenchymal and drug-resistant phenotypes in human breast cancer cells . Int. J. Cancer . 126 . 11 . 2575–83 . June 2010 . 19839049 . 10.1002/ijc.24972 . free .
13. Dykxhoorn DM, Wu Y, Xie H, etal . Blagosklonny . Mikhail V. . miR-200 enhances mouse breast cancer cell colonization to form distant metastases . PLOS ONE . 4 . 9 . e7181 . 2009 . 19787069 . 2749331 . 10.1371/journal.pone.0007181 . 2009PLoSO...4.7181D . free .
14. Elson-Schwab . I . Lorentzen . A . Marshall . CJ . Danen . Erik H. J. . MicroRNA-200 family members differentially regulate morphological plasticity and mode of melanoma cell invasion . PLOS ONE . 5 . 10 . e13176. 2010 . 20957176 . 2949394 . 10.1371/journal.pone.0013176 . 2010PLoSO...513176E . free .
15. Hu X, Macdonald DM, Huettner PC, Feng Z, El Naqa IM, Schwarz JK, Mutch DG, Grigsby PW, Powell SN, Wang X . A miR-200 microRNA cluster as prognostic marker in advanced ovarian cancer. . Gynecol Oncol . 114 . 3 . 457–64 . 2009 . 19501389 . 10.1016/j.ygyno.2009.05.022.
16. Li Y, VandenBoom TG, Kong D, Wang Z, Ali S, Philip PA, Sarkar FH . Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. . Cancer Res . 69 . 16 . 6704–12 . 2009 . 19654291 . 10.1158/0008-5472.CAN-09-1298 . 2727571.
17. Kong D, Li Y, Wang Z, Banerjee S, Ahmad A, Kim HR, Sarkar FH . miR-200 regulates PDGF-D-mediated epithelial-mesenchymal transition, adhesion, and invasion of prostate cancer cells. . Stem Cells . 27 . 8 . 1712–21 . 2009 . 19544444 . 10.1002/stem.101. 3400149 .
18. Shinozaki A, Sakatani T, Ushiku T, Hino R, Isogai M, Ishikawa S, Uozaki H, Takada K, Fukayama M . Downregulation of microRNA-200 in EBV-associated gastric carcinoma. . Cancer Res . 70 . 11 . 4719–27 . 2010 . 20484038 . 10.1158/0008-5472.CAN-09-4620. free .
19. Gibbons DL, Lin W, Creighton CJ, Rizvi ZH, Gregory PA, Goodall GJ, Thilaganathan N, Du L, Zhang Y, Pertsemlidis A, Kurie JM . Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expression. . Genes Dev . 23 . 18 . 2140–51 . 2009 . 19759262 . 2751985 . 10.1101/gad.1820209.
20. 24504363. 2014. Pichler. M. MiR-200a regulates epithelial to mesenchymal transition-related gene expression and determines prognosis in colorectal cancer patients. British Journal of Cancer. Ress. A. L.. Winter. E. Stiegelbauer. V. Karbiener. M. Schwarzenbacher. D. Scheideler. M. Ivan. C. Jahn. S. W.. Kiesslich. T. Gerger. A. Bauernhofer. T. Calin. G. A.. Hoefler. G. 10.1038/bjc.2014.51 . 110 . 6 . 1614–21. 3960623.