let-7 microRNA precursor

Predicted secondary structure and sequence conservation of let-7

Identifiers
Symbol| let-7
Rfam| RF00027
miRBase| MI0000001
miRBase family| MIPF0000002
Other data
RNA type| Gene; miRNA
Domain(s)| Eukaryota
GO| GO:0035195 GO:0035068
SO| SO:0001244
PDB structures| PDBe

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

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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

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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

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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

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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

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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

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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

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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

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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

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### Oncogenes: RAS, HMGA2

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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

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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

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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

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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

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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

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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

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This "Further reading" section may need cleanup. Please read the editing guide and help improve the section. (August 2024) (Learn how and when to remove this message)

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* 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.
* Nie K, Zhang T, Allawi H, Gomez M, Liu Y, Chadburn A, et al. (September 2010). "Epigenetic down-regulation of the tumor suppressor gene PRDM1/Blimp-1 in diffuse large B cell lymphomas: a potential role of the microRNA let-7". The American Journal of Pathology. 177 (3): 1470–1479. doi:10.2353/ajpath.2010.091291. PMC 2928978. PMID 20651244.
* 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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* 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.

## External links

[edit]

*   * Page for let-7 microRNA precursor at Rfam
* miRBase family entry for let-7

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miRNA precursor families

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Other|

* BART1
* BART2
* BHRF1-1
* BHRF1-2
* BHRF1-3
* Let-7
* Lin-4
* Lsy-6

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