mir-200

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]

mir-200
miR-200 microRNA secondary structure and sequence conservation
Identifiers
Symbolmir-200
RfamRF00982
miRBase familyMIPF0000019
NCBI Gene406983
HGNC31578
OMIM612090
Other data
RNA typemicroRNA
Domain(s)Eukaryota; Chordata;
PDB structuresPDBe

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:

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. Bibcode:2005Natur.435..834L. doi:10.1038/nature03702. PMID 15944708. S2CID 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. 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. Bibcode:2010PLoSO...5.8697V. 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. Eggers, Julia (2016). "microRNA miR-200b affects proliferation, invasiveness and stemness of endometriotic cells by targeting ZEB1, ZEB2 and KLF4". Reproductive Biomedicine Online. 32 (4): 434–45. doi:10.1016/j.rbmo.2015.12.013. PMID 26854065.
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  10. 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. PMC 5938624. PMID 19671845.
  11. 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.
  12. 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.
  13. 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. Bibcode:2009PLoSO...4.7181D. doi:10.1371/journal.pone.0007181. PMC 2749331. PMID 19787069.
  14. 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. Bibcode:2010PLoSO...513176E. doi:10.1371/journal.pone.0013176. PMC 2949394. PMID 20957176.
  15. 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.
  16. 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.
  17. 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. PMC 3400149. PMID 19544444.
  18. 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.
  19. 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.
  20. 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. PMC 3960623. PMID 24504363.

Further reading
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