let-7 microRNA precursor

let-7 microRNA precursor
let-7 microRNA precursor
RF00027.jpg
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 0035195 0035068
SO 0001244

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 (MIPF000002). miRNAs are transcribed as pri-miRNAs, which are processed in the nucleus by Drosha and Pasha to hairpin structures of about ~70 nucleotide called pre-miRNAs. These precursors 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.

Contents

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.[3]

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).[4] 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.[5] 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.[6] 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.[7] Most animals with loss-of-function let-7 mutation burst through their vulvas and die, and therefore the mutant is lethal (let).[4] 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.[8]

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.[9] 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.[10] 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.[11]

In vertebrates

The let-7 family has a lot more members in vertebrates than in C.elegans and Drosophila.[9] And the sequences, expression timing, as well as genomic clustering of these miRNAs members are all conserved across species.[12] 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 temporal during developmental processes.[13] Given that the expression levels of let-7 members are significantly low in human cancers and cancer stem cells,[14] 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.[15] 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 four genes involved in induced pluripotent stem (iPS) cells reprogramming,[16] LIN28 expression is reciprocal to that of mature let-7.[17] LIN28 selectively binds the primary and precursor forms of let-7, and inhibits the processing of pri-let-7 to form the hairpin precursor.[18] This binding is facilitated by the conserved loop sequence of primary let-7 family members and RNA-binding domains of LIN28 proteins.[19] On the other hand, let-7 miRNAs in mammals have been shown to regulate LIN28,[20] which implies that let-7 might enhance its own level by repressing LIN28, its negative regulator.

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.[21] 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.[22] 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.[23]

Targets of let-7

Oncogenes: RAS, HMGA2

Let-7 has been demonstrated to be a direct regulator of RAS expression in human cells[24] 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.[25] Removal of let-7 binding site by 3'UTR deletion cause overexpression of HMGA2 and formation of tumor. MYC is also considered as a oncogenic target of let-7.

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.[26] Subsequent experiments confirmed the direct effects of some of these genes, such as CDC25A and CDK6.[27] Let-7 also inhibits several components of DNA replication machinery, transcription factors, even some tumor suppressor genes and checkpoint regulators.[26] Apoptosis is regulated by let-7 as well, through Casp3, Bcl2, Map3k1 and Cdk5 modulation.[28]

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.[3] 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.[29] In lung cancer, for example, reduced expression of let-7 is significantly correlated with reduced postoperative survival.[30]

Therapy

Let-7 is also a very attractive potential therapeutic that can prevent tumorigenesis and angiogenesis, typically in cancers that underexpress let-7.[31] Lung cancer, for instance, have several key oncogenic mutations including p53, RAS and MYC, part of which may directly correlates with the reduced expression of let-7, and may be repressed by introduction of let-7.[30] Intranasal administration of let-7 has already be found effective in reducing tumor growth in a transgenic mouse model of lung cancer.[32] Similar restoration of let-7 was also shown to inhibit cell proliferation in breast, colon and hepatic cancers, lymphoma, and uterine leiomyoma.[33]

References

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Further reading

  1. ^ Dangi-Garimella S, Strouch MJ, Grippo PJ, Bentrem DJ, Munshi HG (2010). "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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3172057. 
  2. ^ Yang X, Lin X, Zhong X, Kaur S, Li N, Liang S, Lassus H, Wang L, Katsaros D, Montone K, Zhao X, Zhang Y, Bützow R, Coukos G, Zhang L (2010). "Double negative feedback loop between reprogramming factor LIN28 and microRNA let-7 regulates aldehyde dehydrogenase 1-positive cancer stem cells". Cancer Res 70 (22): 9463–9472. doi:10.1158/0008-5472.CAN-10-2388. PMC 3057570. PMID 21045151. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3057570. 
  3. ^ Ohshima K, Inoue K, Fujiwara A, Hatakeyama K, Kanto K, Watanabe Y, Muramatsu K, Fukuda Y, Ogura S, Yamaguchi K, Mochizuki T (2010). Wölfl, Stefan. 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. doi:10.1371/journal.pone.0013247. PMC 2951912. PMID 20949044. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2951912. 
  4. ^ Ramachandran R, Fausett BV, Goldman D (2010). "Ascl1a regulates Müller glia dedifferentiation and retina regeneration via a Lin-28-dependent, let-7 miRNA signaling pathway". Nat Cell Biol 12 (11): 1101–7. doi:10.1038/ncb2115. PMC 2972404. PMID 20935637. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2972404. 
  5. ^ Ruzzo A, Canestrari E, Galluccio N, Santini D, Vincenzi B, Tonini G, Magnani M, Graziano F (2010). "Role of KRAS let-7 LCS6 SNP in metastatic colorectal cancer patients". Ann Oncol 22 (1): 234–5. doi:10.1093/annonc/mdq472. PMID 20926546. 
  6. ^ Garbuzov A, Tatar M (2010). "Hormonal regulation of Drosophila microRNA let-7 and miR-125 that target innate immunity". Fly (Austin) 4 (4): 306–11. doi:10.4161/fly.4.4.13008. PMC 3174482. PMID 20798594. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3174482. 
  7. ^ Ji J, Wang XW (2010). "A Yin-Yang Balancing Act of the Lin28/Let-7 Link in Tumorigenesis". J Hepatol 53 (5): 974–5. doi:10.1016/j.jhep.2010.07.001. PMC 2949515. PMID 20739081. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2949515. 
  8. ^ Osada H, Takahashi T (2010). "Review Article: let-7 and miR-17-92: Small-sized major players in lung cancer development". Cancer Sci 102 (1): 9–17. doi:10.1111/j.1349-7006.2010.01707.x. PMID 20735434. 
  9. ^ He Y, Yang C, Kirkmire CM, Wang ZJ (2010). "Regulation of opioid tolerance by let-7 family microRNA targeting the μ opioid receptor". J Neurosci 30 (30): 10251–8. doi:10.1523/JNEUROSCI.2419-10.2010. PMC 2943348. PMID 20668208. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2943348. 
  10. ^ Cevec M, Thibaudeau C, Plavec J (2010). "NMR structure of the let-7 miRNA interacting with the site LCS1 of lin-41 mRNA from Caenorhabditis elegans". Nucleic Acids Res 38 (21): 7814–21. doi:10.1093/nar/gkq640. PMC 2995062. PMID 20660479. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2995062. 
  11. ^ Nie K, Zhang T, Allawi H, Gomez M, Liu Y, Chadburn A, Wang YL, Knowles DM, Tam W (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". Am J Pathol 177 (3): 1470–9. doi:10.2353/ajpath.2010.091291. PMC 2928978. PMID 20651244. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2928978. 
  12. ^ Polikepahad S, Knight JM, Naghavi AO, Oplt T, Creighton CJ, Shaw C, Benham AL, Kim J, Soibam B, Harris RA, Coarfa C, Zariff A, Milosavljevic A, Batts LM, Kheradmand F, Gunaratne PH, Corry DB (2010). "Proinflammatory Role for let-7 MicroRNAS in Experimental Asthma". J Biol Chem 285 (39): 30139–49. doi:10.1074/jbc.M110.145698. PMC 2943272. PMID 20630862. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2943272. 
  13. ^ Newman MA, Hammond SM (2010). "Lin-28: an early embryonic sentinel that blocks Let-7 biogenesis". Int J Biochem Cell Biol 42 (8): 1330–3. doi:10.1016/j.biocel.2009.02.023. PMID 20619222. 
  14. ^ Lee ST, Chu K, Oh HJ, Im WS, Lim JY, Kim SK, Park CK, Jung KH, Lee SK, Kim M, Roh JK (2010). "Let-7 microRNA inhibits the proliferation of human glioblastoma cells". J Neurooncol 102 (1): 19–24. doi:10.1007/s11060-010-0286-6. PMID 20607356. 
  15. ^ Zhang W, Winder T, Ning Y, Pohl A, Yang D, Kahn M, Lurje G, Labonte MJ, Wilson PM, Gordon MA, Hu-Lieskovan S, Mauro DJ, Langer C, Rowinsky EK, Lenz HJ (2010). "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". Ann Oncol 22 (1): 104–9. doi:10.1093/annonc/mdq315. PMID 20603437. 
  16. ^ Zhao Y, Deng C, Wang J, Xiao J, Gatalica Z, Recker RR, Xiao GG (2010). "Let-7 family miRNAs regulate estrogen receptor alpha signaling in estrogen receptor positive breast cancer". Breast Cancer Res Treat 127 (1): 69–80. doi:10.1007/s10549-010-0972-2. PMID 20535543. 
  17. ^ Hu G, Zhou R, Liu J, Gong AY, Chen XM (2010). "MicroRNA-98 and let-7 Regulate Expression of Suppressor of Cytokine Signaling-4 in Biliary Epithelial Cells in Response to Cryptosporidium parvum Infection". J Infect Dis 202 (1): 125–35. doi:10.1086/653212. PMC 2880649. PMID 20486857. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2880649. 
  18. ^ Steinemann D, Tauscher M, Praulich I, Niemeyer CM, Flotho C, Schlegelberger B (2010). "Mutations in the let-7 binding site - a mechanism of RAS activation in juvenile myelomonocytic leukemia?". Haematologica 95 (9): 1616. doi:10.3324/haematol.2010.024984. PMC 2930968. PMID 20460640. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2930968. 
  19. ^ Wong TS, Man OY, Tsang CM, Tsao SW, Tsang RK, Chan JY, Ho WK, Wei WI, To VS (2010). "MicroRNA let-7 suppresses nasopharyngeal carcinoma cells proliferation through downregulating c-Myc expression". J Cancer Res Clin Oncol 137 (3): 415–422. doi:10.1007/s00432-010-0898-4. PMC 3036828. PMID 20440510. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3036828. 
  20. ^ Shimizu S, Takehara T, Hikita H, Kodama T, Miyagi T, Hosui A, Tatsumi T, Ishida H, Noda T, Nagano H, Doki Y, Mori M, Hayashi N (2010). "The let-7 family of microRNAs inhibits Bcl-xL expression and potentiates sorafenib-induced apoptosis in human hepatocellular carcinoma". J Hepatol 52 (5): 698–704. doi:10.1016/j.jhep.2009.12.024. PMID 20347499. 
  21. ^ Jakymiw A, Patel RS, Deming N, Bhattacharyya I, Shah P, Lamont RJ, Stewart CM, Cohen DM, Chan EK (2010). "Overexpression of Dicer as a Result of Reduced let-7 microRNA Levels Contributes to Increased Cell Proliferation of Oral Cancer Cells". Genes Chromosomes Cancer 49 (6): 549–59. doi:10.1002/gcc.20765. PMC 2859695. PMID 20232482. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2859695. 
  22. ^ Koh W, Sheng CT, Tan B, Lee QY, Kuznetsov V, Kiang LS, Tanavde V (2010). "Analysis of deep sequencing microRNA expression profile from human embryonic stem cells derived mesenchymal stem cells reveals possible role of let-7 microRNA family in downstream targeting of Hepatic Nuclear Factor 4 Alpha". BMC Genomics 11 Suppl 1: S6. doi:10.1186/1471-2164-11-S1-S6. PMC 2822534. PMID 20158877. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2822534. 
  23. ^ Barh D, Malhotra R, Ravi B, Sindhurani P (2010). "Microrna let-7: an emerging next-generation cancer therapeutic". Curr Oncol 17 (1): 70–80. PMC 2826782. PMID 20179807. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2826782. 
  24. ^ Balzer E, Heine C, Jiang Q, Lee VM, Moss EG (2010). "LIN28 alters cell fate succession and acts independently of the let-7 microRNA during neurogliogenesis in vitro". Development 137 (6): 891–900. doi:10.1242/dev.042895. PMID 20179095. 
  25. ^ Graziano F, Canestrari E, Loupakis F, Ruzzo A, Galluccio N, Santini D, Rocchi M, Vincenzi B, Salvatore L, Cremolini C, Spoto C, Catalano V, D'Emidio S, Giordani P, Tonini G, Falcone A, Magnani M (2010). "Genetic modulation of the Let-7 microRNA binding to KRAS 3'-untranslated region and survival of metastatic colorectal cancer patients treated with salvage cetuximab-irinotecan". Pharmacogenomics J 10 (5): 458–64. doi:10.1038/tpj.2010.9. PMID 20177422. 
  26. ^ Klemke M, Meyer A, Hashemi Nezhad M, Belge G, Bartnitzke S, Bullerdiek J (2010). "Loss of let-7 binding sites resulting from truncations of the 3' untranslated region of HMGA2 mRNA in uterine leiomyomas". Cancer Genet Cytogenet 196 (2): 119–23. doi:10.1016/j.cancergencyto.2009.09.021. PMID 20082846. 
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