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let-7 microRNA family

(Redirected from Let-7 microRNA precursor)

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.

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 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

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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.[7]

The let-7 family

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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

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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

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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.[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

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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

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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.[20] 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,[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

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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.[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

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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[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

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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.[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

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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.[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

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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

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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.[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

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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.[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

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Further reading

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