The Molecular Basis and Therapeutic Potential of Let-7 ...downloads.hindawi.com/journals/cjgh/2018/5769591.pdf · microRNA Cancer microRNA- Lung[] microRNA-Neuroblastoma[ ] ... Recent

Review ArticleThe Molecular Basis and Therapeutic Potential ofLet-7 MicroRNAs against Colorectal Cancer

Rei Mizuno Kenji Kawada and Yoshiharu Sakai

Department of Surgery Graduate School of Medicine Kyoto University Kyoto Japan

Correspondence should be addressed to Kenji Kawada kkawadakuhpkyoto-uacjp

Received 22 March 2018 Accepted 6 June 2018 Published 19 June 2018

Academic Editor Maikel P Peppelenbosch

Copyright copy 2018 Rei Mizuno et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Although a number of studies have revealed the underlying mechanisms which regulate the development of colorectal cancer(CRC) we have not completely overcome this disease yet Accumulating evidence has shown that the posttranscriptional regulationby the noncoding RNAs such as microRNAs plays an important role in the development or progression of CRC Among a numberof microRNAs the let-7 microRNA family that was first discovered in C elegans and conserved from worms to humans has beenlinked with the development of many types of cancers including CRC The expression level of let-7 microRNAs is temporally lowduring the normal developmental processes while elevated in the differentiated tissues The let-7 microRNAs regulate the cellproliferation cell cycle apoptosis metabolism and stemness In CRC expressions of let-7 microRNAs have been reported to bereduced and so let-7 microRNAs are considered to be a tumor suppressor In this review we discuss the mechanisms regulatingthe let-7 microRNA expression and the downstream targets of let-7 in the context of intestinal tumorigenesis The application oflet-7 mimics is also highlighted as a novel therapeutic agent

1 Introduction

Colorectal cancer (CRC) is one of the most common causesof cancer deaths worldwide [1ndash3] and the number of CRCpatients is increasing more and more [4] Many studieshave revealed the molecular mechanisms of the colonictumorigenesis and have proposed various models such asthe adenoma-carcinoma sequence (ie multistep carcino-genesis) and colitis-associated carcinogenesis observed ininflammatory bowel diseases (IBD) However we have notyet completely understood the molecular basis of CRCtumorigenesis One of the reasons which makes our under-standing difficult is that not only genetic changes such asmutationdeletion of oncogenes or tumor suppressor genesbut also the epigenetic modification or posttranscriptionalregulation by RNA binding proteins and microRNAs isinvolved in the colonic tumorigenesis

The let-7 microRNAs are noncoding RNAs which consistof sim22 nucleotides [5] They are first discovered in C elegansas a critical regulator of developmental process [6 7] Let-7microRNAs have been experimentally confirmed to be con-served in awide range of species including humans [8] As the

let-7 family 9 members are identified so far let-7a let-7b let-7c let-7d let-7e let-7f let-7g let-7i and miR-98 The maturelet-7 negatively regulates the expression of target mRNAs ata posttranslational level via imperfect base pairing to the 3-UTR of their target mRNAs [9] During normal developmen-tal process the expression levels of let-7 microRNAs in stemand progenitor cells are maintained low As progenitor cellsdifferentiate let-7 expression is increasing [10]

Let-7 microRNAs are downregulated in various typesof cancers such as hepatocellular carcinoma (HCC) gastricadenocarcinoma pancreatic cancer ovarian cancer prostatecancer Burkitt lymphoma renal cell carcinoma breastcancer and melanoma [11] In the context of CRC let-7 microRNAs are also downregulated which affects theposttranscriptional regulation of target mRNAs resulting inthe colonic tumorigenesis and progression

In this review we discuss the molecular mechanisms bywhich let-7 microRNAs regulate the colonic tumorigenesistumor progression and chemotherapy resistance by a post-transcriptional regulation and also highlight the possibility ofthe application of let-7 targeting therapy against CRC

HindawiCanadian Journal of Gastroenterology and HepatologyVolume 2018 Article ID 5769591 7 pageshttpsdoiorg10115520185769591

2 Canadian Journal of Gastroenterology and Hepatology

pre-let-7

LIN28AB

let-7

CSDZFD

pri-let-7

Drosha

exportin-5 pre-let-7

Dicer

Nucleus

CytoplasmTUTase

let-7

LIN28AB

Degradation

maturation

Figure 1 A schematic diagram of the let-7 biogenesis Pri-let-7 microRNA precursors are processed in the nucleus by Drosha to pre-let-7Pre-let-7 microRNA precursors are exported to the cytoplasm by exportin-5 where they are subsequently processed by Dicer resulting in themature let-7 RNA binding protein LIN28A or LIN28B binds to either pri-let-7 or pre-let-7 using RNA binding domains cold shock domain(CSD) and two zinc finger domains (ZFDs) and blocks the processing Upon binding to pre-let-7 LIN28A or LIN28B recruits TUTase whichcauses oligouridylation resulting in the degradation of pre-let-7

2 Biogenesis of Let-7 MicroRNAs (Figure 1)

Mature let-7 microRNAs are synthesized through the mul-tiple processing by microprocessors [12] Let-7 microRNAsare initially transcribed in long transcripts called primary let-7 (pri-let-7) which are processed in the nucleus by Droshaand Pasha to pre-let-7 with hairpin structures of about 70nucleotides Next pre-let-7 are exported to the cytoplasmby exportin-5 where they are subsequently processed bythe enzyme Dicer resulting in the mature let-7 [12] Let-7is known to be negatively regulated by the RNA bindingproteins LIN28A or LIN28B LIN28A or LIN28B has twoRNA binding domains cold shock domain (CSD) and twoCys-Cys-His-Cys- (CCHC-) type zinc finger domains (ZFDs)[13ndash16] which bind to the conserved GGAG motif in theterminal loop of pri-let-7 or pre-let-7 respectively resultingin the inhibition of the maturation of let-7 [17 18] Thebinding of LIN28A or LIN28B to either pri-let-7 or pre-let-7 inhibits the processing of let-7 precursors by Drosha andDicer [19] Upon binding to pre-let-7 LIN28A or LIN28Brecruits TUT4TUT7 which causes oligouridylation at the31015840 terminal of pre-let-7 [20ndash22] Under normal conditionsDicer recognizes the two nucleotides at the 31015840 terminalvia its PAZ domain however oligouridylation elongates the31015840 terminal resulting in the resistance to Dicer cleavageOligouridylated pre-let-7 can also be degenerated by the 31015840-51015840 exonuclease Dis312 [23 24] Thus LIN28A or LIN28Bnot only inhibits the biogenesis of let-7 family miRNAs butalso induces their degradation LIN28A and LIN28B are thenegative regulators of let-7microRNAs and so the expressionlevel of LIN28A is high in the developmental process whilethat of LIN28B is low in the adult tissues [10] LIN28B has twoisoforms LIN28B-long and LIN28B-short isoforms Both

isoforms preserve the binding ability to pre-let-7 HoweverLIN28B-short isoform lacks the inhibitory ability againstthe processing by microprocessors Namely LIN28B-shortisoform functions as a competitor against the LIN28B-longisoform in the context of let-7 maturation [25]

3 Let-7 and Colon Cancer

Regarding the LIN28ABlet-7 axis the downregulation oflet-7 or upregulation of either LIN28A or LIN28B has beenreported to be related to the worse prognosis in CRCpatients Stage III CRC patients with high expression ofLIN28B exhibit poorer prognosis compared to those withno LIN28B expression [26] King et al reported that theexpression level of LIN28B was inversely correlated to thatof mature let-7a in human CRC [27] Tu et al exam-ined the expression of LIN28A or LIN28B in the cohortof almost 600 CRC patients and found that LIN28A orLIN28B was highly expressed in 38 of CRC patients[28] Importantly the overall survival was lower in thepatients with high expression of LIN28A or LIN28B than inthose with low expression of LIN28A or LIN28B Madisonet al demonstrated that intestinal tumors were sponta-neously developed in the transgenic mice with intestinal-specific LIN28B expression (Villin-Lin28b) which suggeststhat LIN28B functions as an oncogene [29] Let-7b and let-7c can escape the downregulation by LIN28B in mice There-fore they crossed these mice with let-7b and let-7c knock-outmice (let-7IEC-KO) and found that the additional downreg-ulation of let-7b and let-7c resulted in the increase of tumorincidence [30]These results suggest that let-7b or let-7c playsan important role in the intestinal tumorigenesis in mice

Canadian Journal of Gastroenterology and Hepatology 3

4 Let-7 Target mRNAs in Intestine

As let-7 target mRNAs in the intestinal epithelium Madisonet al revealed that HMGA1 HMGA2 IGF2BP2 HIF3AARID3A and E2F5 were the most highly induced targetsof let-7 microRNAs in the context of intestinal homeostasis[31] Among these target molecules the protein expressionlevels of HMGA1 HMGA2 ARID3A and HIF3A weredramatically increased in the intestinal tumors They alsodemonstrated that HMGA2 plays an important role in thedownstream of let-7 in the context of colonic tumorigenesisThey found that the forced expression of HMGA2 couldincrease the colony forming capacity in intestinal organoidsand that the haploinsufficiency of HMGA2 significantlydecreased the tumor incidence in villin-Lin28b miceHMGA2 is a member of the High Mobility Group A class ofproteins which bind to AT-rich DNA stretches and modulategene expression by introducing structural alterations in thechromatin landscape [32] HMGA2-deficiency impairedthe growth in mice whereas the transgenic expression ofHMGA2 variants enhanced the formation of benign tumorsindicating that HMGA2 confers a growth advantage andthus promotes tumorigenesis [33] In fact overexpression ofHMGA2 was reported to promote metastasis and impact thesurvival of CRC patients [34] RNA binding protein IGF2BP1(IMP1) is also considered as a let-7 targetmolecule and highlyexpressed during developmental process and prominent up-regulation andor de novo synthesis are observed in varioustumors [33 35] Hamilton et al demonstrated that enforcedexpression of IMP1 in SW480 cells could increase the growthof xenografts [36] which indicates that IMP1 plays an import-ant role in the formation or dissemination of colon cancer

5 Functions of Let-7 inthe Colonic Tumorigenesis

51 Cell Cycle Proliferation and Apoptosis The downregula-tion of let-7 promotes cell proliferation through the activationof a variety of cellular proliferation signaling and cell cyclesignaling pathways For instance let-7 negatively regulatesRAS expression through direct binding which could down-regulate MAPK pathway and PI3KAKT pathway [11 37]Let-7 also directly downregulates some oncoproteins such asMYC HMGA2 and IGF1 [38ndash41] that are known as criticalregulators for the growth of CRC

The downregulation of let-7 upregulates some cell cycleregulators such as cyclin A2 cyclin D12 CDK6 CDC34CDC25A Aurora A and B kinases CDK8 PLAGL2 andTRIM71 which results in the activation of cell cycle [11 42]Let-7 also inhibits cell proliferation by regulating transcrip-tional factors such as STAT3 E2F5 E2F6 CBFB PLAGL2SOX9 GZF1 YAP1 GTF2I and ARID3A [42 43] Let-7microRNAs also suppress cell proliferation by regulatingWntsignalingThe inhibition ofWnt signaling by let-7 is reportedin various types of cancers [44ndash47] In the context of intesti-nal tumorigenesis Tu et al demonstrated that overexpressedLIN28 could accelerate the growth of intestinal tumors inApcMin + mice and that this tumor-promoting effect was let-7dependent [28]

The relationship between let-7 microRNAs and apoptosisin CRC is still controversial Geng et al reported that let-7 inhibited apoptosis by decreasing the expression of Fasthrough the direct inhibition against FasmRNA inHT29 cells[48] They demonstrated that let-7 inhibition increased Fasexpression and the sensitivity to the FAS-related apoptosisConversely Zhang et al demonstrated that forced expressionof let-7c promoted apoptosis in CRC cell lines at least bytargeting BCL2L1 [49] Mongroo et al showed that the loss ofIMP1 a let-7 target promoted caspase- and lamin-mediatedcell death through CYFIP2 by the cross-talk with KRAS inSW480 cells [50] Another let-7 target in intestine HMGA2was reported to inhibit apoptosis [51] The effect of let-7microRNAs on apoptosis might be context-dependent and sofurther investigation will be needed

52 Let-7 and Intestinal Stem Cells Intestinal stem cellmarker LGR5 is known to be upregulated in human coloncancers and sporadic adenomas [67] The intestinal stemcell markers such as LGR5 ASCL2 SMOC2 Msi1 andTert are also known to be increased in colitis-associatedcarcinogenesis [68] Madison et al examined the expressionlevels of let-7 microRNAs and intestinal stem cell markers(eg LGR5 EPHB2 and ASCL2) in human CRC tissues andnormal adjacent tissues Let-7a and let-7b were significantlydownregulated in CRC specimens while intestinal stem cellmarkers were significantly upregulated which suggests thatdepletion of let-7a and let-7b may contribute to a stem cellphenotype in CRC [31] They also demonstrated that tumorsfrom Villin-Lin28blet-7IEC-KO mice exhibited a significantupregulation of stem cell markers including Bmi1 Lrig1Olfm4 ASCL2 Prom1 LGR5 Msi1 and SOX9 suggesting anexpansion of CRC and +4 stem cell-like compartmentsTheyevaluated the coexpression of let-7 target mRNAs and stemcell markers in mouse samples and found that HMGA1 andHMGA2 were intensely correlated with stem cell markersHMGA2 expressionwas also correlatedwithLGR5 expressionin human CRC samples [31]

53 Tumor Progression and Let-7 MicroRNAs in CRC Thedownregulation of let-7 promotes migration and invasionof normal intestinal epithelial cells and CRC cells [27]Xenografts of the DLD-1 cells in which let-7 expressionwas decreased by LIN28B overexpression developed lungand liver metastases in a mouse model which suggests thatLIN28Blet-7 axis could affect the metastasis in CRC [26]Some let-7 target oncogenes such as RAS and MYC mightcontribute to the tumor progression [69 70] HMGA2 one ofthe let-7 target molecules in intestine is reported to promoteepithelial-to-mesenchymal transition (EMT) through theinduction of transcription factor Slug [71] Forced expressionof another let-7 target IMP1 in CRC cell line promoted thegrowth of xenograft tumors and dissemination into the bloodin amousemodel IMP1 overexpression decreased the expres-sion of E-cadherin suggesting that IMP1 contributes to thetumor progression through the loss of epithelial identity [36]

54 Let-7 and Chemoresistance The downregulation of let-7 has been reported to contribute to the acquisition of


Table 1 MicroRNA replacement therapy with mimics

microRNA CancermicroRNA-29 Lung [52]microRNA-31 Neuroblastoma [53]microRNA-34a Neuroblastoma [54] Lung [55ndash57] HCC [58] Pancreas [59] Lymphoma [60] Prostate [61] Multiple Myeloma [62]microRNA-113b Lung [63]microRNA-143 CRC [64] Pancreas [59]microRNA-145 Pancreas [59] Lung [65]microRNA-365 CRC [66]LET-7 Lung [55]CRC colorectal cancer HCC hepatocellular carcinoma

resistance against chemotherapy in many types of cancerssuch as breast cancer [72] esophageal cancer [43] acutemyeloid leukemia [73] pancreatic cancer [74] ovarian cancer[75] and HCC [76] Although only a single paper reportedthat the high let-7g expression was significantly associatedwith the chemoresistance against S-1 in CRC patients [77]most of the studies have shown that the downregulation oflet-7 contributes to the chemoresistance in the context ofCRCOne of the underlyingmechanisms bywhich the down-regulated let-7 contributes to the chemoresistance is thatthe decreased let-7 induces the expression of DNA excisionrepair protein excision repair cross-complementing group 1(ERCC1) which contributes to the resistance against cisplatinor 5-FU [25]

Let-7 microRNAs play an important role in regulatingthe response to antiepidermal growth factor receptor (EGFR)therapies in CRC patients Cappuzzo et al demonstrated thatthe KRAS wild-type metastatic CRC patients with high let-7c exhibited better response to EGFR monoclonal antibodies[78] Although anti-EGFR treatment is not effective in CRCpatients with mutated KRAS Ruzzo et al reported that theupregulation of let-7amay rescue the sensitivity of anti-EGFRtherapies in such CRC patients [79] A functional variant of alet-7 complementary site (LCS6) in the KRAS 31015840UTRmRNAmight be a useful biomarker to predict the sensitivity of anti-EGFR therapies in patients with metastatic CRC and furtherprospective confirmation is needed [80]

6 Let-7 MicroRNAs as a Therapeutic Target

As discussed above accumulating evidence has indicatedthat let-7 microRNAs function as a tumor suppressor inCRC Therefore gene replacement therapy which attemptsto introduce the analogous let-7 molecules could be effec-tive Recent advances in genetic engineering have enabledus to make the microRNA mimics artificial structures ofRNA duplexes that are identical to the mature microRNAsequence An microRNA mimic is designed to have thefunction of the endogenousmicroRNA attempting to restoreits loss of function as a tumor suppressor [81] Howeversystemic administration of microRNAsmimics might induceunexpected side effects because microRNAs including let-7can be functional not only in cancer cells but also in normalcells (ie development cell proliferation apoptosis cell cyclecontrol differentiation migration and metabolism [82 83])

Therefore alternative delivery systems functionalized withmiRNA using nanoparticles have recently gained intenseattention [53] and have been investigated in vitroin vivo andalso in clinical trials Different types of microRNA mimicshave been used in the medical field as therapeutic agentsloaded on the surface of nanoparticles (Table 1) Let-7mimicshave been proved to have therapeutic efficacy in mousemodels of lung and prostate cancers [55 84] These deliverysystems have been tested on several animalmodels and somedisadvantages regarding toxicity immune and inflammatoryresponses were observed [85]

For clinical application gene replacement therapy withmicroRNA mimics met many obstacles the instability oftherapeutic molecules nonspecific inflammation controlledrelease of therapeutic molecules specificity and efficiency ofthe delivery systems [53] Advanced delivery strategies arestill needed

7 Conclusions

Accumulating evidence has showed that let-7 microRNAsfunction as tumor suppressor through the posttranscriptionalregulation of target mRNAs in CRC Let-7 microRNAs reg-ulate various biological events such as cell proliferation cellcycle migration progression stem cell biology metabolismand chemoresistance Gene replacement therapy with let-7 mimics which attempts to restore the tumor suppressivefunction of let-7 is tested and therapeutic efficacy has beenproved in both in vitro experiments and in vivo animalmodels However many obstacles still remain to be overcomefor the safe clinical application Advanced drug deliverystrategies are required

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding this paper

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[64] P M Borralho B T Kren R E Castro I B Moreira da SilvaC J Steer and C M P Rodrigues ldquoMicroRNA-143 reducesviability and increases sensitivity to 5-fluorouracil in HCT116human colorectal cancer cellsrdquo FEBS Journal vol 276 no 22pp 6689ndash6700 2009

[65] G-Y Chiou J-Y Cherng H-S Hsu et al ldquoCationic poly-urethanes-short branch PEI-mediated delivery ofMir145 inhib-ited epithelial-mesenchymal transdifferentiation and cancerstem-like properties and in lung adenocarcinomardquo Journal ofControlled Release vol 159 no 2 pp 240ndash250 2012

[66] J Nie L Liu W Zheng et al ldquomicroRNA-365 down-regulatedin colon cancer inhibits cell cycle progression and promotesapoptosis of colon cancer cells by probably targeting Cyclin D1and Bcl-2rdquo Carcinogenesis vol 33 no 1 pp 220ndash225 2012

[67] H Uchida K Yamazaki M Fukuma et al ldquoOverexpression ofleucine-rich repeat-containing G protein-coupled receptor 5 incolorectal cancerrdquo Cancer Science vol 101 no 7 pp 1731ndash17372010

[68] H S Kim C Lee W H Kim Y H Maeng and B G JangldquoExpression profile of intestinal stem cell markers in colitis-associated carcinogenesisrdquo Scientific Reports vol 7 no 1 2017

[69] SGoel JHuang andLKlampfer ldquoK-Ras Intestinal homeosta-sis and colon cancerrdquoCurrent Clinical Pharmacology vol 10 no1 pp 73ndash81 2015

[70] S J Garte ldquoThe c-myc oncogene in tumor progressionrdquoCriticalReviews in Oncogenesis vol 4 no 4 pp 435ndash449 1993

[71] Y Li Z Zhao C Xu Z Zhou Z Zhu and T YouldquoHMGA2 induces transcription factor Slug expression to pro-mote epithelial-to-mesenchymal transition and contributes to


colon cancer progressionrdquo Cancer Letters vol 355 no 1 pp130ndash140 2014

[72] K Lv L Liu LWang et al ldquoLin28mediates paclitaxel resistancebymodulating p21 Rb andLet-7amiRNA in breast cancer cellsrdquoPLoS ONE vol 7 no 7 Article ID e40008 2012

[73] Y Chen R Jacamo M Konopleva R Garzon C Croceand M Andreeff ldquoCXCR4 downregulation of let-7a driveschemoresistance in acute myeloid leukemiardquo The Journal ofClinical Investigation vol 123 no 6 pp 2395ndash2407 2013

[74] Y D Bhutia S W Hung M Krentz et al ldquoDifferential proc-essing of let-7a precursors influences RRM2 expression andchemosensitivity in pancreatic cancer role of LIN-28 and SEToncoproteinrdquo PLoS ONE vol 8 no 1 Article ID e53436 2013

[75] H Zhu S-CNg A V Segr et al ldquoTheLin28let-7 axis regulatesglucose metabolismrdquo Cell vol 147 no 1 pp 81ndash94 2011

[76] XMa C Li L Sun et al ldquoLin28let-7 axis regulates aerobic gly-colysis and cancer progression via PDK1rdquo Nature Communica-tions vol 5 article no 5212 2014

[77] G Nakajima K Hayashi Y Xi et al ldquoNon-coding microRNAshsa-let-7g and hsa-miR-181b are associated with chemore-sponse to S-1 in colon cancerrdquo Cancer Genomics amp Proteomicsvol 3 no 5 pp 317ndash324 2006

[78] F Cappuzzo A Sacconi L Landi et al ldquoMicroRNA signaturein metastatic colorectal cancer patients treated with anti-EGFRmonoclonal antibodiesrdquo Clinical Colorectal Cancer vol 13 no1 pp 37ndash45e4 2014

[79] A Ruzzo F Graziano B Vincenzi et al ldquoHigh let-7amicroRNAlevels in KRAS-mutated colorectal carcinomas may rescue anti-EGFR therapy effects in patients with chemotherapy-refractorymetastatic diseaserdquo The Oncologist vol 17 no 6 pp 823ndash8292012

[80] Z Saridaki J BWeidhaas H-J Lenz et al ldquoA let-7 microRNA-binding site polymorphism in KRAS predicts improved out-come in patients with metastatic colorectal cancer treated withsalvage cetuximabpanitumumabmonotherapyrdquoClinical cancerresearch an official journal of the American Association for Can-cer Research vol 20 no 17 pp 4499ndash4510 2014

[81] C Braicu C Tomuleasa P Monroig A Cucuianu I Berindan-Neagoe and G A Calin ldquoExosomes as divine messengers arethey the Hermes of modernmolecular oncologyrdquoCell Death ampDifferentiation vol 22 no 1 pp 34ndash45 2015

[82] M D Jansson and A H Lund ldquoMicroRNA and cancerrdquo Mole-cular Oncology vol 6 no 6 pp 590ndash610 2012

[83] A Ekin O F Karatas M Culha and M Ozen ldquoDesigning agold nanoparticle-based nanocarrier for microRNA transfec-tion into the prostate and breast cancer cellsrdquo The Journal ofGene Medicine vol 16 no 11-12 pp 331ndash335 2014

[84] P Hydbring and G Badalian-Very ldquoClinical applications ofmicroRNAsrdquo F1000Research vol 2 article 136 2013

[85] W GuoW ChenW YuW Huang andW Deng ldquoSmall inter-fering RNA-based molecular therapy of cancersrdquo Chinese Jour-nal of Cancer vol 32 no 9 pp 488ndash493 2013

Stem Cells International

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EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

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Volume 2018

Immunology ResearchHindawiwwwhindawicom Volume 2018

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Volume 2018Hindawiwwwhindawicom

Submit your manuscripts atwwwhindawicom


pre-let-7

LIN28AB

let-7

CSDZFD

pri-let-7

Drosha

exportin-5 pre-let-7

Dicer

Nucleus

CytoplasmTUTase

let-7

LIN28AB

Degradation

maturation

Figure 1 A schematic diagram of the let-7 biogenesis Pri-let-7 microRNA precursors are processed in the nucleus by Drosha to pre-let-7Pre-let-7 microRNA precursors are exported to the cytoplasm by exportin-5 where they are subsequently processed by Dicer resulting in themature let-7 RNA binding protein LIN28A or LIN28B binds to either pri-let-7 or pre-let-7 using RNA binding domains cold shock domain(CSD) and two zinc finger domains (ZFDs) and blocks the processing Upon binding to pre-let-7 LIN28A or LIN28B recruits TUTase whichcauses oligouridylation resulting in the degradation of pre-let-7

2 Biogenesis of Let-7 MicroRNAs (Figure 1)

Mature let-7 microRNAs are synthesized through the mul-tiple processing by microprocessors [12] Let-7 microRNAsare initially transcribed in long transcripts called primary let-7 (pri-let-7) which are processed in the nucleus by Droshaand Pasha to pre-let-7 with hairpin structures of about 70nucleotides Next pre-let-7 are exported to the cytoplasmby exportin-5 where they are subsequently processed bythe enzyme Dicer resulting in the mature let-7 [12] Let-7is known to be negatively regulated by the RNA bindingproteins LIN28A or LIN28B LIN28A or LIN28B has twoRNA binding domains cold shock domain (CSD) and twoCys-Cys-His-Cys- (CCHC-) type zinc finger domains (ZFDs)[13ndash16] which bind to the conserved GGAG motif in theterminal loop of pri-let-7 or pre-let-7 respectively resultingin the inhibition of the maturation of let-7 [17 18] Thebinding of LIN28A or LIN28B to either pri-let-7 or pre-let-7 inhibits the processing of let-7 precursors by Drosha andDicer [19] Upon binding to pre-let-7 LIN28A or LIN28Brecruits TUT4TUT7 which causes oligouridylation at the31015840 terminal of pre-let-7 [20ndash22] Under normal conditionsDicer recognizes the two nucleotides at the 31015840 terminalvia its PAZ domain however oligouridylation elongates the31015840 terminal resulting in the resistance to Dicer cleavageOligouridylated pre-let-7 can also be degenerated by the 31015840-51015840 exonuclease Dis312 [23 24] Thus LIN28A or LIN28Bnot only inhibits the biogenesis of let-7 family miRNAs butalso induces their degradation LIN28A and LIN28B are thenegative regulators of let-7microRNAs and so the expressionlevel of LIN28A is high in the developmental process whilethat of LIN28B is low in the adult tissues [10] LIN28B has twoisoforms LIN28B-long and LIN28B-short isoforms Both

isoforms preserve the binding ability to pre-let-7 HoweverLIN28B-short isoform lacks the inhibitory ability againstthe processing by microprocessors Namely LIN28B-shortisoform functions as a competitor against the LIN28B-longisoform in the context of let-7 maturation [25]

3 Let-7 and Colon Cancer

Regarding the LIN28ABlet-7 axis the downregulation oflet-7 or upregulation of either LIN28A or LIN28B has beenreported to be related to the worse prognosis in CRCpatients Stage III CRC patients with high expression ofLIN28B exhibit poorer prognosis compared to those withno LIN28B expression [26] King et al reported that theexpression level of LIN28B was inversely correlated to thatof mature let-7a in human CRC [27] Tu et al exam-ined the expression of LIN28A or LIN28B in the cohortof almost 600 CRC patients and found that LIN28A orLIN28B was highly expressed in 38 of CRC patients[28] Importantly the overall survival was lower in thepatients with high expression of LIN28A or LIN28B than inthose with low expression of LIN28A or LIN28B Madisonet al demonstrated that intestinal tumors were sponta-neously developed in the transgenic mice with intestinal-specific LIN28B expression (Villin-Lin28b) which suggeststhat LIN28B functions as an oncogene [29] Let-7b and let-7c can escape the downregulation by LIN28B in mice There-fore they crossed these mice with let-7b and let-7c knock-outmice (let-7IEC-KO) and found that the additional downreg-ulation of let-7b and let-7c resulted in the increase of tumorincidence [30]These results suggest that let-7b or let-7c playsan important role in the intestinal tumorigenesis in mice




















7 Conclusions




References































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of






































7 Conclusions




References































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




























7 Conclusions




References































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of















































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of









































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of







































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of























of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of



















Documents

The Molecular Basis and Therapeutic Potential of Let-7 ...downloads.hindawi.com/journals/cjgh/2018/5769591.pdf · microRNA Cancer microRNA- Lung[] microRNA-Neuroblastoma[ ] ... Recent