Let-7 microRNA precursor

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
GOGO:0035195 GO:0035068
SOSO:0001244
PDB structuresPDBe

The Let-7 microRNA precursor was identified from a study of developmental timing in C. elegans,[1] and was later shown to be part of a much larger class of non-coding RNAs termed microRNAs.[2] miR-98 microRNA precursor from human is a let-7 family member. Let-7 miRNAs have now been predicted or experimentally confirmed in a wide range of species (MIPF0000002[3]). miRNAs are initially transcribed in long transcripts (up to several hundred nucleotides) called primary miRNAs (pri-miRNAs), which are processed in the nucleus by Drosha and Pasha to hairpin structures of about 70 nucleotide. These precursors (pre-miRNAs) are exported to the cytoplasm by exportin5, where they are subsequently processed by the enzyme Dicer to a ~22 nucleotide mature miRNA. The involvement of Dicer in miRNA processing demonstrates a relationship with the phenomenon of RNA interference.

Genomic Locations

In 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-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.[4]

The let-7 family

The lethal-7 (let-7) gene was first discovered in the nematode as a key developmental regulator and became one of the first two known microRNAs (the other one is lin-4).[5] Soon, let-7 was found in fruit fly, and identified as the first known human miRNA by a BLAST (basic local alignment search tool) research.[6] 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.[7] Among them, let-7, mir-84, mir-48 and mir-241 are involved in C.elegans heterochronic pathway, sequentially controlling developmental timing of larva transitions.[8] Most animals with loss-of-function let-7 mutation burst through their vulvas and die, and therefore the mutant is lethal (let).[5] 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.[9]

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.[10] 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.[11] 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.[12]

In vertebrates

The let-7 family has a lot more members in vertebrates than in C.elegans and Drosophila.[10] The sequences, expression timing, as well as genomic clustering of these miRNAs members are all conserved across species.[13] 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.[14] Functionally, let-7 has been shown in early vertebrates to control the differentiation of mesoderm and ectoderm.[15] Given that the expression levels of let-7 members are significantly low in human cancers and cancer stem cells,[16] 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.[17] 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,[18] LIN28 expression is reciprocal to that of mature let-7.[19] LIN28 selectively binds the primary and precursor forms of let-7, and inhibits the processing of pri-let-7 to form the hairpin precursor.[20] This binding is facilitated by the conserved loop sequence of primary let-7 family members and RNA-binding domains of LIN28 proteins.[21] Lin-28 uses two zinc knuckle domains to recognize the NGNNG motif in the let-7 precursors,[22] while the Cold-shock domain, connected by a flexible linker, binds to a closed loop in the precursors.[23] On the other hand, let-7 miRNAs in mammals have been shown to regulate LIN28,[24] which implies that let-7 might enhance its own level by repressing LIN28, its negative regulator.[25]

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.[26] 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.[27] 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.[28]

Targets of let-7

Oncogenes: RAS, HMGA2

Let-7 has been demonstrated to be a direct regulator of RAS expression in human cells[29] 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.[30] 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.[29] Subsequent experiments confirmed the direct effects of some of these genes, such as CDC25A and CDK6.[31] Let-7 also inhibits several components of DNA replication machinery, transcription factors, even some tumor suppressor genes and checkpoint regulators.[29] Apoptosis is regulated by let-7 as well, through Casp3, Bcl2, Map3k1 and Cdk5 modulation.[32]

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.[33][34] 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 signalling and expression.[35][36] 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.[37] 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.[38]

Potential clinical use in cancer

Given the prominent phenotype of cell overproliferation and undifferentiation 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.

Diagnosis

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.[4] 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.[39] In lung cancer, for example, reduced expression of let-7 is significantly correlated with reduced postoperative survival.[40] The expression of let-7b and let-7g microRNAs are significantly associated with overall survival in 1262 breast cancer patients.[41]

Therapy

Let-7 is also a very attractive potential therapeutic that can prevent tumorigenesis and angiogenesis, typically in cancers that underexpress let-7.[42] 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.[40] Intranasal administration of let-7 has already been found effective in reducing tumor growth in a transgenic mouse model of lung cancer.[43] Similar restoration of let-7 was also shown to inhibit cell proliferation in breast, colon and hepatic cancers, lymphoma, and uterine leiomyoma.[44]

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Further reading

  • Dangi-Garimella S, Strouch MJ, Grippo PJ, Bentrem DJ, Munshi HG (February 2011). "Collagen regulation of let-7 in pancreatic cancer involves TGF-β1-mediated membrane type 1-matrix metalloproteinase expression". Oncogene. 30 (8): 1002–1008. doi:10.1038/onc.2010.485. PMC 3172057. PMID 21057545.
  • Yang X, Lin X, Zhong X, Kaur S, Li N, Liang S, et al. (November 2010). "Double-negative feedback loop between reprogramming factor LIN28 and microRNA let-7 regulates aldehyde dehydrogenase 1-positive cancer stem cells". Cancer Research. 70 (22): 9463–9472. doi:10.1158/0008-5472.CAN-10-2388. PMC 3057570. PMID 21045151.
  • Ohshima K, Inoue K, Fujiwara A, Hatakeyama K, Kanto K, Watanabe Y, et al. (October 2010). Wölfl S (ed.). "Let-7 microRNA family is selectively secreted into the extracellular environment via exosomes in a metastatic gastric cancer cell line". PLOS ONE. 5 (10): e13247. Bibcode:2010PLoSO...513247O. doi:10.1371/journal.pone.0013247. PMC 2951912. PMID 20949044.
  • Ramachandran R, Fausett BV, Goldman D (November 2010). "Ascl1a regulates Müller glia dedifferentiation and retinal regeneration through a Lin-28-dependent, let-7 microRNA signalling pathway". Nature Cell Biology. 12 (11): 1101–1107. doi:10.1038/ncb2115. PMC 2972404. PMID 20935637.
  • Ruzzo A, Canestrari E, Galluccio N, Santini D, Vincenzi B, Tonini G, et al. (January 2011). "Role of KRAS let-7 LCS6 SNP in metastatic colorectal cancer patients". Annals of Oncology. 22 (1): 234–235. doi:10.1093/annonc/mdq472. PMID 20926546.
  • Garbuzov A, Tatar M (2010). "Hormonal regulation of Drosophila microRNA let-7 and miR-125 that target innate immunity". Fly. 4 (4): 306–311. doi:10.4161/fly.4.4.13008. PMC 3174482. PMID 20798594.
  • Ji J, Wang XW (November 2010). "A Yin-Yang balancing act of the lin28/let-7 link in tumorigenesis". Journal of Hepatology. 53 (5): 974–975. doi:10.1016/j.jhep.2010.07.001. PMC 2949515. PMID 20739081.
  • Osada H, Takahashi T (January 2011). "let-7 and miR-17-92: small-sized major players in lung cancer development". Cancer Science. 102 (1): 9–17. doi:10.1111/j.1349-7006.2010.01707.x. PMID 20735434.
  • He Y, Yang C, Kirkmire CM, Wang ZJ (July 2010). "Regulation of opioid tolerance by let-7 family microRNA targeting the mu opioid receptor". The Journal of Neuroscience. 30 (30): 10251–10258. doi:10.1523/JNEUROSCI.2419-10.2010. PMC 2943348. PMID 20668208.
  • Cevec M, Thibaudeau C, Plavec J (November 2010). "NMR structure of the let-7 miRNA interacting with the site LCS1 of lin-41 mRNA from Caenorhabditis elegans". Nucleic Acids Research. 38 (21): 7814–7821. doi:10.1093/nar/gkq640. PMC 2995062. PMID 20660479.
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  • Polikepahad S, Knight JM, Naghavi AO, Oplt T, Creighton CJ, Shaw C, et al. (September 2010). "Proinflammatory role for let-7 microRNAS in experimental asthma". The Journal of Biological Chemistry. 285 (39): 30139–30149. doi:10.1074/jbc.M110.145698. PMC 2943272. PMID 20630862.
  • Newman MA, Hammond SM (August 2010). "Lin-28: an early embryonic sentinel that blocks Let-7 biogenesis". The International Journal of Biochemistry & Cell Biology. 42 (8): 1330–1333. doi:10.1016/j.biocel.2009.02.023. PMID 20619222.
  • Lee ST, Chu K, Oh HJ, Im WS, Lim JY, Kim SK, et al. (March 2011). "Let-7 microRNA inhibits the proliferation of human glioblastoma cells". Journal of Neuro-Oncology. 102 (1): 19–24. doi:10.1007/s11060-010-0286-6. PMID 20607356. S2CID 29835621.
  • Zhang W, Winder T, Ning Y, Pohl A, Yang D, Kahn M, et al. (January 2011). "A let-7 microRNA-binding site polymorphism in 3'-untranslated region of KRAS gene predicts response in wild-type KRAS patients with metastatic colorectal cancer treated with cetuximab monotherapy". Annals of Oncology. 22 (1): 104–109. doi:10.1093/annonc/mdq315. PMC 8890483. PMID 20603437.
  • Zhao Y, Deng C, Wang J, Xiao J, Gatalica Z, Recker RR, Xiao GG (May 2011). "Let-7 family miRNAs regulate estrogen receptor alpha signaling in estrogen receptor positive breast cancer". Breast Cancer Research and Treatment. 127 (1): 69–80. doi:10.1007/s10549-010-0972-2. PMID 20535543. S2CID 29668405.
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  • Johnson SM, Lin SY, Slack FJ (July 2003). "The time of appearance of the C. elegans let-7 microRNA is transcriptionally controlled utilizing a temporal regulatory element in its promoter". Developmental Biology. 259 (2): 364–379. doi:10.1016/S0012-1606(03)00202-1. PMID 12871707.
  • Pasquinelli AE, McCoy A, Jiménez E, Saló E, Ruvkun G, Martindale MQ, Baguñà J (2003). "Expression of the 22 nucleotide let-7 heterochronic RNA throughout the Metazoa: a role in life history evolution?". Evolution & Development. 5 (4): 372–378. doi:10.1046/j.1525-142X.2003.03044.x. PMID 12823453. S2CID 32723915.
  • Sempere LF, Dubrovsky EB, Dubrovskaya VA, Berger EM, Ambros V (April 2002). "The expression of the let-7 small regulatory RNA is controlled by ecdysone during metamorphosis in Drosophila melanogaster". Developmental Biology. 244 (1): 170–179. doi:10.1006/dbio.2002.0594. PMID 11900466.
  • Hutvágner G, McLachlan J, Pasquinelli AE, Bálint E, Tuschl T, Zamore PD (August 2001). "A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA". Science. 293 (5531): 834–838. doi:10.1126/science.1062961. PMID 11452083. S2CID 6177608.
  • Slack FJ, Basson M, Liu Z, Ambros V, Horvitz HR, Ruvkun G (April 2000). "The lin-41 RBCC gene acts in the C. elegans heterochronic pathway between the let-7 regulatory RNA and the LIN-29 transcription factor". Molecular Cell. 5 (4): 659–669. doi:10.1016/S1097-2765(00)80245-2. PMID 10882102.
  • Lin S, Li H, Mu H, Luo W, Li Y, Jia X, et al. (July 2012). "Let-7b regulates the expression of the growth hormone receptor gene in deletion-type dwarf chickens". BMC Genomics. 13: 306. doi:10.1186/1471-2164-13-306. PMC 3428657. PMID 22781587.
  • Shen Y, Wollam J, Magner D, Karalay O, Antebi A (December 2012). "A steroid receptor-microRNA switch regulates life span in response to signals from the gonad". Science. 338 (6113): 1472–1476. Bibcode:2012Sci...338.1472S. doi:10.1126/science.1228967. PMC 3909774. PMID 23239738.
  • Page for let-7 microRNA precursor at Rfam
  • miRBase family entry for let-7


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miRNA precursor families
1-100101-200201-300301-400401-500501-600601+Other