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.elegansheterochronic 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
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]
^Esquela-Kerscher A, Slack FJ (April 2006). "Oncomirs - microRNAs with a role in cancer". Nature Reviews. Cancer. 6 (4): 259–269.
doi:
10.1038/nrc1840.
PMID16557279.
S2CID10620165.
^Kumar M, Ahmad T, Sharma A, Mabalirajan U, Kulshreshtha A, Agrawal A, Ghosh B (November 2011). "Let-7 microRNA-mediated regulation of IL-13 and allergic airway inflammation". The Journal of Allergy and Clinical Immunology. 128 (5): 1077–1085.
doi:
10.1016/j.jaci.2011.04.034.
PMID21616524.
^Lánczky A, Nagy Á, Bottai G, Munkácsy G, Szabó A, Santarpia L, Győrffy B (December 2016). "miRpower: a web-tool to validate survival-associated miRNAs utilizing expression data from 2178 breast cancer patients". Breast Cancer Research and Treatment. 160 (3): 439–446.
doi:
10.1007/s10549-016-4013-7.
PMID27744485.
S2CID11165696.
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.
PMID20619222.
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.
PMID20607356.
S2CID29835621.
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.
PMID20535543.
S2CID29668405.
Shimizu S, Takehara T, Hikita H, Kodama T, Miyagi T, Hosui A, et al. (May 2010). "The let-7 family of microRNAs inhibits Bcl-xL expression and potentiates sorafenib-induced apoptosis in human hepatocellular carcinoma". Journal of Hepatology. 52 (5): 698–704.
doi:
10.1016/j.jhep.2009.12.024.
PMID20347499.
Klemke M, Meyer A, Hashemi Nezhad M, Belge G, Bartnitzke S, Bullerdiek J (January 2010). "Loss of let-7 binding sites resulting from truncations of the 3' untranslated region of HMGA2 mRNA in uterine leiomyomas". Cancer Genetics and Cytogenetics. 196 (2): 119–123.
doi:
10.1016/j.cancergencyto.2009.09.021.
PMID20082846.
Oh JS, Kim JJ, Byun JY, Kim IA (January 2010). "Lin28-let7 modulates radiosensitivity of human cancer cells with activation of K-Ras". International Journal of Radiation Oncology, Biology, Physics. 76 (1): 5–8.
doi:
10.1016/j.ijrobp.2009.08.028.
PMID20005451.
Mu G, Liu H, Zhou F, Xu X, Jiang H, Wang Y, Qu Y (April 2010). "Correlation of overexpression of HMGA1 and HMGA2 with poor tumor differentiation, invasion, and proliferation associated with let-7 down-regulation in retinoblastomas". Human Pathology. 41 (4): 493–502.
doi:
10.1016/j.humpath.2009.08.022.
PMID20004941.
Rybak A, Fuchs H, Hadian K, Smirnova L, Wulczyn EA, Michel G, et al. (December 2009). "The let-7 target gene mouse lin-41 is a stem cell specific E3 ubiquitin ligase for the miRNA pathway protein Ago2". Nature Cell Biology. 11 (12): 1411–1420.
doi:
10.1038/ncb1987.
PMID19898466.
S2CID10902783.
Wang X, Hulshizer RL, Erickson-Johnson MR, Flynn HC, Jenkins RB, Lloyd RV, Oliveira AM (August 2009). "Identification of novel HMGA2 fusion sequences in lipoma: evidence that deletion of let-7 miRNA consensus binding site 1 in the HMGA2 3' UTR is not critical for HMGA2 transcriptional upregulation". Genes, Chromosomes & Cancer. 48 (8): 673–678.
doi:
10.1002/gcc.20674.
PMID19431195.
S2CID5328884.
Torrisani J, Bournet B, du Rieu MC, Bouisson M, Souque A, Escourrou J, et al. (August 2009). "let-7 MicroRNA transfer in pancreatic cancer-derived cells inhibits in vitro cell proliferation but fails to alter tumor progression". Human Gene Therapy. 20 (8): 831–844.
doi:
10.1089/hum.2008.134.
PMID19323605.
Garfield D (May 2008). "let-7 microRNA expression and the distinction between nonmucinous and mucinous bronchioloalveolar carcinomas". Lung Cancer. 60 (2): 307.
doi:
10.1016/j.lungcan.2008.02.010.
PMID18395292.
Inamura K, Togashi Y, Nomura K, Ninomiya H, Hiramatsu M, Satoh Y, et al. (December 2007). "let-7 microRNA expression is reduced in bronchioloalveolar carcinoma, a non-invasive carcinoma, and is not correlated with prognosis". Lung Cancer. 58 (3): 392–396.
doi:
10.1016/j.lungcan.2007.07.013.
PMID17728006.
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.
PMID12823453.
S2CID32723915.
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.elegansheterochronic 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
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]
^Esquela-Kerscher A, Slack FJ (April 2006). "Oncomirs - microRNAs with a role in cancer". Nature Reviews. Cancer. 6 (4): 259–269.
doi:
10.1038/nrc1840.
PMID16557279.
S2CID10620165.
^Kumar M, Ahmad T, Sharma A, Mabalirajan U, Kulshreshtha A, Agrawal A, Ghosh B (November 2011). "Let-7 microRNA-mediated regulation of IL-13 and allergic airway inflammation". The Journal of Allergy and Clinical Immunology. 128 (5): 1077–1085.
doi:
10.1016/j.jaci.2011.04.034.
PMID21616524.
^Lánczky A, Nagy Á, Bottai G, Munkácsy G, Szabó A, Santarpia L, Győrffy B (December 2016). "miRpower: a web-tool to validate survival-associated miRNAs utilizing expression data from 2178 breast cancer patients". Breast Cancer Research and Treatment. 160 (3): 439–446.
doi:
10.1007/s10549-016-4013-7.
PMID27744485.
S2CID11165696.
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.
PMID20619222.
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.
PMID20607356.
S2CID29835621.
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.
PMID20535543.
S2CID29668405.
Shimizu S, Takehara T, Hikita H, Kodama T, Miyagi T, Hosui A, et al. (May 2010). "The let-7 family of microRNAs inhibits Bcl-xL expression and potentiates sorafenib-induced apoptosis in human hepatocellular carcinoma". Journal of Hepatology. 52 (5): 698–704.
doi:
10.1016/j.jhep.2009.12.024.
PMID20347499.
Klemke M, Meyer A, Hashemi Nezhad M, Belge G, Bartnitzke S, Bullerdiek J (January 2010). "Loss of let-7 binding sites resulting from truncations of the 3' untranslated region of HMGA2 mRNA in uterine leiomyomas". Cancer Genetics and Cytogenetics. 196 (2): 119–123.
doi:
10.1016/j.cancergencyto.2009.09.021.
PMID20082846.
Oh JS, Kim JJ, Byun JY, Kim IA (January 2010). "Lin28-let7 modulates radiosensitivity of human cancer cells with activation of K-Ras". International Journal of Radiation Oncology, Biology, Physics. 76 (1): 5–8.
doi:
10.1016/j.ijrobp.2009.08.028.
PMID20005451.
Mu G, Liu H, Zhou F, Xu X, Jiang H, Wang Y, Qu Y (April 2010). "Correlation of overexpression of HMGA1 and HMGA2 with poor tumor differentiation, invasion, and proliferation associated with let-7 down-regulation in retinoblastomas". Human Pathology. 41 (4): 493–502.
doi:
10.1016/j.humpath.2009.08.022.
PMID20004941.
Rybak A, Fuchs H, Hadian K, Smirnova L, Wulczyn EA, Michel G, et al. (December 2009). "The let-7 target gene mouse lin-41 is a stem cell specific E3 ubiquitin ligase for the miRNA pathway protein Ago2". Nature Cell Biology. 11 (12): 1411–1420.
doi:
10.1038/ncb1987.
PMID19898466.
S2CID10902783.
Wang X, Hulshizer RL, Erickson-Johnson MR, Flynn HC, Jenkins RB, Lloyd RV, Oliveira AM (August 2009). "Identification of novel HMGA2 fusion sequences in lipoma: evidence that deletion of let-7 miRNA consensus binding site 1 in the HMGA2 3' UTR is not critical for HMGA2 transcriptional upregulation". Genes, Chromosomes & Cancer. 48 (8): 673–678.
doi:
10.1002/gcc.20674.
PMID19431195.
S2CID5328884.
Torrisani J, Bournet B, du Rieu MC, Bouisson M, Souque A, Escourrou J, et al. (August 2009). "let-7 MicroRNA transfer in pancreatic cancer-derived cells inhibits in vitro cell proliferation but fails to alter tumor progression". Human Gene Therapy. 20 (8): 831–844.
doi:
10.1089/hum.2008.134.
PMID19323605.
Garfield D (May 2008). "let-7 microRNA expression and the distinction between nonmucinous and mucinous bronchioloalveolar carcinomas". Lung Cancer. 60 (2): 307.
doi:
10.1016/j.lungcan.2008.02.010.
PMID18395292.
Inamura K, Togashi Y, Nomura K, Ninomiya H, Hiramatsu M, Satoh Y, et al. (December 2007). "let-7 microRNA expression is reduced in bronchioloalveolar carcinoma, a non-invasive carcinoma, and is not correlated with prognosis". Lung Cancer. 58 (3): 392–396.
doi:
10.1016/j.lungcan.2007.07.013.
PMID17728006.
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.
PMID12823453.
S2CID32723915.