mir-31

miR-31 has been characterised as a tumour suppressor miRNA, with its levels varying in breast cancer cells according to the metastatic state of the tumour.[1] From its typical abundance in healthy tissue is a moderate decrease in non-metastatic breast cancer cell lines, and levels are almost completely absent in mouse and human metastatic breast cancer cell lines.[2] Mir-31-5p has also been observed upregulated in Zinc Deficient rats compared to normal in ESCC (Esophageal Squamous Cell Carcinoma) and in other types of cancers when using this animal model.[3] There has also been observed a strong encapsulation of tumour cells expressing miR-31, as well as a reduced cell survival rate.[4] miR-31's antimetastatic effects therefore make it a potential therapeutic target for breast cancer. However, these two papers were formally retracted by the authors in 2015.

mir-31
Conserved secondary structure of mir-31
Identifiers
Symbolmir-31
RfamRF00661
miRBase familyMIPF0000064
Other data
RNA typemicroRNA
Domain(s)Eukaryota
PDB structuresPDBe

Functions

mir-31 has been linked to Duchenne muscular dystrophy − a genetic disorder characterised by a lack of the protein dystrophin − as a potential therapeutic target. Duchenne muscular dystrophy is caused by mutations arising in the dystrophin gene, which impair the translation of dystrophin through the formation of premature termination codons.[5]

miR-31 overexpression is more abundant in human Duchenne muscular dystrophy than in healthy controls, with levels remaining high only in Duchenne muscular dystrophy myoblasts. miR-31 levels in healthy controls are instead decreased with the onset of cell differentiation. miR-31 is part of the circuit controlling late muscle differentiation by repression of dystrophin synthesis, and its expression is localised specifically to regenerating myoblasts of dystrophic muscles.[6] miR-31 is believed to repress the expression of dystrophin by antisense binding of the dystrophin mRNA 3′ untranslated region, and in this way it is thought that miR-31 manipulation could aid treatment for Duchenne muscular dystrophy.

Applications

In serous ovarian cancer, miR-31 is frequently deleted and is the most underexpressed microRNA in this cancer type. It has been shown to affect the levels of gene transcription factor p53, responsible for encoding the tumour suppressor protein p53.[7] Cancer cell lines with an inactive p53 pathway show a vulnerability to miR-31 overexpression, whilst there is resistance to overexpression in cell lines with a functional p53 pathway.[8] miR-31 overexpression is associated with a better prognosis in tumours, suggesting that therapeutic delivery of miR-31 may be beneficial in patients with p53-deficient cancers. Conversely, in gastric cancer miR-31 levels have been found to be significantly lower in tumour cells relative to healthy cells, meaning further potential for use as a diagnostic marker.[9] However, high expression levels of miR-31 correlate to shorter survival in patients with malignant pleural mesothelioma, whereas longer survival has been associated with normal/low expression of miR-31 from blood-based samples.[10] Furthermore, in vivo, anti-miR-31 has proved to reduce miR-31-5p overexpression suppressing the esophageal preneoplasia in Zinc deficient rats. This leads to the repression of miR-31-5p target Stk40 by the inhibition of the STK40-NF-κΒ-controlled inflammatory pathway, with resultant decreased cellular proliferation and activated apoptosis. Notably Zn replenishment is able to restore the regulation of miR-31-5p targets leading to a normal esophageal phenotype.[11] miR-31 has further been shown to negatively regulate FOXP3, the master regulator in T-lymphocyte development and function.[12] This is through direct binding of miR-31 at its target site in the 3′UTR of FOXP3 mRNA.[13]

References
  1. O'Day, E; Lal, A (2010). "MicroRNAs and their target gene networks in breast cancer". Breast Cancer Research. 12 (2): 201. doi:10.1186/bcr2484. PMC 2879559. PMID 20346098.
  2. Valastyan S, Reinhardt F, Benaich N, Calogrias D, Szász AM, Wang ZC, et al. (2009). "A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis". Cell. 137 (6): 1032–1046. doi:10.1016/j.cell.2009.03.047. PMC 2766609. PMID 19524507.
  3. Fong LY, Taccioli C, Jing R, Smalley KJ, Alder H, Jiang Y, Fadda P, Farber JL, Croce CM (2016). "MicroRNA dysregulation and esophageal cancer development depend on the extent of zinc dietary deficiency". Oncotarget. 7 (10): 10723–38. doi:10.18632/oncotarget.7561. PMC 4905434. PMID 26918602.
  4. Valastyan S, Chang A, Benaich N, Reinhardt F, Weinberg RA (2011). "Activation of miR-31 function in already-established metastases elicits metastatic regression". Genes Dev. 25 (6): 646–659. doi:10.1101/gad.2004211. PMC 3059837. PMID 21406558.
  5. Cacchiarelli, D; Incitti, T; Martone, J; Cesana, M; Cazzella, V; Santini, T; Sthandier, O; Bozzoni, I (February 2011). "miR-31 modulates dystrophin expression: new implications for Duchenne muscular dystrophy therapy". EMBO Reports. 12 (2): 136–141. doi:10.1038/embor.2010.208. PMC 3049433. PMID 21212803.
  6. Cacchiarelli D, Incitti T, Martone J, Cesana M, Cazzella V, Santini T, et al. (2011). "miR-31 modulates dystrophin expression: new implications for Duchenne muscular dystrophy therapy". EMBO Rep. 12 (2): 136–141. doi:10.1038/embor.2010.208. PMC 3049433. PMID 21212803.
  7. Louis DN, von Deimling A, Chung RY, Rubio MP, Whaley JM, Eibl RH, et al. (1993). "Comparative study of p53 gene and protein alterations in human astrocytic tumors". J Neuropathol Exp Neurol. 52 (1): 31–38. doi:10.1097/00005072-199301000-00005. PMID 8381161. S2CID 21836130.
  8. Creighton CJ, Fountain MD, Yu Z, Nagaraja AK, Zhu H, Khan M, et al. (2010). "Molecular profiling uncovers a p53-associated role for microRNA-31 in inhibiting the proliferation of serous ovarian carcinomas and other cancers". Cancer Res. 70 (5): 1906–1915. doi:10.1158/0008-5472.CAN-09-3875. PMC 2831102. PMID 20179198.
  9. Zhang, Y; Guo, J; Li, D; Xiao, B; Miao, Y; Jiang, Z; Zhuo, H (September 2010). "Down-regulation of miR-31 expression in gastric cancer tissues and its clinical significance". Medical Oncology (Northwood, London, England). 27 (3): 685–689. doi:10.1007/s12032-009-9269-x. PMID 19598010. S2CID 22851497.
  10. Reid, Glen (June 2015). "MicroRNAs in mesothelioma: from tumour suppressors and biomarkers to therapeutic targets". Journal of Thoracic Disease. 7 (6): 1031–1040. doi:10.3978/j.issn.2072-1439.2015.04.56. PMC 4466421. PMID 26150916.
  11. Cristian Taccioli; Michela Garofalo; Hongping Chen; Yubao Jiang; Guidantonio Malagoli Tagliazucchi; Gianpiero Di Leva; Hansjuerg Alder; Paolo Fadda; Justin Middleton; Karl J Smalley; Tommaso Selmi; Srivatsava Naidu; John L Farber; Carlo M Croce; Louise Y Fong (2015). "Repression of Esophageal Neoplasia and Inflammatory Signaling by Anti-miR-31 Delivery In Vivo". J Natl Cancer Inst. 107 (11): 1–11. doi:10.1093/jnci/djv220. PMC 4675101. PMID 26286729.
  12. Rouas R, Fayyad-Kazan H, El Zein N, Lewalle P, Rothé F, Simion A, et al. (2009). "Human natural Treg microRNA signature: role of microRNA-31 and microRNA-21 in FOXP3 expression". Eur J Immunol. 39 (6): 1608–1618. doi:10.1002/eji.200838509. PMID 19408243.
  13. Divekar AA, Dubey S, Gangalum PR, Singh RR (2011). "Dicer insufficiency and microRNA-155 overexpression in lupus regulatory T cells: an apparent paradox in the setting of an inflammatory milieu". J Immunol. 186 (2): 924–930. doi:10.4049/jimmunol.1002218. PMC 3038632. PMID 21149603.

Further reading
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