mir-200

mir-200
miR-200 microRNA secondary structure and sequence conservation
Identifiers
Symbol	mir-200
Rfam	RF00982
miRBase family	MIPF0000019
Entrez	406983
HUGO	31578
OMIM	612090
Other data
RNA type	microRNA
Domain(s)	Eukaryota; Chordata;

In molecular biology 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 are growing evidences 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 miR200b has been shown to reduce E-cadherin expression thus increasing cell motility and inducing EMT.^[6][7]

Cancer

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

• Bladder cancer ^[8][9]
• Breast cancer^[10][11]
• Melanoma^[12]
• Ovarian cancer^[13]
• Pancreatic cancer^[14][15]
• Prostate cancer^[16]
• Stomach cancer^[17]
• Lung Cancer^[18]
• Colorectal cancer: MiR-200a regulates epithelial to mesenchymal transition-related gene expression and determines prognosis in colorectal cancer patients.^[19]

References

1. Korpal M, Lee ES, Hu G, Kang Y (May 2008). "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. doi:10.1074/jbc.C800074200. PMC 3258899. PMID 18411277.
2. Lu J, Getz G, Miska EA, et al. (June 2005). "MicroRNA expression profiles classify human cancers". Nature. 435 (7043): 834–8. doi:10.1038/nature03702. PMID 15944708.
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. doi:10.1101/gr.123935.111. PMC 3227093. PMID 21873453.
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. doi:10.1371/journal.pone.0008697. PMC 2805718. PMID 20084174.
5. Dykxhoorn DM (2010). "MicroRNAs and metastasis: little RNAs go a long way". Cancer Res. 70 (16): 6401–6406. doi:10.1158/0008-5472.CAN-10-1346. PMC 2922433. PMID 20663901.
6. Gregory PA, Bert AG, Paterson EL, et al. (May 2008). "The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1". Nat. Cell Biol. 10 (5): 593–601. doi:10.1038/ncb1722. PMID 18376396.
7. Park SM, Gaur AB, Lengyel E, Peter ME (April 2008). "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. doi:10.1101/gad.1640608. PMC 2279201. PMID 18381893.
8. Adam L, Zhong M, Choi W, et al. (August 2009). "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. doi:10.1158/1078-0432.CCR-08-2245. PMID 19671845.
9. Wiklund ED, Bramsen JB, Hulf T, et al. (May 2010). "Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer". Int J Cancer. 128 (6): 1327–34. doi:10.1002/ijc.25461. PMID 20473948.
10. Tryndyak VP, Beland FA, Pogribny IP (June 2010). "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. doi:10.1002/ijc.24972. PMID 19839049.
11. Dykxhoorn DM, Wu Y, Xie H, et al. (2009). Blagosklonny MV, ed. "miR-200 enhances mouse breast cancer cell colonization to form distant metastases". PLoS ONE. 4 (9): e7181. doi:10.1371/journal.pone.0007181. PMC 2749331. PMID 19787069.
12. Elson-Schwab, I; Lorentzen, A; Marshall, CJ (2010). Danen, Erik H. J., ed. "MicroRNA-200 family members differentially regulate morphological plasticity and mode of melanoma cell invasion". PLoS ONE. 5 (10): e13176. doi:10.1371/journal.pone.0013176. PMC 2949394. PMID 20957176.
13. Hu X, Macdonald DM, Huettner PC, Feng Z, El Naqa IM, Schwarz JK, Mutch DG, Grigsby PW, Powell SN, Wang X (2009). "A miR-200 microRNA cluster as prognostic marker in advanced ovarian cancer.". Gynecol Oncol. 114 (3): 457–64. doi:10.1016/j.ygyno.2009.05.022. PMID 19501389.
14. Ali S, Ahmad A, Banerjee S, Padhye S, Dominiak K, Schaffert JM, Wang Z, Philip PA, Sarkar FH (2010). "Gemcitabine sensitivity can be induced in pancreatic cancer cells through modulation of miR-200 and miR-21 expression by curcumin or its analogue CDF.". Cancer Res. 70 (9): 3606–17. doi:10.1158/0008-5472.CAN-09-4598. PMC 2978024. PMID 20388782.
15. Li Y, VandenBoom TG, Kong D, Wang Z, Ali S, Philip PA, Sarkar FH (2009). "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. doi:10.1158/0008-5472.CAN-09-1298. PMC 2727571. PMID 19654291.
16. Kong D, Li Y, Wang Z, Banerjee S, Ahmad A, Kim HR, Sarkar FH (2009). "miR-200 regulates PDGF-D-mediated epithelial-mesenchymal transition, adhesion, and invasion of prostate cancer cells.". Stem Cells. 27 (8): 1712–21. doi:10.1002/stem.101. PMID 19544444.
17. Shinozaki A, Sakatani T, Ushiku T, Hino R, Isogai M, Ishikawa S, Uozaki H, Takada K, Fukayama M (2010). "Downregulation of microRNA-200 in EBV-associated gastric carcinoma.". Cancer Res. 70 (11): 4719–27. doi:10.1158/0008-5472.CAN-09-4620. PMID 20484038.
18. Gibbons DL, Lin W, Creighton CJ, Rizvi ZH, Gregory PA, Goodall GJ, Thilaganathan N, Du L, Zhang Y, Pertsemlidis A, Kurie JM (2009). "Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expression.". Genes Dev. 23 (18): 2140–51. doi:10.1101/gad.1820209. PMC 2751985. PMID 19759262.
19. Pichler, M; 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 (2014). "MiR-200a regulates epithelial to mesenchymal transition-related gene expression and determines prognosis in colorectal cancer patients". British Journal of Cancer. 110 (6): 1614–21. doi:10.1038/bjc.2014.51. PMID 24504363.

Further reading

• Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y, Goodall GJ (2008). "The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1.". Nat Cell Biol. 10 (5): 593–601. doi:10.1038/ncb1722. PMID 18376396.
• Iliopoulos D, Lindahl-Allen M, Polytarchou C, Hirsch HA, Tsichlis PN, Struhl K (2010). "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. doi:10.1016/j.molcel.2010.08.013. PMC 2938080. PMID 20832727.
• Brabletz S, Brabletz T (2010). "The ZEB/miR-200 feedback loop--a motor of cellular plasticity in development and cancer?". EMBO Rep. 11 (9): 670–7. doi:10.1038/embor.2010.117. PMC 2933868. PMID 20706219.
• Mongroo PS, Rustgi AK (2010). "The role of the miR-200 family in epithelial-mesenchymal transition.". Cancer Biol Ther. 10 (3): 219–22. doi:10.4161/cbt.10.3.12548. PMID 20592490.
• Lin Z, Wang X, Fewell C, Cameron J, Yin Q, Flemington EK (2010). "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. doi:10.1128/JVI.00379-10. PMC 2897641. PMID 20484493.
• Teleman AA (2010). "miR-200 de-FOGs insulin signaling.". Cell Metab. 11 (1): 8–9. doi:10.1016/j.cmet.2009.12.004. PMID 20085731.
• Hyun S, Lee JH, Jin H, Nam J, Namkoong B, Lee G, Chung J, Kim VN (2009). "Conserved MicroRNA miR-8/miR-200 and its target USH/FOG2 control growth by regulating PI3K.". Cell. 139 (6): 1096–108. doi:10.1016/j.cell.2009.11.020. PMID 20005803.
• 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 (2010). "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. doi:10.1016/j.ygyno.2009.08.009. PMC 2867670. PMID 19854497.
• Spaderna S, Brabletz T, Opitz OG (2009). "The miR-200 family: central player for gain and loss of the epithelial phenotype.". Gastroenterology. 136 (5): 1835–7. doi:10.1053/j.gastro.2009.03.009. PMID 19324106.
• Peter ME (2009). "Let-7 and miR-200 microRNAs: guardians against pluripotency and cancer progression.". Cell Cycle. 8 (6): 843–52. doi:10.4161/cc.8.6.7907. PMC 2688687. PMID 19221491.
• Korpal M, Kang Y (2008). "The emerging role of miR-200 family of microRNAs in epithelial-mesenchymal transition and cancer metastasis.". RNA Biol. 5 (3): 115–9. doi:10.4161/rna.5.3.6558. PMID 19182522.
• Paterson EL, Kolesnikoff N, Gregory PA, Bert AG, Khew-Goodall Y, Goodall GJ (2008). "The microRNA-200 family regulates epithelial to mesenchymal transition.". ScientificWorldJournal. 8: 901–4. doi:10.1100/tsw.2008.115. PMID 18836656.
• Bracken CP, Gregory PA, Kolesnikoff N, Bert AG, Wang J, Shannon MF, Goodall GJ (2008). "A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition.". Cancer Res. 68 (19): 7846–54. doi:10.1158/0008-5472.CAN-08-1942. PMID 18829540.
• Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S, Brabletz T (2008). "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. doi:10.1038/embor.2008.74. PMC 2396950. PMID 18483486.

External links

• Page for mir-200 microRNA precursor family at Rfam