Review Article -Catenin Signaling Pathway in Skin...

Review ArticleWnt120573-Catenin Signaling Pathway in SkinCarcinogenesis and Therapy

Jing Li1 Ling Ji1 Jieping Chen2 Wengeng Zhang3 and Zhijia Ye1

1 Institute of Tropical Medicine Third Military Medical University 30 Gaotanyan Street Chongqing 400038 China2Department of Hematology Southwest Hospital Third Military Medical University 30 Gaotanyan Street Chongqing 400038 China3Center for Engineering in Medicine Department of Surgery Massachusetts General Hospital Harvard Medical School51 Blossom Street Boston MA 02114 USA

Correspondence should be addressed to Wengeng Zhang wengengzhangmghharvardedu and Zhijia Ye zjyetmmueducn

Received 9 January 2015 Revised 6 April 2015 Accepted 21 April 2015

Academic Editor Pascale Quatresooz

Copyright copy 2015 Jing Li et al This is an open access article distributed under the Creative Commons Attribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Cooperating with other signaling pathways Wnt signaling controls cell proliferation morphology motility and embryonicdevelopment destination and maintains the homeostasis of tissues including skin blood intestine and brain by regulating somaticstem cells and their niches throughout adult life Abnormal regulation of Wnt pathways leads to neoplastic proliferation in thesetissues Recent research shows thatWnt signaling is also associated with the regulation of cancer stem cells (CSCs) through a similarmechanism to that observed in normal adult stem cells Thus the Wnt120573-catenin signaling pathway has been intensively studiedand characterized For this review we will focus on the regulation of theWnt120573-catenin signaling pathway in skin cancer With theimportant role in stemness and skin CSC proliferation theWnt120573-catenin signaling pathway and its elements have the potential tobe targets for skin cancer therapy

1 Introduction

Drs Nusse andVarmus identified the protooncogene integra-tion-1 in 1982 [1] then int-1 was found to be the mammalianhomolog of the segment polarity gene in winglessDrosophila(wg) [2] The name ldquoWntrdquo is thus a combination of the twoterms int and wg [3]

In humans Wnt proteins are a family of 19 lipidatedand glycosylated proteins This type of glycosylated proteininitiates signaling through binding with the N-terminalextracellular cysteine-rich region of the Frizzled family(a seven-span transmembrane receptor) and with eitherLRP5 or LRP6 (two members of the low-density-lipoproteinreceptor-related protein family) proteins [4 5] Wnt proteinsmodulate several major signaling cascades including canon-ical (120573-catenin-dependent) and noncanonical (120573-catenin-independent) Wnt signaling pathways In the canonical Wntsignaling pathway 120573-catenin is stabilized and translocatedto the nucleus and then it stimulates the target genes andcontrols gene expression by cooperating with other signalingreceptors [6] In the noncanonical Wnt pathway 120573-catenin

is not activated instead signals are transmitted to impactcell polarity and migration through the planar cell polaritypathway and small GTPase proteins [3 4]

Several proteins interactingwithWnt120573-catenin signalingpathways have been identified such as plakoglobin a newprotein that functions similarly to the 120573-catenin and thusis an important therapeutic drug target In addition moreand more evidence supports that Wnt120573-catenin signalingfunctions in skin stem cells through cooperation with Cdc42Notch and vitaminD [7]Thereby theWnt120573-catenin signal-ing pathway can be controlled by regulating Cdc42 Notchand vitamin D

2 Wnt120573-Catenin Signaling Pathway inSkin Stem Cells

There are three populations of skin stemcells in humansTheyare located in epidermal proliferative units (EPUs) wherebasal layer cells are generated hair follicles (HF) includinganagen and telogen follicles and the bulge where hair folliclestem cells are located (Figure 1) [8]

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015 Article ID 964842 8 pageshttpdxdoiorg1011552015964842

2 BioMed Research International

Bulge

ORSIRS

HSLate anagen

melHM

Early catagen

FP

AnagenCata

gen

Telogen

Follicular cycle

Early anagen

Latecatagen

BM

Club

APM

SG

telogen

Figure 1 Hair follicle cyclingThe initial developmental phase of hair follicle development terminates with catagen and the first telogen afterwhich repetitive cycles of anagen (the growth phase) catagen (the regression phase) and telogen (the resting phase) occur throughout the lifespan of the animal In general the hair follicle spends most of its time in anagen but cycle duration varies according to location gender ageand species The bulge is the source of stem cells for the regenerating hair follicle that is responding to signals from the dermal or follicularpapilla (FP) ORS outer root sheath IRS inner root sheath HS hair shaft mel melanin for the hair shaft HM hair matrix BM basementmembrane SG sebaceous gland and APM arrector pili muscle [8]

The epidermis forms the outermost layer of mammalianskin Cells within the basal layer of the epidermis are theprogenitors of the epithelium which constantly proliferate toensure renewal of the epithelium Except for the basal layerthe bulge is an important niche for skin stem cells the bulgeis attached to the hair follicles (HFs) Many Lgr6+ cells resideabove the bulge area andhave been demonstrated to representthe ability to generate all cell lineages of skin [9] Almostall types of skin come from the bulge such as hair folliclesand glands Moreover bulge stem cells express the stem cellmarker CD34 and contain label-retaining cells such as slowcycling cells In addition bulge cells can participate in tissuerepair after wounding [3]

Evidence supports that theWnt120573-catenin signal controlsthe fate of the bulge stem cells and plays an essential role in

hair but not epidermal differentiation Using creloxP recom-bining system driven by the cytokeratin (K)14 promoterto induce the conditional mutation of 120573-catenin in micePeter Wendrsquos Laboratory demonstrates that the epidermisof young mutant animals develops normally but withouthair [10] However there are unusual cyst-like structuresappearing in the skin of these mice Meanwhile it is foundthat multilayered epithelium surrounds the cysts [11ndash13] Atthe same time there is another similar phenotype witha lack of hair but containing stem cells however thesecells can only differentiate into epidermal cells but not intohair follicles Moreover after ectopic expression of Wntinhibitor Dkk1 in the skin it is observed that transgenicexpression of dominant-negative Lef1 results in the formationof cysts and other epidermal appendages such as teeth and

BioMed Research International 3

mammary glands A study using cultured epidermal ker-atinocytes in which a loss-of-function mutation in Wnt120573-catenin is introduced by Adenovirus-mediated gene transferof creloxP system demonstrated that Wnt120573-catenin plays aminor role in epidermal but not in hair development [14]

In the epidermis mesenchymal stem cells are self-renewing and differentiate into hair follicles (HFs) whenproper stimulations are performed During this processsignals that are initiated from the dermis can induce epithe-lium thickening elongation of epithelial cells and formationof placodes that contain Wnt-responsive cells [15ndash17] Inresponse placodes signal dermal cells to condense to formthe dermal papilla component of theHFwhich is also respon-sive to Wnt signaling [17] The fully formed HF then retainsdetectable levels of120573-catenin in the dermal papilla andmatrixcells inwhich120573-catenin contributes to themaintenance ofHFstructures [17 18]

Neural crest cells represent a transient and highly migra-tory embryonic cell population and neural crest stem cells(NCSCs) are characterized by their multipotency and self-renewal abilities [19] It is demonstrated that NCSCs canrenew and differentiate into different types of cells includingglia neurons smooth muscle cells adipocytes osteoblastschondrocytes and melanocytes during embryonic develop-ment It is generally believed that NCSCs exist only in thedeveloping embryo However Kruger et al have found thatthere are cells with neural crest features similar to embryonicNCSCs in adult gut [20] This finding initiated numerousstudies that have demonstrated the presence of postmigratoryNCSCs in a variety of adult organs such as skin [21ndash26]

Although a substantial number of reports have demon-strated the existence of NCSCs in adult tissues the physiolog-ical role of these cells still remains unknown Recently for thefirst time a study by Johnstonrsquos group [27] demonstrated thatneural crest precursor cells could function in wound healingin mature mouse skin Previously Johnston et al identifiedthat multipotent self-renewing cells reside in adult skin andthen they named these stem cells skin derived precursor(SKP) cells [21] Subsequent research demonstrated that SKPcells have neural crest-like features such as expressing neuralcrest markers and having the same differentiation potentialas NCSCs cells [22] A study using a genetic lineage tracingmethod inWnt1-Cre R26Rmice found that SKP cells were thesame as the cells derived from the neural crest lineage [22]Moreover the presence of innervation is necessary for organregeneration in amphibians [28] and neural crest-derivedSchwann cells can provide signals for successful tissue repairAfter these discoveries Johnston et al demonstrated thatnerve terminal-associated cells can express the transcriptionfactor Sox2 by cooperating with other markers of neuralcrest cells including p75NTR nestin and S100 b [27] Afterwounding some Sox2-positive cells started to proliferate andmigrate into the regenerating dermis Moreover knockingSox2 out can lead to a significantly decreased rate of woundclosure which proves that Sox2-positive neural crest-derivedcells play an essential role in the successful repair of injuredskin

Wnt120573-catenin signaling plays a critical role in drivingneural crest cells toward a melanocyte cell fate through

regulating the homeobox gene microphthalmia transcriptionfactor (MITF) [29ndash32] It is observed that nuclear 120573-cateninis in the majority of benign nevi however there is no nuclear120573-catenin in melanoma progression [33ndash35]Thus activationof Wnt120573-catenin signaling may be essential for cellularhomeostasis Consequently a loss ofWnt120573-catenin signalingmay result in the dysregulation of specific transcriptionalprograms in melanocytes and nevus cells which may lead tolower survival rates in melanoma patients [33ndash35]

3 Wnt120573-Catenin Signaling Pathway Crosstalkwith Other Signaling in Skin Stem Cells

It is very important to consider the intersection betweenWnt120573-catenin and other signaling pathways There are twopathways interacting with Wnt120573-catenin signaling in theepidermis Notch and vitamin D pathways Notch1 plays anessential role in the development and homeostasis of postna-tal hair follicles [36] Wnt4 can be negatively regulated by p21[37] meanwhile p21 is a direct transcriptional target of theNotch pathwayWe suggest that theNotch pathwaymay affectthe function of Wnt4 that is necessary for the developmentand homeostasis of postnatal hair follicles The vitamin Dreceptor (VDR) is very important for hair maintenance andthe loss ormutation ofVDRwill result in hair loss inmice andhumans [38] For example 120573-catenin can bind to and activatethe vitaminD receptor (VDR) by cooperating with vitaminDresponse elements that significantly function in the postnatalmaintenance of HFs [39 40] From the research of Watt andCollins we can get a comprehensive view about interactionsamong 120573-catenin TCFLef and VDR In wild-type epider-mis initiation of the growth phase inHF anagen is dependentonWnt signaling activationHFs are kept in the telogen phasein a mouse model with the functional loss of Wnt signalingHowever the cycling of hair growth was not maintained andHFs were degenerated in the absence of VDR A high levelof Wnt signaling activation in the presence of endogenousvitamin D or a topically applied vitamin D analog not onlywas able to trigger anagen but also induced ectopic formationofHFsWnt activationwas unable to induce differentiation ofectopic follicles without the presence of VDR (Figure 2) [40]

In addition one of the pathways that is upregulatedby 120573-catenin activation in the epidermis is Sonic hedgehog(Shh) signaling [41] Combined with the modest activationof 120573-catenin pharmacological inhibition of Shh signalingcan block de novo hair follicle formation Conversely a highlevel of 120573-catenin activation can make the inhibition of Shhsignaling to improve morphogenesis [41] The expressionof Sox9 is dependent on Shh and deletion of Sox9 in theepidermis can lead to hair loss and bulge forming failure [42]which results in the sameoutcome as the effects of blocking120573-catenin signaling [43 44] Thus we can reach the conclusionthat 120573-catenin affects hair development via Shh and Shh canfunction similarly to 120573-catenin Therefore we can target notonly 120573-catenin but also Shh when we consider therapy forskin cancer


Transcriptionalcomplexes

Wnt activity

VDR activity

Epidermalphenotype

Wild-type VDR K0VDR K0

EF

EF

EF

R

R

RTCFLef TCFLef TCFLef TCFLef

VDR VDR VDR VDR

ΔN120573-cat

ΔN120573-cat

ΔN120573-cat

High High

High

Low

Low

Low

Telogen HF Anagen HFectopic HF andpilomatricomas

None None

Postnatal HFdegeneration

BCCs

⋆

BCC

K14-ΔN-120573-catenin-ER K14-ΔN-120573-catenin-ER

Figure 2 Interaction among 120573-catenin LefTcf transcription factors and VDR The epidermal phenotypes and WntVDR transcriptionalactivity of wild-type and VDRndashndashmice are compared in the presence or absence of 120573-catenin activation in 4OHT-treated K14-ΔN-120573-catenin-ER transgenic mice EF ectopic hair follicle BCC basal cell carcinoma TCFLef and VDR are shown bound to DNA in the presence oftranscriptional corepressors (R) or 120573-catenin The vitamin D ligand is indicated by an asterisk [40]

4 Wnt120573-Catenin Signaling Pathway inSkin Cancer Stem Cells (CSCs)

Skin cancer is one of the most common forms of cancerwith an especially high incidence in the white popula-tion [45] There are many types of skin cancer includingsquamous cell carcinoma basal cell carcinoma malignantmelanoma malignant lymphoma idiopathic hemorrhagicsarcoma fibrosarcoma and sweat gland carcinoma

Wnt120573-catenin signaling plays a critical role in skin CSCsRecently a population of CSCs was identified by Malanchiet al These cells show similar molecular characteristics tonormal stem cells in the bulge [46] CD34+ bulge stem cellsthat reside in normal mouse skin account for nearly 2of the keratinocytes It is observed that there is nearly 10-fold increase of this type of CD34+ cell population in earlyskin tumors induced by the classical two-step chemical car-cinogenesis protocol DMBA and TPA or by overexpressionof mutant Ras (HRAS-R12T59) Furthermore it has beenidentified that the ability of the CD34+ cells to induce sec-ondary tumors is over 100-fold greater than that of unsorted

cells Therefore it is clear that these CD34+ bulge stem cellsindeed represent CSCs In addition the secondary tumorsresemble the parental tumors and have maintained a smallpopulation of CD34+ CSCs This discovery shows that thereis a preferential location of 120573-catenin in the nucleus Humansquamous cell carcinomas also exhibit a preferential nuclearlocation of 120573-catenin Remarkably conditional ablation of120573-catenin will result in complete regression of the tumorsand terminal differentiation of the tissues through tamoxifen-induced mutagenesis in DMBA-TPA or Ras-induced tumorsThus Wnt120573-catenin signals are essential in normal skinto drive bulge stem cells toward the hair cell fate whereasthey play a critical role in the maintenance of skin CSCs inepidermal tumors [11]

5 Wnt120573-Catenin Signaling Pathway inTherapy of Skin Cancer

Because of drug resistance and the relapse and metastasis ofcancer stem cells skin cancer therapy is faced with a numberof technical challenges and regulatory hurdles that must be


overcome In order to avoid all of these negative effects it isvery important to search for targeted and effective treatmentsfor skin cancer As described above Wnt120573-catenin signalingcontributes to the homeostasis of normal skin stem cells anditsmalfunction results in production of skin cancer stem cellsThus we can prevent the generation of CSCs by regulatingWnt signaling specificallyThereby the therapy of skin cancertargetingWnt120573-catenin signaling is an innovative strategy tocure skin cancer Herein several approaches will be intro-duced

51 Inhibitors of Acyltransferase Porcupine Porcupine (Porcn)a member of the membrane-bound O-acyltransferase(MBOAT) family catalyzes the palmitoylation family of Wntproteins [47] Palmitoylation is a necessary process for thesecretion and activity of Wnt Compromised Porcn activitycommonly results in developmental disorders including focaldermal hypoplasia (Goltz syndrome) whereas the hyperac-tivity of Porcn is associated with proliferation and metastasisof cancer cells Constitutive activation of the Wnt signalingpathway is a feature of a number of cancers including malig-nant melanoma with aberrant nuclear accumulation andthe subsequent upregulation of the 120573-catenin transcriptionresponse [48] We can hypothesize that inhibition of Porcncould be the most effective strategy for broadly suppressingWnt signaling More importantly Porcn inhibitors haveproven to be remarkably nontoxic in rodents Therefore theinhibitors of Porcn hold great potential in the therapy of skincancers with aberrant activation of Wnt signaling The fourIWPs (IWPs 1ndash4) (inhibitors of Wnt production) the firstidentified Porcn inhibitors and LGK974 a novel Porcn inhib-itor have entered Phase I clinical trials

52 Transcriptional Coactivator Antagonists Several coacti-vators forWnt120573-catenin transcription such as CBP p300 B-cell lymphoma 9 (BCL9) and pygopus have been identified[49ndash51] The lead compound ICG-001 that was selectivelybound to CBP and prevented its interaction with 120573-cateninwas identified using a cell-based reporter screen While itis a small molecule secondary structure-template chemicallibrary ICG-001 does not interact with the homologous coac-tivator p300Therefore fundamental stem andprogenitor cellswitching points are regulated by the switch from 120573-cateninCBP to 120573-cateninp300 [52 53] Since CBP120573-catenin targetscellular proliferation and p300120573-catenin responds to cellulardifferentiation the balance of CBP120573-catenin and p300120573-catenin may be very important for a cell to decide to eithermaintain its level of potency or go on to differentiate and losea level of potencyTherefore itmay be an effective therapeuticstrategy to find the inhibitors of CBP120573-catenin [54]

53 Nonsteroidal Anti-Inflammatory Drugs NSAIDs includ-ing aspirin flurbiprofen sulindac and indomethacin func-tion by inhibiting the activity of cyclooxygenase (COX)which is a key enzyme in the arachidonic acid cascadeRecently many experimental and epidemiological studiesin humans have provided evidence that aspirin and otherNSAIDs exhibit chemopreventive effects against multiple

cancer types by inhibiting the Wnt120573-catenin signaling path-way As for skin cancer the Wnt120573-catenin pathway hasbeen related to malignancy in nonmelanoma skin cancers(NMSCs) such as squamous cell carcinoma (SCC) andbasal cell carcinoma (BCC) [55ndash57] Previous evidence hasdemonstrated that NSAIDs have a chemopreventive effectagainst SCC andBCC [58]The data suggested that long-termuse (gt5 years) of NSAIDs was related to a better protectiveeffect of developing cutaneous melanoma [59] Regular useof NSAIDs induces several serious side effects concerningthe gastrointestinal renal and cardiovascular systems [60ndash62] To overcome this defect nitric-oxide-releasing NSAIDs(NO-NSAIDs) a new class of chemopreventive agents weredeveloped They consist of a traditional NSAID attached toNO-releasing moiety through an aromatic spacer Animaland human models have concluded that many NO-NSAIDsare safer for the gastrointestinal mucosa than the parentNSAID [63ndash66] One example of this type of NO-NSAIDsis the newly synthesized flurbiprofen benzyl nitrate (FBNNBS-242) which contains an aromatic spacer Regarding themechanism FBN functions in skin cancer by inhibiting thegrowth of A-431 cells affecting proliferation and inducingapoptosis and targeting components of the Wnt pathwayand inducing caspase-3 Except for this mechanism severalsystematic reviews have suggested that NSAIDs function asa chemopreventive agent for patients that are predisposed tononmelanoma skin cancer (NMSC) [45 67]

54 Vitamin D 125-Dihydroxyvitamin D3 (125(OH)2D3)the active metabolite of vitamin D suppresses the prolifer-ation while promoting the differentiation of keratinocytesthrough the vitamin D receptor (VDR) However 120573-cateninpromotes proliferation and blocks epidermal differentiationalthough it stimulates hair follicle differentiation [68] Arecent study suggested that while 125(OH)2D3VDR inhibitsthe actions of 120573-catenin to promote keratinocyte prolifera-tion 125(OH)2D3VDR promotes the ability of 120573-cateninto stimulate hair follicle differentiation The mechanisminvolved 4 aspects 125(OH)2D3 and VDR suppress tran-scriptional activity of 120573-cateninTCF 125(OH)2D3 repressesmRNA expression of the 120573-catenin target gene of Gli1 butinduces the 120573-catenin target gene PADI1 in vitro VDRablation reduces 120573-catenin target genes involved in hairdifferentiation in vivo and 125(OH)2D3VDR suppresses thetranscriptional activity of 120573-catenin and represses the mRNAexpression of Gli1 [69] Recently it has also been identifiedthat both vitamin A and vitamin D might induce Wnt120573-catenin inhibitory proteins for instance disabled-2 (Dab2)is induced by retinoic acids and Dickkopf-1 and Dickkopf-4(Dkk-1 and Dkk-4) are induced by vitamin D [70 71]

55 Natural Products With the exception of chemical syn-thetic products natural products particularly traditionalChinese medicines (TCMs) are rich sources of pharma-cologically active substances Through the investigationsit has been discovered that stem cell signaling pathwayscould be targeted by the natural products [6] Epidemio-logical evidence indicates that flavonoids that are rich ina plant-based diet are effective against cancer [72] Fisetin


(373101584041015840-tetrahydroxyflavone) belongs to the flavonol sub-group of flavonoids and is found in many fruits andvegetables Interestingly the dietary flavonoid fisetin wasobserved to decrease cell viability of 451Lumelanoma cells bydisruption of Wnt120573-catenin signaling Fisetin-treated cellsshowed increased cytosolic levels of Axin and 120573-TrCP anddecreased phosphorylation of glycogen synthase kinase 3120573associated with decreased 120573-catenin stabilization Fisetin-mediated interference with functional cooperation between120573-catenin and T-cell factor- (TCF-) 2 resulted in the down-regulation of positively regulated TCF targets such as c-myc Brn-2 and Mitf Those data suggest that fisetin can bedeveloped as an effective agent against melanoma becauseof its potential inhibitory effect on 120573-cateninMitf signaling[72]

56 Engineered Mouse Models (GEM) Although mice rarelydevelopmelanoma spontaneously the genetically engineeredmouse models of melanoma have been generated by differentgroups Compared to xenograft hosts mice used for GEMmodels have a fully functional immune system Thereforethey serve as reliable and repeatable models to study therole of the immune system cells in melanoma biology anddrug resistance [73 74] Dankort and colleagues developed amouse melanoma model in which BRafV600E cooperates withPten loss to induce metastatic melanoma [75] This modelprovided a system to study features of melanoma metastasisand evaluate drugs for melanoma therapy which could beused to prevent melanoma metastasis The accumulatingevidence shows that the Wnt120573-catenin signaling pathwayis frequently upregulated in melanoma but its functionalimplication is unclear Damsky and colleagues studiedthe functional role of 120573-catenin by modulating it in theBRafV600EPtenminusminus model They showed that 120573-catenin is themediator of melanoma metastasis to lymph nodes and lungsIn addition to its role in metastasis 120573-catenin levels controlcell differentiation and regulate both the MAPK and thePI3KAKT signaling pathways [76] This model is useful fordrug screening of melanoma metastasis

6 Conclusions

Stem cell research has a significant potential to enhance ourunderstanding of cancer stem cells and thus revolutionizetumor therapy Wnt120573-catenin signaling plays a critical rolein both normal stem cells and CSCs Over the past fewyears remarkable progress has been achieved in research onWnt120573-catenin signaling and its inhibitors The pharmaceu-tical industry has placed high expectations on a number ofclinical candidates that target Wnt signaling There are manynovel drugs and natural products targeting Wnt120573-cateninsignaling pathway that have been developed

Disclosure

Jing Li and Ling Ji are first authors Jieping Chen is seniorauthor

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This research was supported by the National Natural ScienceFoundation of China (81170471 31371393) and the NaturalScience Foundation of Chongqing Science amp TechnologyCommission (cstc2013jjB10027)

References

[1] R Nusse and H E Varmus ldquoMany tumors induced by themouse mammary tumor virus contain a provirus integrated inthe same region of the host genomerdquo Cell vol 31 no 1 pp 99ndash109 1982

[2] J D Holland A Klaus A N Garratt andW Birchmeier ldquoWntsignaling in stem and cancer stem cellsrdquoCurrent Opinion in CellBiology vol 25 no 2 pp 254ndash264 2013

[3] P Wend J D Holland U Ziebold and W Birchmeier ldquoWntsignaling in stem and cancer stem cellsrdquo Seminars in Cell ampDevelopmental Biology vol 21 no 8 pp 855ndash863 2010

[4] R T Moon A D Kohn G V De Ferrari and A KaykasldquoWnt and 120573-catenin signalling diseases and therapiesrdquo NatureReviews Genetics vol 5 no 9 pp 691ndash701 2004

[5] R Nusse ldquoWnt signaling and stem cell controlrdquo Cell Researchvol 18 no 5 pp 523ndash527 2008

[6] S M An Q P Ding and L-S Li ldquoStem cell signaling as atarget for novel drug discovery recent progress in theWNTandHedgehog pathwaysrdquoActa Pharmacologica Sinica vol 34 no 6pp 777ndash783 2013

[7] F M Watt C L Celso and V Silva-Vargas ldquoEpidermal stemcells an updaterdquo Current Opinion in Genetics amp Developmentvol 16 no 5 pp 518ndash524 2006

[8] D D Bikle ldquoVitamin D and the skin physiology and patho-physiologyrdquo Reviews in Endocrine amp Metabolic Disorders vol13 no 1 pp 3ndash19 2012

[9] H J Snippert A Haegebarth M Kasper et al ldquoLgr6 marksstem cells in the hair follicle that generate all cell lineages of theskinrdquo Science vol 327 no 5971 pp 1385ndash1389 2010

[10] J Huelsken R Vogel B Erdmann G Cotsarelis and WBirchmeier ldquo120573-catenin controls hair folliclemorphogenesis andstem cell differentiation in the skinrdquoCell vol 105 no 4 pp 533ndash545 2001

[11] P Wend J D Holland U Ziebold and W Birchmeier ldquoWntsignaling in stem and cancer stem cellsrdquo Seminars in Cell andDevelopmental Biology vol 21 no 8 pp 855ndash863 2010

[12] J Huelsken R Vogel B Erdmann G Cotsarelis and WBirchmeier ldquo120573-Catenin controls hair follicle morphogenesisand stem cell differentiation in the skinrdquo Cell vol 105 no 4pp 533ndash545 2001

[13] T Grigoryan PWend A Klaus andW Birchmeier ldquoDecipher-ing the function of canonical Wnt signals in development anddisease Conditional loss- and gain-of-function mutations ofbeta-catenin in micerdquo Genes amp Development vol 22 no 17 pp2308ndash2341 2008

[14] H Posthaus LWilliamsonD Baumann et al ldquo120573-catenin is notrequired for proliferation and differentiation of epidemalmouse


keratinocytesrdquo Journal of Cell Science vol 115 no 23 pp 4587ndash4595 2002

[15] L Alonso and E Fuchs ldquoStem cells in the skin waste not Wntnotrdquo Genes amp Development vol 17 no 10 pp 1189ndash1200 2003

[16] C Blanpain and E Fuchs ldquoEpidermal homeostasis a balancingact of stem cells in the skinrdquo Nature Reviews Molecular CellBiology vol 10 no 3 pp 207ndash217 2009

[17] S Maretto M Cordenonsi S Dupont et al ldquoMapping Wnt120573-catenin signaling during mouse development and in colorectaltumorsrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 100 no 6 pp 3299ndash3304 2003

[18] S Reddy T Andl A Bagasra et al ldquoCharacterization of Wntgene expression in developing and postnatal hair follicles andidentification of Wnt5a as a target of Sonic hedgehog in hairfollicle morphogenesisrdquo Mechanisms of Development vol 107no 1-2 pp 69ndash82 2001

[19] O Shakhova ldquoNeural crest stem cells in melanoma develop-mentrdquo Current Opinion in Oncology vol 26 no 2 pp 215ndash2212014

[20] G M Kruger J T Mosher S Bixby N Joseph T Iwashitaand S J Morrison ldquoNeural crest stem cells persist in the adultgut but undergo changes in self-renewal neuronal subtypepotential and factor responsivenessrdquo Neuron vol 35 no 4 pp657ndash669 2002

[21] J G Toma M Akhavan K J L Fernandes et al ldquoIsolationof multipotent adult stem cells from the dermis of mammalianskinrdquo Nature Cell Biology vol 3 no 9 pp 778ndash784 2001

[22] K J L Fernandes I A McKenzie P Mill et al ldquoA dermal nichefor multipotent adult skin-derived precursor cellsrdquo Nature CellBiology vol 6 no 11 pp 1082ndash1093 2004

[23] M Sieber-Blum M Grim Y F Hu and V Szeder ldquoPluripotentneural crest stem cells in the adult hair folliclerdquo DevelopmentalDynamics vol 231 no 2 pp 258ndash269 2004

[24] M Belicchi F Pisati R Lopa et al ldquoHuman skin-derivedstem cells migrate throughout forebrain and differentiate intoastrocytes after injection into adult mouse brainrdquo Journal ofNeuroscience Research vol 77 no 4 pp 475ndash486 2004

[25] J G Toma I A McKenzie D Bagli and F D Miller ldquoIsolationand characterization of multipotent skin-derived precursorsfrom human skinrdquo Stem Cells vol 23 no 6 pp 727ndash737 2005

[26] C E Wong C Paratore M T Dours-Zimmermann et alldquoNeural crest-derived cells with stem cell features can be tracedback to multiple lineages in the adult skinrdquo Journal of CellBiology vol 175 no 6 pp 1005ndash1015 2006

[27] A P W Johnston S Naska K Jones H Jinno D R Kaplanand F DMiller ldquoSox2-mediated regulation of adult neural crestprecursors and skin repairrdquo Stem Cell Reports vol 1 no 1 pp38ndash45 2013

[28] A Kumar and J P Brockes ldquoNerve dependence in tissue organand appendage regenerationrdquo Trends in Neurosciences vol 35no 11 pp 691ndash699 2012

[29] J F Crane and P A Trainor ldquoNeural crest stem and progenitorcellsrdquoAnnual Review of Cell and Developmental Biology vol 22pp 267ndash286 2006

[30] K W Vance and C R Goding ldquoThe transcription networkregulating melanocyte development and melanomardquo PigmentCell Research vol 17 no 4 pp 318ndash325 2004

[31] L Larue M Kumasaka and C R Goding ldquo120573-catenin in themelanocyte lineagerdquo Pigment Cell Research vol 16 no 3 pp312ndash317 2003

[32] R I Dorsky D W Raible and R T Moon ldquoDirect regulationof nacre a zebrafish MITF homolog required for pigment cellformation by the Wnt pathwayrdquo Genes and Development vol14 no 2 pp 158ndash162 2000

[33] I M Bachmann O Straume H E Puntervoll M B Kalvenesand L A Akslen ldquoImportance of P-cadherin 120573-catenin andWnt5aFrizzled for progression of melanocytic tumors andprognosis in cutaneous melanomardquo Clinical Cancer Researchvol 11 no 24 pp 8606ndash8614 2005

[34] T Kageshita C V Hamby T Ishihara K Matsumoto T Saidaand T Ono ldquoLoss of 120573-catenin expression associated withdisease progression in malignant melanomardquo British Journal ofDermatology vol 145 no 2 pp 210ndash216 2001

[35] G M Maeliglandsmo R Holm J M Nesland Oslash Fodstad and VA Floslashrenes ldquoReduced 120573-catenin expression in the cytoplasmof advanced-stage superficial spreading malignant melanomardquoClinical Cancer Research vol 9 no 9 pp 3383ndash3388 2003

[36] S Vauclair M Nicolas Y Barrandon and F Radtke ldquoNotch1 isessential for postnatal hair follicle development and homeosta-sisrdquo Developmental Biology vol 284 no 1 pp 184ndash193 2005

[37] V Devgan C Mammucari S E Millar C Brisken and G PDotto ldquop21WAF1Cip1 is a negative transcriptional regulator ofWnt4 expression downstream of Notch1 activationrdquo Genes andDevelopment vol 19 no 12 pp 1485ndash1495 2005

[38] S Shah M N Islam S Dakshanamurthy et al ldquoThe molecularbasis of vitamin D receptor and 120573-catenin crossregulationrdquoMolecular Cell vol 21 no 6 pp 799ndash809 2006

[39] F M Watt C L Celso and V Silva-Vargas ldquoEpidermal stemcells an updaterdquo Current Opinion in Genetics and Developmentvol 16 no 5 pp 518ndash524 2006

[40] F M Watt and C A Collins ldquoRole of 120573-catenin in epidermalstem cell expansion lineage selection and cancerrdquo Cold SpringHarbor Symposia on Quantitative Biology vol 73 pp 503ndash5122008

[41] V Silva-Vargas C Lo Celso A Giangreco et al ldquo120573-catenin andhedgehog signal strength can specify number and location ofhair follicles in adult epidermis without recruitment of bulgestem cellsrdquo Developmental Cell vol 9 no 1 pp 121ndash131 2005

[42] V P I Vidal M-C Chaboissier S Lutzkendorf et al ldquoSox9 isessential for outer root sheath differentiation and the formationof the hair stem cell compartmentrdquo Current Biology vol 15 no15 pp 1340ndash1351 2005

[43] C Niemann and F M Watt ldquoDesigner skin Lineage commit-ment in postnatal epidermisrdquo Trends in Cell Biology vol 12 no4 pp 185ndash192 2002

[44] E Fuchs T Tumbar and G Guasch ldquoSocializing with theneighbors stem cells and their nicherdquo Cell vol 116 no 6 pp769ndash778 2004

[45] C Muranushi C M Olsen N Pandeya and A C GreenldquoAspirin and nonsteroidal anti-inflammatory drugs can preventcutaneous squamous cell carcinoma a systematic review andmeta-analysisrdquo Journal of InvestigativeDermatology vol 135 no4 pp 975ndash983 2014

[46] I Malanchi H Peinado D Kassen et al ldquoCutaneous cancerstem cell maintenance is dependent on 120573-catenin signallingrdquoNature vol 452 no 7187 pp 650ndash653 2008

[47] J Liu S Pan M H Hsieh et al ldquoTargeting Wnt-driven cancerthrough the inhibition of Porcupine by LGK974rdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 110 no 50 pp 20224ndash20229 2013


[48] L Larue and V Delmas ldquoThe WNTbeta-catenin pathway inmelanomardquo Frontiers in Bioscience vol 11 no 1 pp 733ndash7422006

[49] A Hecht K Vleminckx M P Stemmler F Van Roy and RKemler ldquoThe p300CBP acetyltransferases function as tran-scriptional coactivators of 120573-catenin in vertebratesrdquoThe EMBOJournal vol 19 no 8 pp 1839ndash1850 2000

[50] T Kramps O Peter E Brunner et al ldquoWntWingless signalingrequires BCL9legless-mediated recruitment of pygopus to thenuclear 120573-catenin-TCF complexrdquo Cell vol 109 no 1 pp 47ndash602002

[51] R Hoffmans R Stadeli and K Basler ldquoPygopus and leg-less provide essential transcriptional coactivator functions toArmadillo120573-cateninrdquo Current Biology vol 15 no 13 pp 1207ndash1211 2005

[52] K H Emami C Nguyen H Ma et al ldquoA small moleculeinhibitor of 120573-cateninCREB-binding protein transcriptionrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 101 no 34 pp 12682ndash12687 2004

[53] M McMillan and M Kahn ldquoInvestigating Wnt signaling achemogenomic safarirdquoDrug Discovery Today vol 10 no 21 pp1467ndash1474 2005

[54] F Takahashi-Yanaga and M Kahn ldquoTargeting Wnt signalingcan we safely eradicate cancer stem cellsrdquo Clinical CancerResearch vol 16 no 12 pp 3153ndash3162 2010

[55] C Tataroglu TKarabacak andDDApa ldquo120573-catenin andCD44expression in keratoacanthoma and squamous cell carcinoma ofthe skinrdquo Tumori vol 93 no 3 pp 284ndash289 2007

[56] C Doglioni S Piccinin S Demontis et al ldquoAlterations of beta-catenin pathway in non-melanoma skin tumors loss of 120572-ABCnuclear reactivity correlates with the presence of 120573-catenin genemutationrdquoTheAmerican Journal of Pathology vol 163 no 6 pp2277ndash2287 2003

[57] M El-Bahrawy N El-Masry M Alison R Poulsom and MFallowfield ldquoExpression of beta-catenin in basal cell carci-nomardquo British Journal of Dermatology vol 148 no 5 pp 964ndash970 2003

[58] M C Clouser D J Roe J A Foote and R B Harris ldquoEffect ofnon-steroidal anti-inflammatory drugs on non-melanoma skincancer incidence in the SKICAP-AK trialrdquo Pharmacoepidemiol-ogy and Drug Safety vol 18 no 4 pp 276ndash283 2009

[59] C Curiel-Lewandrowski T Nijsten M L Gomez L MHollestein M B Atkins and R S Stern ldquoLong-term useof nonsteroidal anti-inflammatory drugs decreases the risk ofcutaneous melanoma results of a united states casendashcontrolstudyrdquo Journal of Investigative Dermatology vol 131 no 7 pp1460ndash1468 2011

[60] D J Bjorkman ldquoCurrent status of nonsteroidal anti-inflam-matory drug (NSAID) use in the United States risk factors andfrequency of complicationsrdquoThe American Journal of Medicinevol 107 no 6 pp 3Sndash8S 1999

[61] G A FitzGerald ldquoCoxibs and cardiovascular diseaserdquoThe NewEngland Journal of Medicine vol 351 no 17 pp 1709ndash1711 2004

[62] J M Scheiman and A M Fendrick ldquoSumming the risk ofNSAID therapyrdquo The Lancet vol 369 no 9573 pp 1580ndash15812007

[63] N M Davies A G Rooslashseth C B Appleyard et alldquoNO-naproxen vs naproxen ulcerogenic analgesic and anti-inflammatory effectsrdquoAlimentary Pharmacology andTherapeu-tics vol 11 no 1 pp 69ndash79 1997

[64] J L Wallace B Reuter C Cicala WMcKnight M B Grishamand G Cirino ldquoNovel nonsteroidal anti-inflammatory drugderivatives withmarkedly reduced ulcerogenic properties in theratrdquo Gastroenterology vol 107 no 1 pp 173ndash179 1994

[65] S Fiorucci L Santucci P Gresele R M Faccino P DelSoldato and A Morelli ldquoGastrointestinal safety of NO-aspirin(NCX-4016) in healthy human volunteers a proof of conceptendoscopic studyrdquoGastroenterology vol 124 no 3 pp 600ndash6072003

[66] S Fiorucci L Santucci J L Wallace et al ldquoInteraction ofa selective cyclooxygenase-2 inhibitor with aspirin and NO-releasing aspirin in the human gastric mucosardquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 100 no 19 pp 10937ndash10941 2003

[67] D Reinau C Surber S S Jick and C R Meier ldquoNonsteroidalanti-inflammatory drugs and the risk of nonmelanoma skincancerrdquo International Journal of Cancer vol 137 no 1 pp 144ndash153 2015

[68] D D Bikle Y Oda C-L Tu and Y Jiang ldquoNovel mechanismsfor the vitaminD receptor (VDR) in the skin and in skin cancerrdquoThe Journal of Steroid Biochemistry and Molecular Biology vol148 pp 47ndash51 2015

[69] L Hu D D Bikle and Y Oda ldquoReciprocal role of vitamin Dreceptor on 120573-catenin regulated keratinocyte proliferation anddifferentiationrdquoThe Journal of Steroid Biochemistry ampMolecularBiology vol 144 pp 237ndash241 2013

[70] Y Jiang C Prunier and P H Howe ldquoThe inhibitory effectsof Disabled-2 (Dab2) on Wnt signaling are mediated throughAxinrdquo Oncogene vol 27 no 13 pp 1865ndash1875 2008

[71] N Pendas-Franco O Aguilera F Pereira J M Gonzalez-Sancho andAMunoz ldquoVitaminDandWnt120573-catenin pathwayin colon cancer role and regulation of DICKKOPF genesrdquoAnticancer Research vol 28 no 5 pp 2613ndash2623 2008

[72] D N Syed F Afaq N Maddodi et al ldquoInhibition of humanmelanoma cell growth by the dietary flavonoid fisetin is associ-ated with disruption of Wnt120573-catenin signaling and decreasedmitf levelsrdquo Journal of Investigative Dermatology vol 131 no 6pp 1291ndash1299 2011

[73] L Larue and F Beermann ldquoCutaneousmelanoma in geneticallymodified animalsrdquoPigment Cell Research vol 20 no 6 pp 485ndash497 2007

[74] G J Walker H P Soyer T Terzian and N F Box ldquoModellingmelanoma inmicerdquo Pigment Cell ampMelanoma Research vol 24no 6 pp 1158ndash1176 2011

[75] D Dankort D P Curley R A Cartlidge et al ldquoBraf(V600E)cooperates with Pten loss to induce metastatic melanomardquoNature Genetics vol 41 no 5 pp 544ndash552 2009

[76] W E Damsky D P Curley M Santhanakrishnan et al ldquo120573-catenin signaling controls metastasis in Braf-activated Pten-deficient melanomasrdquo Cancer Cell vol 20 no 6 pp 741ndash7542011

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Bulge

ORSIRS

HSLate anagen

melHM

Early catagen

FP

AnagenCata

gen

Telogen

Follicular cycle

Early anagen

Latecatagen

BM

Club

APM

SG

telogen

Figure 1 Hair follicle cyclingThe initial developmental phase of hair follicle development terminates with catagen and the first telogen afterwhich repetitive cycles of anagen (the growth phase) catagen (the regression phase) and telogen (the resting phase) occur throughout the lifespan of the animal In general the hair follicle spends most of its time in anagen but cycle duration varies according to location gender ageand species The bulge is the source of stem cells for the regenerating hair follicle that is responding to signals from the dermal or follicularpapilla (FP) ORS outer root sheath IRS inner root sheath HS hair shaft mel melanin for the hair shaft HM hair matrix BM basementmembrane SG sebaceous gland and APM arrector pili muscle [8]

The epidermis forms the outermost layer of mammalianskin Cells within the basal layer of the epidermis are theprogenitors of the epithelium which constantly proliferate toensure renewal of the epithelium Except for the basal layerthe bulge is an important niche for skin stem cells the bulgeis attached to the hair follicles (HFs) Many Lgr6+ cells resideabove the bulge area andhave been demonstrated to representthe ability to generate all cell lineages of skin [9] Almostall types of skin come from the bulge such as hair folliclesand glands Moreover bulge stem cells express the stem cellmarker CD34 and contain label-retaining cells such as slowcycling cells In addition bulge cells can participate in tissuerepair after wounding [3]

Evidence supports that theWnt120573-catenin signal controlsthe fate of the bulge stem cells and plays an essential role in

hair but not epidermal differentiation Using creloxP recom-bining system driven by the cytokeratin (K)14 promoterto induce the conditional mutation of 120573-catenin in micePeter Wendrsquos Laboratory demonstrates that the epidermisof young mutant animals develops normally but withouthair [10] However there are unusual cyst-like structuresappearing in the skin of these mice Meanwhile it is foundthat multilayered epithelium surrounds the cysts [11ndash13] Atthe same time there is another similar phenotype witha lack of hair but containing stem cells however thesecells can only differentiate into epidermal cells but not intohair follicles Moreover after ectopic expression of Wntinhibitor Dkk1 in the skin it is observed that transgenicexpression of dominant-negative Lef1 results in the formationof cysts and other epidermal appendages such as teeth and













Wnt activity

VDR activity

Epidermalphenotype


EF

EF

EF

R

R


VDR VDR VDR VDR

ΔN120573-cat

ΔN120573-cat

ΔN120573-cat

High High

High

Low

Low

Low


None None


BCCs

⋆

BCC




















6 Conclusions


Disclosure




Acknowledgments


References





















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























Wnt activity

VDR activity

Epidermalphenotype


EF

EF

EF

R

R


VDR VDR VDR VDR

ΔN120573-cat

ΔN120573-cat

ΔN120573-cat

High High

High

Low

Low

Low


None None


BCCs

⋆

BCC




















6 Conclusions


Disclosure




Acknowledgments


References





















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























6 Conclusions


Disclosure




Acknowledgments


References





















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Review Article -Catenin Signaling Pathway in Skin...

Documents

Transcript of Review Article -Catenin Signaling Pathway in Skin...