Biology:let-7 microRNA family

From HandWiki
let-7 microRNA precursor
Predicted secondary structure and sequence conservation of let-7
Identifiers
Symbollet-7
RfamRF00027
miRBaseMI0000001
miRBase familyMIPF0000002
Other data
RNA typeGene; miRNA
Domain(s)Eukaryota
GO0035195 0035068
SO0001244
PDB structuresPDBe

The Let-7 microRNA precursor gives rise to let-7, a microRNA (miRNA) involved in control of stem-cell division and differentiation.[1] let-7, short for "lethal-7", was discovered along with the miRNA lin-4 in a study of developmental timing in C. elegans,[2] making these miRNAs the first ever discovered. let-7 was later identified in humans as the first human miRNA, and is highly conserved across many species.[3][4] Dysregulation of let-7 contributes to cancer development in humans by preventing differentiation of cells, leaving them stuck in a stem-cell like state.[1] let-7 is therefore classified as a tumor suppressor.

The let-7 microRNA family refers to the many slight variations of let-7 that exist both within a single organism and across species. In humans, for example, there are ten unique let-7 family member sequences: let-7a through g, let-7i, mir-98, and mir-202.[1]

In humans, mature let-7 acts via RNA-induced silencing by complexing with RISC and binding to target mRNA, preventing translation into protein. Known targets of let-7 include proteins related to the cell cycle and proliferation, such as MYC, RAS, cyclin D, HMGA2, and CDC25A.[1] Knockdown of these proteins by let-7 prevents proliferation and induces differentiation of cells. Important inhibitors of let-7 include LIN28, which binds to let-7 directly,[5] and the proto-oncogene MYC, which suppresses expression.[6]

Genomic locations

In the human genome, the cluster let-7a-1/let-7f-1/let-7d is inside the region B at 9q22.3, with the defining marker D9S280-D9S1809. One minimal LOH (loss of heterozygosity) region, between loci D11S1345 and D11S1316, contains the cluster miR-125b1/let-7a-2/miR-100. The cluster miR-99a/let-7c/miR-125b-2 is in a 21p11.1 region of HD (homozygous deletions). The cluster let-7g/miR-135-1 is in region 3 at 3p21.1–p21.2.[7]

The let-7 family

The lethal-7 (let-7) gene was first discovered in the nematode C. elegans as a key developmental regulator and became one of the first two known microRNAs (the other one is lin-4).[8] Soon, let-7 was found in the fruit fly (Drosophila), and identified as the first known human miRNA by a BLAST (basic local alignment search tool) research.[9] The mature form of let-7 family members is highly conserved across species.

In C. elegans

In C. elegans, the let-7 family consists of genes encoding nine miRNAs sharing the same seed sequence.[10] Among them, let-7, mir-84, mir-48 and mir-241 are involved in the C. elegans heterochronic pathway, sequentially controlling developmental timing of larva transitions.[11] Most animals with loss-of-function let-7 mutation burst through their vulvas and die, and therefore the mutant is lethal (let).[8] The mutants of other let-7 family members have a radio-resistant phenotype in vulval cells, which may be related to their ability to repress RAS.[12]

In Drosophila

There is only one single let-7 gene in the Drosophila genome, which has the identical mature sequence to the one in C. elegans.[13] The role of let-7 has been demonstrated in regulating the timing of neuromuscular junction formation in the abdomen and cell-cycle in the wing.[14] Furthermore, the expression of pri-, pre- and mature let-7 have the same rhythmic pattern with the hormone pulse before each cuticular molt in Drosophila.[15]

In vertebrates

The let-7 family has a lot more members in vertebrates than in C. elegans and Drosophila.[13] The sequences, expression timing, as well as genomic clustering of these miRNAs members are all conserved across species.[16] The direct role of let-7 family in vertebrate development has not been clearly shown as in less complex organisms, yet the expression pattern of let-7 family is indeed temporally regulated during developmental processes.[17] Functionally, let-7 has been shown in early vertebrates to control the differentiation of mesoderm and ectoderm.[18] Given that the expression levels of let-7 members are significantly low in human cancers and cancer stem cells,[19] the major function of let-7 genes may be to promote terminal differentiation in development and tumor suppression.

Regulation of expression

Although the levels of mature let-7 members are undetectable in undifferentiated cells, the primary transcripts and the hairpin precursors of let-7 are present in these cells.[20] It indicates that the mature let-7 miRNAs may be regulated in a post-transcriptional manner.

By pluripotency promoting factor LIN28

As one of the genes involved in (but not essential for) induced pluripotent stem (iPS) cell reprogramming,[21] LIN28 expression is reciprocal to that of mature let-7.[5] LIN28 selectively binds the primary and precursor forms of let-7, and inhibits the processing of pri-let-7 to form the hairpin precursor.[22] This binding is facilitated by the conserved loop sequence of primary let-7 family members and RNA-binding domains of LIN28 proteins.[23] Lin-28 uses two zinc knuckle domains to recognize the NGNNG motif in the let-7 precursors,[24] while the Cold-shock domain, connected by a flexible linker, binds to a closed loop in the precursors.[25] On the other hand, let-7 miRNAs in mammals have been shown to regulate LIN28,[26] which implies that let-7 might enhance its own level by repressing LIN28, its negative regulator.[27]

In autoregulatory loop with MYC

Expression of let-7 members is controlled by MYC binding to their promoters. The levels of let-7 have been reported to decrease in models of MYC-mediated tumorigenesis, and to increase when MYC is inhibited by chemicals.[6] In a twist, there are let-7-binding sites in MYC 3' untranslated region(UTR) according to bioinformatic analysis, and let-7 overexpression in cell culture decreased MYC mRNA levels.[28] Therefore, there is a double-negative feedback loop between MYC and let-7. Furthermore, let-7 could lead to IMP1 (insulin-like growth factor II mRNA-binding protein) depletion, which destabilizes MYC mRNA, thus forming an indirect regulatory pathway.[29]

Targets of let-7

Oncogenes: RAS, HMGA2

Let-7 has been demonstrated to be a direct regulator of RAS expression in human cells[30] All the three RAS genes in human, K-, N-, and H-, have the predicted let-7 binding sequences in their 3'UTRs. In lung cancer patient samples, expression of RAS and let-7 showed reciprocal pattern, which has low let-7 and high RAS in cancerous cells, and high let-7 and low RAS in normal cells. Another oncogene, high mobility group A2 (HMGA2), has also been identified as a target of let-7. Let-7 directly inhibits HMGA2 by binding to its 3'UTR.[31] Removal of let-7 binding site by 3'UTR deletion cause overexpression of HMGA2 and formation of tumor.

Cell cycle, proliferation, and apoptosis regulators

Microarray analyses revealed many genes regulating cell cycle and cell proliferation that are responsive to alteration of let-7 levels, including cyclin A2, CDC34, Aurora A and B kinases (STK6 and STK12), E2F5, and CDK8, among others.[30] Subsequent experiments confirmed the direct effects of some of these genes, such as CDC25A and CDK6.[32] Let-7 also inhibits several components of DNA replication machinery, transcription factors, even some tumor suppressor genes and checkpoint regulators.[30] Apoptosis is regulated by let-7 as well, through Casp3, Bcl2, Map3k1 and Cdk5 modulation.[33]

Immunity

Let-7 has been implicated in post-transcriptional control of innate immune responses to pathogenic agents. Macrophages stimulated with live bacteria or purified microbial components down-regulate the expression of several members of the let-7 microRNA family to relieve repression of immune-modulatory cytokines IL-6 and IL-10.[34][35] Let-7 has also been implicated in the negative regulation of TLR4, the major immune receptor of microbial lipopolysaccharide and down-regulation of let-7 both upon microbial and protozoan infection might elevate TLR4 signaling and expression.[36][37] Let-7 has furthermore been reported to regulate the production of cytokine IL-13 by T lymphocytes during allergic airway inflammation thus linking this microRNA to adaptive immunity as well.[38] Down-modulation of let-7 negative regulator Lin28b in human T lymphocytes is believed to accrue during early neonate development to reprogram the immune system towards defense.[39]

Potential clinical use in cancer

Given the prominent phenotype of cell overproliferation and dedifferentiation by let-7 loss-of-function in nematodes, and the role of its targets on cell destiny determination, let-7 is closely associated with human cancer and acts as a tumor suppressor.

Prognostic Biomarkers

Numerous reports have shown that the expression levels of let-7 are frequently low and the chromosomal clusters of let-7 are often deleted in many cancers.[7] Let-7 is expressed at higher levels in more differentiated tumors, which also have lower levels of activated oncogenes such as RAS and HMGA2. Therefore, expression levels of let-7 could be prognostic markers in several cancers associated with differentiation stages.[40] In lung cancer, for example, reduced expression of let-7 is significantly correlated with reduced postoperative survival.[41] The expression of let-7b and let-7g microRNAs are significantly associated with overall survival in 1262 breast cancer patients.[42]

Therapy

Let-7 is also a very attractive potential therapeutic that can prevent tumorigenesis and angiogenesis, typically in cancers that underexpress let-7.[43] Lung cancer, for instance, has several key oncogenic mutations including p53, RAS and MYC, some of which may directly correlate with the reduced expression of let-7, and may be repressed by introduction of let-7.[41] Intranasal administration of let-7 has already been found effective in reducing tumor growth in a transgenic mouse model of lung cancer.[44] Similar restoration of let-7 was also shown to inhibit cell proliferation in breast, colon and hepatic cancers, lymphoma, and uterine leiomyoma.[45]

References

  1. ↑ 1.0 1.1 1.2 1.3 Roush, Sarah; Slack, Frank J. (2008). "The let-7 family of microRNAs" (in en). Trends in Cell Biology 18 (10): 505–516. doi:10.1016/j.tcb.2008.07.007. PMID 18774294. https://linkinghub.elsevier.com/retrieve/pii/S0962892408002109. 
  2. ↑ "Control of developmental timing in animals". Nature Reviews. Genetics 2 (9): 690–701. September 2001. doi:10.1038/35088566. PMID 11533718. 
  3. ↑ Pasquinelli, Amy E.; Reinhart, Brenda J.; Slack, Frank; Martindale, Mark Q.; Kuroda, Mitzi I.; Maller, Betsy; Hayward, David C.; Ball, Eldon E. et al. (2000). "Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA" (in en). Nature 408 (6808): 86–89. doi:10.1038/35040556. ISSN 1476-4687. PMID 11081512. Bibcode: 2000Natur.408...86P. https://www.nature.com/articles/35040556. 
  4. ↑ Pasquinelli, Amy E.; McCoy, Adam; Jiménez, Eva; Saló, Emili; Ruvkun, Gary; Martindale, Mark Q.; Baguñà, Jaume (2003). "Expression of the 22 nucleotide let-7 heterochronic RNA throughout the Metazoa: a role in life history evolution?" (in en). Evolution & Development 5 (4): 372–378. doi:10.1046/j.1525-142X.2003.03044.x. ISSN 1520-541X. PMID 12823453. https://onlinelibrary.wiley.com/doi/10.1046/j.1525-142X.2003.03044.x. 
  5. ↑ 5.0 5.1 "Selective blockade of microRNA processing by Lin28". Science 320 (5872): 97–100. April 2008. doi:10.1126/science.1154040. PMID 18292307. Bibcode: 2008Sci...320...97V. 
  6. ↑ 6.0 6.1 "Widespread microRNA repression by Myc contributes to tumorigenesis". Nature Genetics 40 (1): 43–50. January 2008. doi:10.1038/ng.2007.30. PMID 18066065. 
  7. ↑ 7.0 7.1 "Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers". Proceedings of the National Academy of Sciences of the United States of America 101 (9): 2999–3004. March 2004. doi:10.1073/pnas.0307323101. PMID 14973191. Bibcode: 2004PNAS..101.2999C. 
  8. ↑ 8.0 8.1 "The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans". Nature 403 (6772): 901–906. February 2000. doi:10.1038/35002607. PMID 10706289. Bibcode: 2000Natur.403..901R. 
  9. ↑ "Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA". Nature 408 (6808): 86–89. November 2000. doi:10.1038/35040556. PMID 11081512. Bibcode: 2000Natur.408...86P. 
  10. ↑ "The microRNAs of Caenorhabditis elegans". Genes & Development 17 (8): 991–1008. April 2003. doi:10.1101/gad.1074403. PMID 12672692. 
  11. ↑ "Heterochronic genes and the nature of developmental time". Current Biology 17 (11): R425–R434. June 2007. doi:10.1016/j.cub.2007.03.043. PMID 17550772. Bibcode: 2007CBio...17.R425M. 
  12. ↑ "MicroRNAs as potential agents to alter resistance to cytotoxic anticancer therapy". Cancer Research 67 (23): 11111–11116. December 2007. doi:10.1158/0008-5472.CAN-07-2858. PMID 18056433. 
  13. ↑ 13.0 13.1 "Identification of novel genes coding for small expressed RNAs". Science 294 (5543): 853–858. October 2001. doi:10.1126/science.1064921. PMID 11679670. Bibcode: 2001Sci...294..853L. 
  14. ↑ "Temporal regulation of metamorphic processes in Drosophila by the let-7 and miR-125 heterochronic microRNAs". Current Biology 18 (13): 943–950. July 2008. doi:10.1016/j.cub.2008.06.020. PMID 18571409. Bibcode: 2008CBio...18..943C. 
  15. ↑ "Molecular mechanisms of developmental timing in C. elegans and Drosophila". Developmental Cell 1 (4): 453–465. October 2001. doi:10.1016/S1534-5807(01)00060-0. PMID 11703937. 
  16. ↑ "Identification of mammalian microRNA host genes and transcription units". Genome Research 14 (10A): 1902–1910. October 2004. doi:10.1101/gr.2722704. PMID 15364901. 
  17. ↑ "The diverse functions of microRNAs in animal development and disease". Developmental Cell 11 (4): 441–450. October 2006. doi:10.1016/j.devcel.2006.09.009. PMID 17011485. 
  18. ↑ "Whole-genome microRNA screening identifies let-7 and mir-18 as regulators of germ layer formation during early embryogenesis". Genes & Development 26 (23): 2567–2579. December 2012. doi:10.1101/gad.200758.112. PMID 23152446. 
  19. ↑ "Oncomirs - microRNAs with a role in cancer". Nature Reviews. Cancer 6 (4): 259–269. April 2006. doi:10.1038/nrc1840. PMID 16557279. 
  20. ↑ "Extensive post-transcriptional regulation of microRNAs and its implications for cancer". Genes & Development 20 (16): 2202–2207. August 2006. doi:10.1101/gad.1444406. PMID 16882971. 
  21. ↑ "Induced pluripotent stem cell lines derived from human somatic cells". Science 318 (5858): 1917–1920. December 2007. doi:10.1126/science.1151526. PMID 18029452. Bibcode: 2007Sci...318.1917Y. 
  22. ↑ "Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing". RNA 14 (8): 1539–1549. August 2008. doi:10.1261/rna.1155108. PMID 18566191. 
  23. ↑ "Determinants of microRNA processing inhibition by the developmentally regulated RNA-binding protein Lin28". The Journal of Biological Chemistry 283 (31): 21310–21314. August 2008. doi:10.1074/jbc.C800108200. PMID 18550544. 
  24. ↑ "Structural basis of pre-let-7 miRNA recognition by the zinc knuckles of pluripotency factor Lin28". Nature Structural & Molecular Biology 19 (1): 84–89. December 2011. doi:10.1038/nsmb.2202. PMID 22157959. 
  25. ↑ "Molecular basis for interaction of let-7 microRNAs with Lin28". Cell 147 (5): 1080–1091. November 2011. doi:10.1016/j.cell.2011.10.020. PMID 22078496. 
  26. ↑ "Conservation of the heterochronic regulator Lin-28, its developmental expression and microRNA complementary sites". Developmental Biology 258 (2): 432–442. June 2003. doi:10.1016/S0012-1606(03)00126-X. PMID 12798299. 
  27. ↑ "Recognition of the let-7g miRNA precursor by human Lin28B". FEBS Letters 586 (22): 3986–3990. November 2012. doi:10.1016/j.febslet.2012.09.034. PMID 23063642. Bibcode: 2012FEBSL.586.3986S. 
  28. ↑ "Prediction and preliminary validation of oncogene regulation by miRNAs". BMC Molecular Biology 8: 79. September 2007. doi:10.1186/1471-2199-8-79. PMID 17877811. 
  29. ↑ "CRD-BP/IMP1 expression characterizes cord blood CD34+ stem cells and affects c-myc and IGF-II expression in MCF-7 cancer cells". The Journal of Biological Chemistry 280 (20): 20086–20093. May 2005. doi:10.1074/jbc.M410036200. PMID 15769738. 
  30. ↑ 30.0 30.1 30.2 "RAS is regulated by the let-7 microRNA family". Cell 120 (5): 635–647. March 2005. doi:10.1016/j.cell.2005.01.014. PMID 15766527. 
  31. ↑ "Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation". Science 315 (5818): 1576–1579. March 2007. doi:10.1126/science.1137999. PMID 17322030. Bibcode: 2007Sci...315.1576M. 
  32. ↑ "The let-7 microRNA represses cell proliferation pathways in human cells". Cancer Research 67 (16): 7713–7722. August 2007. doi:10.1158/0008-5472.CAN-07-1083. PMID 17699775. 
  33. ↑ He YJ, Guo L, D ZH. (2009) Let-7 and mir-24 in uvb-induced apoptosis [Chinese]. Zhonghua Fang She Yi Xue Yu Fang Hu Za Zhi. 29, 234–6.
  34. ↑ "Analysis of the host microRNA response to Salmonella uncovers the control of major cytokines by the let-7 family". The EMBO Journal 30 (10): 1977–1989. May 2011. doi:10.1038/emboj.2011.94. PMID 21468030. 
  35. ↑ "MicroRNA-98 negatively regulates IL-10 production and endotoxin tolerance in macrophages after LPS stimulation". FEBS Letters 585 (12): 1963–1968. June 2011. doi:10.1016/j.febslet.2011.05.029. PMID 21609717. Bibcode: 2011FEBSL.585.1963L. 
  36. ↑ "MicroRNA-98 and let-7 confer cholangiocyte expression of cytokine-inducible Src homology 2-containing protein in response to microbial challenge". Journal of Immunology 183 (3): 1617–1624. August 2009. doi:10.4049/jimmunol.0804362. PMID 19592657. 
  37. ↑ "The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs". Immunity 31 (2): 220–231. August 2009. doi:10.1016/j.immuni.2009.06.024. PMID 19699171. 
  38. ↑ "Let-7 microRNA-mediated regulation of IL-13 and allergic airway inflammation". The Journal of Allergy and Clinical Immunology 128 (5): 1077–1085. November 2011. doi:10.1016/j.jaci.2011.04.034. PMID 21616524. 
  39. ↑ "Lin28b reprograms adult bone marrow hematopoietic progenitors to mediate fetal-like lymphopoiesis". Science 335 (6073): 1195–1200. March 2012. doi:10.1126/science.1216557. PMID 22345399. Bibcode: 2012Sci...335.1195Y. 
  40. ↑ "Let-7 expression defines two differentiation stages of cancer". Proceedings of the National Academy of Sciences of the United States of America 104 (27): 11400–11405. July 2007. doi:10.1073/pnas.0704372104. PMID 17600087. Bibcode: 2007PNAS..10411400S. 
  41. ↑ 41.0 41.1 "Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival". Cancer Research 64 (11): 3753–3756. June 2004. doi:10.1158/0008-5472.CAN-04-0637. PMID 15172979. 
  42. ↑ "miRpower: a web-tool to validate survival-associated miRNAs utilizing expression data from 2178 breast cancer patients". Breast Cancer Research and Treatment 160 (3): 439–446. December 2016. doi:10.1007/s10549-016-4013-7. PMID 27744485. 
  43. ↑ "Role of Dicer and Drosha for endothelial microRNA expression and angiogenesis". Circulation Research 101 (1): 59–68. July 2007. doi:10.1161/CIRCRESAHA.107.153916. PMID 17540974. 
  44. ↑ "The let-7 microRNA reduces tumor growth in mouse models of lung cancer". Cell Cycle 7 (6): 759–764. March 2008. doi:10.4161/cc.7.6.5834. PMID 18344688. 
  45. ↑ "MicroRNA let-7: an emerging next-generation cancer therapeutic". Current Oncology 17 (1): 70–80. February 2010. doi:10.3747/co.v17i1.356. PMID 20179807. 

Further reading



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:Let-7_microRNA_family&oldid=4597169"