let-7 microRNA precursor

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let-7 microRNA precursor
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 (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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

The let-7 family has a lot more members in vertebrates than in C.elegans and Drosophila.[10] And 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 temporal during developmental processes.[14] Given that the expression levels of let-7 members are significantly low in human cancers and cancer stem cells,[15] the major function of let-7 genes may be to promote terminal differentiation in development and tumor suppression.

Regulation of expression[edit]

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.[16] It indicates that the mature let-7 miRNAs may be regulated in a post-transcriptional manner.

By pluripotency promoting factor LIN28[edit]

As one of the four genes involved in induced pluripotent stem (iPS) cells reprogramming,[17] LIN28 expression is reciprocal to that of mature let-7.[18] LIN28 selectively binds the primary and precursor forms of let-7, and inhibits the processing of pri-let-7 to form the hairpin precursor.[19] This binding is facilitated by the conserved loop sequence of primary let-7 family members and RNA-binding domains of LIN28 proteins.[20] On the other hand, let-7 miRNAs in mammals have been shown to regulate LIN28,[21] which implies that let-7 might enhance its own level by repressing LIN28, its negative regulator.[22]

In autoregulatory loop with MYC[edit]

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.[23] 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.[24] 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.[25]

Targets of let-7[edit]

Oncogenes: RAS, HMGA2[edit]

Let-7 has been demonstrated to be a direct regulator of RAS expression in human cells[26] 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.[27] Removal of let-7 binding site by 3'UTR deletion cause overexpression of HMGA2 and formation of tumor.

Cell cycle, proliferation, and apoptosis regulators[edit]

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.[28] 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.[29]


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.[30][31] 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.[32][33] 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.[34] Down-modulation of let-7 negative regulator Lin28b in human T lymphocytes is believed to accrue during early neonate development to reprogramm the immune system towards defense.[35]

Potential clinical use in cancer[edit]

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.


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.[36] In lung cancer, for example, reduced expression of let-7 is significantly correlated with reduced postoperative survival.[37] The expression of let-7b and let-7g microRNAs are significantly associated with overall survival in 1262 breast cancer patients.[38]


Let-7 is also a very attractive potential therapeutic that can prevent tumorigenesis and angiogenesis, typically in cancers that underexpress let-7.[39] 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.[37] Intranasal administration of let-7 has already been found effective in reducing tumor growth in a transgenic mouse model of lung cancer.[40] Similar restoration of let-7 was also shown to inhibit cell proliferation in breast, colon and hepatic cancers, lymphoma, and uterine leiomyoma.[41]


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