MiR-206

MiR-206 is a microRNA with a sequence conserved across most mammalian species, and in humans is a member of the myo-miR family of miRNAs, which includes miR-1, miR-133, and miR-208a/b.[1][2][3][4] Mir-206 is well established for the regulation of cellular processes involving skeletal muscle development, as well as mitochondrial functioning. miR-206 is studied in C2C12 myoblast cells as this is a widely used model for the study of cellular differentiation of skeletal muscle.[5] The biogenesis of miR-206 is unique in that the primary mature transcript is generated from the 3p arm of the precursor microRNA hairpin rather than the 5p arm.[6] Currently, miR-206 has approximately twelve miRNA family members (six of which are shown in Table 1), and the cognate seed sequence (nucleotides 2-8) of the miR-206 family is conserved across all twelve miRNA members.

The structure of pre-miR-206 as determined by RNA folding algorithms
Identifiers for miR-206 sequence in various RNA and genomic databases

While miR-206 is tightly regulated during the embryonic development of skeletal muscle, miR-206 is also regulated by the nuclear steroid hormone receptor 17β-estradiol.[7][8] Further evidence supporting the role of miR-206 in tumorigenesis originates from studies showing miR-206 is highly expressed in triple-negative breast tumors that grow independent of 17β-estradiol when compared to estrogen-receptor positive (ERα+), 17β-estradiol sensitive breast cancer cells. miR-206 is also an indicator of poorer overall survival rates in breast cancer patients.[9] While miR-206 has a well defined role in breast tumor etiology, miR-206 was recently shown to control mesothelioma progression via the regulation of the Ras signaling pathway[10] These studies add to an increasing body of literature showing how small noncoding regulatory RNAs maintain the normal cellular processes that prevent the tumorigenic process. A number of cell lines used to elucidate the role of miR-206 in breast cancer include MCF-7, MDA-MB-231, and MDA-MB-468 cell lines.

Single nucleotide polymorphisms (SNPs) can be located in the miRNA seed sequence, and therefore are known to have functional consequences. One such effect is the altered binding efficacy of a miRNA to the cognate mRNA target based on the altered single nucleotide composition of the miRNA seed region.[11] In fact, a number of studies have indicated that the canonical seed sequence of a miRNA is not a sole determinate in miRNA:mRNA pairing interactions, as mutations of residues outside the seed region can also alter this binding efficacy. The miR-206 regulation of ERα through the direct binding of miR-206 in the ERα 3' UTR,[7] is a good example of how a miRNA:mRNA base pairing interaction can be influenced by SNPs.

A number of additional miR-206 regulatory modules have been identified, such as the lncRNA HOTAIR mediated up-regulation of Bcl-w through sequestration of miR-206 which in turn enhances cellular proliferation in breast cancer cells.[12] This study indicates miR-206 can interact with other non-coding RNAs to control a variety of tumorigenic process in a number of cancer systems. In support of this, SNHG14 can also sponge miR-206 thereby modulating the abundance of YWHAZ in cervical cancer.[13] Together, these studies and the numerous studies not cited here due to space limitations, clearly show the therapeutic potential of a miRNA such as miR-206 in the oncological setting.

Outside the realm of tumor biology, miR-206 is of clinical interest due to the continued detection of this miRNA in samples from those with type 2 diabetes (TIID) and non-alcoholic fatty liver disease (NAFLD). In some studies the therapeutic delivery of miR-206 in a dietary obese mouse model resulted in reduced lipid and glucose production within the liver. The ability of miR-206 to facilitate insulin signaling and modulate lipogenesis indicates miR-206 may be a novel therapy for those with hyperglycemia.[14] Mir-206 has also recently been identified as a biomarker for certain limb dystrophies,[15] while circulating miR-206 levels are associative with preeclampsia.[16]

The conservation associated with miR-206 family members

References
  1. Sempere LF, Freemantle S, Pitha-Rowe I, Moss E, Dmitrovsky E, Ambros V (2004). "Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation". Genome Biology. 5 (3): R13. doi:10.1186/gb-2004-5-3-r13. PMC 395763. PMID 15003116.
  2. van Rooij E, Quiat D, Johnson BA, Sutherland LB, Qi X, Richardson JA, Kelm RJ, Olson EN (November 2009). "A family of microRNAs encoded by myosin genes governs myosin expression and muscle performance". Developmental Cell. 17 (5): 662–73. doi:10.1016/j.devcel.2009.10.013. PMC 2796371. PMID 19922871.
  3. Small EM, O'Rourke JR, Moresi V, Sutherland LB, McAnally J, Gerard RD, Richardson JA, Olson EN (March 2010). "Regulation of PI3-kinase/Akt signaling by muscle-enriched microRNA-486". Proceedings of the National Academy of Sciences of the United States of America. 107 (9): 4218–23. Bibcode:2010PNAS..107.4218S. doi:10.1073/pnas.1000300107. PMC 2840099. PMID 20142475.
  4. van Rooij E, Sutherland LB, Qi X, Richardson JA, Hill J, Olson EN (April 2007). "Control of stress-dependent cardiac growth and gene expression by a microRNA". Science. 316 (5824): 575–9. Bibcode:2007Sci...316..575V. doi:10.1126/science.1139089. PMID 17379774. S2CID 1927839.
  5. Yaffe, D.; Saxel, O. (Dec 22–29, 1977). "Serial passaging and differentiation of myogenic cells isolated from dystrophic mouse muscle". Nature. 270 (5639): 725–727. Bibcode:1977Natur.270..725Y. doi:10.1038/270725a0. ISSN 0028-0836. PMID 563524. S2CID 4196110.
  6. Kozomara A, Griffiths-Jones S (January 2014). "miRBase: annotating high confidence microRNAs using deep sequencing data". Nucleic Acids Research. 42 (Database issue): D68–73. doi:10.1093/nar/gkt1181. PMC 3965103. PMID 24275495.
  7. Adams BD, Furneaux H, White BA (May 2007). "The micro-ribonucleic acid (miRNA) miR-206 targets the human estrogen receptor-alpha (ERalpha) and represses ERalpha messenger RNA and protein expression in breast cancer cell lines". Molecular Endocrinology. 21 (5): 1132–47. doi:10.1210/me.2007-0022. PMID 17312270.
  8. Adams BD, Cowee DM, White BA (August 2009). "The role of miR-206 in the epidermal growth factor (EGF) induced repression of estrogen receptor-alpha (ERalpha) signaling and a luminal phenotype in MCF-7 breast cancer cells". Molecular Endocrinology. 23 (8): 1215–30. doi:10.1210/me.2009-0062. PMC 2718747. PMID 19423651.
  9. Kondo N, Toyama T, Sugiura H, Fujii Y, Yamashita H (July 2008). "miR-206 Expression is down-regulated in estrogen receptor alpha-positive human breast cancer". Cancer Research. 68 (13): 5004–8. doi:10.1158/0008-5472.CAN-08-0180. PMID 18593897.
  10. Singh, Anand; Pruett, Nathanael; Pahwa, Roma; Mahajan, Arushi P.; Schrump, David S.; Hoang, Chuong D. (2021-06-04). "MicroRNA-206 suppresses mesothelioma progression via the Ras signaling axis". Molecular Therapy: Nucleic Acids. 24: 669–681. doi:10.1016/j.omtn.2021.04.001. ISSN 2162-2531. PMC 8093312. PMID 33996251.
  11. Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP (July 2007). "MicroRNA targeting specificity in mammals: determinants beyond seed pairing". Molecular Cell. 27 (1): 91–105. doi:10.1016/j.molcel.2007.06.017. PMC 3800283. PMID 17612493.
  12. Ding, Wei; Ren, Jin; Ren, Hui; Wang, Dan (2017-12-08). "Long Noncoding RNA HOTAIR Modulates MiR-206-mediated Bcl-w Signaling to Facilitate Cell Proliferation in Breast Cancer". Scientific Reports. 7 (1): 17261. Bibcode:2017NatSR...717261D. doi:10.1038/s41598-017-17492-x. ISSN 2045-2322. PMC 5722884. PMID 29222472.
  13. Ji, Nannan; Wang, Yuhuan; Bao, Guangli; Yan, Juanli; Ji, Sha (2019-04-01). "LncRNA SNHG14 promotes the progression of cervical cancer by regulating miR-206/YWHAZ". Pathology - Research and Practice. 215 (4): 668–675. doi:10.1016/j.prp.2018.12.026. ISSN 0344-0338. PMID 30611620. S2CID 58644713.
  14. Wu H, Zhang T, Pan F, Steer CJ, Li Z, Chen X, Song G (April 2017). "MicroRNA-206 prevents hepatosteatosis and hyperglycemia by facilitating insulin signaling and impairing lipogenesis". Journal of Hepatology. 66 (4): 816–824. doi:10.1016/j.jhep.2016.12.016. PMC 5568011. PMID 28025059.
  15. Pegoraro, Valentina; Angelini, Corrado (2021-01-12). "Circulating miR-206 as a Biomarker for Patients Affected by Severe Limb Girdle Muscle Dystrophies". Genes. 12 (1): 85. doi:10.3390/genes12010085. ISSN 2073-4425. PMC 7826967. PMID 33445560.
  16. Schlosser, Kenny; Kaur, Amanpreet; Dayan, Natalie; Stewart, Duncan J.; Pilote, Louise; Delles, Christian (2020-01-31). "Circulating miR-206 and Wnt-signaling are associated with cardiovascular complications and a history of preeclampsia in women". Clinical Science. 134 (2): 87–101. doi:10.1042/CS20190920. ISSN 1470-8736. PMC 8299351. PMID 31899480.
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