MiR-206

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The structure of pre-miR-206 as determined by RNA folding algorithms MiR-206 struc.jpg
The structure of pre-miR-206 as determined by RNA folding algorithms
Identifiers for miR-206 sequence in various RNA and genomic databases MiR-206 identifiers.png
Identifiers for miR-206 sequence in various RNA and genomic databases

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.

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 MiR-206 Sequence Similiarity.png
The conservation associated with miR-206 family members

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Estrogen receptor Proteins activated by the hormone estrogen

Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors, which are members of the nuclear receptor family of intracellular receptors, and membrane estrogen receptors (mERs), which are mostly G protein-coupled receptors. This article refers to the former (ER).

Estrogen receptor alpha

Estrogen receptor alpha (ERα), also known as NR3A1, is one of two main types of estrogen receptor, a nuclear receptor that is activated by the sex hormone estrogen. In humans, ERα is encoded by the gene ESR1.

mir-1 microRNA precursor family

The miR-1 microRNA precursor is a small micro RNA that regulates its target protein's expression in the cell. microRNAs are transcribed as ~70 nucleotide precursors and subsequently processed by the Dicer enzyme to give products at ~22 nucleotides. In this case the mature sequence comes from the 3' arm of the precursor. The mature products are thought to have regulatory roles through complementarity to mRNA. In humans there are two distinct microRNAs that share an identical mature sequence, these are called miR-1-1 and miR-1-2.

mir-7 microRNA precursor

This family represents the microRNA (miRNA) precursor mir-7. This miRNA has been predicted or experimentally confirmed in a wide range of species. miRNAs are transcribed as ~70 nucleotide precursors and subsequently processed by the Dicer enzyme to give a ~22 nucleotide product. In this case the mature sequence comes from the 5' arm of the precursor. The extents of the hairpin precursors are not generally known and are estimated based on hairpin prediction. The involvement of Dicer in miRNA processing suggests a relationship with the phenomenon of RNA interference.

GPER

G protein-coupled estrogen receptor 1 (GPER), also known as G protein-coupled receptor 30 (GPR30), is a protein that in humans is encoded by the GPER gene. GPER binds to and is activated by the female sex hormone estradiol and is responsible for some of the rapid effects that estradiol has on cells.

Estrogen receptor beta

Estrogen receptor beta (ERβ) also known as NR3A2 is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by the ESR2 gene.

MTA1

Metastasis-associated protein MTA1 is a protein that in humans is encoded by the MTA1 gene. MTA1 is the founding member of the MTA family of genes. MTA1 is primarily localized in the nucleus but also found to be distributed in the extra-nuclear compartments. MTA1 is a component of several chromatin remodeling complexes including the nucleosome remodeling and deacetylation complex (NuRD). MTA1 regulates gene expression by functioning as a coregulator to integrate DNA-interacting factors to gene activity. MTA1 participates in physiological functions in the normal and cancer cells. MTA1 is one of the most upregulated proteins in human cancer and associates with cancer progression, aggressive phenotypes, and poor prognosis of cancer patients.

Estrogen-related receptor alpha

Estrogen-related receptor alpha (ERRα), also known as NR3B1, is a nuclear receptor that in humans is encoded by the ESRRA gene. ERRα was originally cloned by DNA sequence homology to the estrogen receptor alpha, but subsequent ligand binding and reporter-gene transfection experiments demonstrated that estrogens did not regulate ERRα. Currently, ERRα is considered an orphan nuclear receptor.

mir-145

In molecular biology, mir-145 microRNA is a short RNA molecule that in humans is encoded by the MIR145 gene. MicroRNAs function to regulate the expression levels of other genes by several mechanisms.

mir-205

In molecular biology miR-205 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms. They are involved in numerous cellular processes, including development, proliferation, and apoptosis. Currently, it is believed that miRNAs elicit their effect by silencing the expression of target genes.

mir-22

In molecular biology mir-22 microRNA is a short RNA molecule. MicroRNAs are an abundant class of molecules, approximately 22 nucleotides in length, which can post-transcriptionally regulate gene expression by binding to the 3' UTR of mRNAs expressed in a cell.

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miR-27

miR-27 is a family of microRNA precursors found in animals, including humans. MicroRNAs are typically transcribed as ~70 nucleotide precursors and subsequently processed by the Dicer enzyme to give a ~22 nucleotide product. The excised region or, mature product, of the miR-27 precursor is the microRNA mir-27.

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Hydroxylation of estradiol

The hydroxylation of estradiol is one of the major routes of metabolism of the estrogen steroid hormone estradiol. It is hydroxylated into the catechol estrogens 2-hydroxyestradiol and 4-hydroxyestradiol and into estriol (16α-hydroxyestradiol), reactions which are catalyzed by cytochrome P450 enzymes predominantly in the liver, but also in various other tissues.

ERX-11

ERX-11, also known as ERα coregulator-binding modulator-11, is a novel antiestrogen and experimental hormonal antineoplastic agent which is being researched for the potential treatment of estrogen receptor-positive breast cancer. It is not a competitive antagonist of the estrogen receptor (ER) like conventional antiestrogens such as tamoxifen or fulvestrant; instead of binding to the ligand-binding site of the ER, ERX-11 interacts with a different part of the ERα and blocks protein–protein interactions of the ERα with coregulators that are necessary for the receptor to act and regulate gene expression. It was designed to bind to the coregulator binding region of the ERα and inhibit the ERα/coactivator interaction, although its precise binding site and mode of action have yet to be fully elucidated and understood. Nonetheless, it is clear that ERX-11 binds within the AF-2 domain of the ERα.

Ann M. Nardulli was an American endocrinologist known for her research into the role of estrogen in breast cancer.

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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. doi:10.1038/270725a0. ISSN   0028-0836. PMID   563524.
  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. 1 2 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. 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. doi:10.1038/s41598-017-17492-x. ISSN   2045-2322.
  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.
  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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