Involvement Of Retinoic Acid Regulates Wnt Signaling .

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Journal of Cancer Biology & ResearchCentral Bringing Excellence in Open AccessReview Article*Corresponding authorInvolvement of Retinoic AcidRegulates Wnt SignalingPathway in Cancer MetastasisZhu SS1 and Luo LZ2*Luo LianZhong, Department of Centre Laboratoryof Xiamen Medical College, Xiamen China, Tel:08615396282225; Email:Submitted: 15 July 2016Accepted: 10 August 2016Published: 12 August 2016Copyright 2016 Luo et al.OPEN ACCESS1Department of Centre Laboratory of Xiamen Medical College, China2Department of Xiamen, Key Laboratory of Marine Medicinal Natural Products andCell Engineering, ChinaAbstractKeywords Retinoic acid Wnt/β-catenin signaling pathway Cancer metastasisCancer is a generic term for a large group of diseases that can affect any part ofthe body. Metastasis is the spread of cancer to other locations in the body. Almost allcancers can metastasize resulting in the major cause of human death. Retinoic acid (RA)is essential for normal regulation of various biological processes including development,differentiation, proliferation, and apoptosis, and also defined as a potent suppressorof the proliferation of cancer cells and has been discovered inhibit various signalingpathways in tumors. Some reports have been found that lack of RA to relate with tumordevelopment and cellular migration Lots of cellular pathways, including Wnt/β-cateninsignaling pathway, are related to cancer metastasis. Many reports have suggested thatexaggerated Wnt signaling can lead to cancer initiation and progression in a widerange of human tissues. Dysregulated Wnt/β-catenin signaling in cancers appear tomore invasive to develop to mesenchymal cells and will undergo metastasis at last. Thedevelopment of new therapeutic compounds targeting the Wnt/β-catenin signalingpathway promises new hope to eliminate cancers, especially metastasis cancersby natural and synthetic RA. In this review, we provide a highlighting various RA inregulates the Wnt/β-catenin signaling pathway. The mechanism of its anti-tumor effectcan be considered as a therapeutic option.ABBREVIATIONSRA: Retinoic acid ; NCDs: Non-Communicable Diseases; EMT:Epithelial to Mesenchymal Transition; GSK-3β: Glycogen SynthaseKinase-3β; CK-1: Casein Kinase-1; APC: Adenomatous PolyposisColi; MMP-7: Matrix Metalloproteinase-7; HCC: HepatocellularCarcinoma Cells; ATRA: All-Trans-Retinoic Acid; 9-cis-RA: 9-CisRetinoic acid; 13-cis-RA: 13-Cis-Retinoic Acid; RARs: RetinoicAcid Receptors; RXRs: Retinoid X Receptors; HNSC CSCs: Headand Neck Cancer Stem Cells; PCP: Planar Cell Polarity; TCF: T CellFactor; EC: Embryonal Carcinoma; NT2: NTERA-2 Clone D; MED:Mammalian MediatorINTRODUCTIONCancer is a generic term to describe a large group of diseasesthat can affect any part of the body. Other terms used are malignanttumours and neoplasms. One defining characteristics of cancer isthe rapid creation of malignant cells that grow beyond their usualboundaries then invade adjoining parts of the body and spread toother organs, which is referred to as metastasizing. Metastasesare the major cause of death result from cancer. According tothe World Health Organization, cancers, cardiovascular diseases,respiratory diseases and diabetes are responsible for 80% ofall deaths from non-communicable diseases (NCDs) worldwide.There were an estimated 14.1 million cancer cases around theworld in 2012, of these 7.4 million cases were in men and 6.7million in women, and this number is expected to increase to24 million by 2035 [1]. Metastasis is a complex process whilethe original is called the primary tumor. Almost all cancers canmetastasize [2]. In some cases, metastatic cancer treatments mayhelp prolong life. Several cellular pathways, including Wnt/βcatenin signaling pathway, are related to cancer metastasis. Thereare three Wnt/β-catenin signaling pathways, such as canonicalWnt/β-catenin signaling pathway, the non canonical planar cellpolarity (PCP) pathway, and the Wnt/Ca2 pathway [3]. A criticaland most studied Wnt pathway is canonical Wnt signaling and isthe primary subject of this review. Many reports have suggestedthat over expressed of Wnt/β-catenin signaling can lead to cancerinitiation and progression in a wide range of human tissues [4-9].Dysregulated Wnt/β-catenin signaling in cancers appear to moremotility and invasive to induction of epithelial to mesenchymaltransition (EMT) and will undergo metastasis at last [10,11]. Thecentral hallmarks of EMT include the downregulation of cell–celladhesion protein E-cadherin which represents the epithelialCite this article: Zhu SS, Luo LZ (2016) Involvement of Retinoic Acid Regulates Wnt Signaling Pathway in Cancer Metastasis. J Cancer Biol Res 4(3): 1086.

Luo et al. (2016)Email: Central Bringing Excellence in Open Accessphenotype and up regulation of vimentin, which represents themesenchymal phenotype [12]. β-catenin plays a pivotal role as atranscriptional co-activator in this process. In the absence of Wntsignaling stimulation, cytoplasmic β-catenin is phosphorylatedby disruption complex including glycogen synthase kinase3β(GSK-3β), Axin and the tumour suppressor adenomatouspolyposis coli (APC) , which is targeted for ubiquitin-mediatedproteasome to degradation [13]. While stimulation by Wnt,β-catenin molecules are freed from the disruption complex andtrans located into the nucleus and binds to LEF1/TCF family oftranscription factors [14,15]. In turn, transactivate its targetoncogenes such as cyclin D1 and C-myc lead to cancer initiationand metastasis (e.g., matrix metalloproteinase-7(MMP-7)) [3,1619]. Uncontrolled Wnt/β-catenin signaling pathway is oftenassociated with tumorigenesis such as in breast cancer cells[20] and in colon cancer [21] and hepato cellular carcinomacells (HCC) [22]. It is now believed that vitamin A, throughits active derivative, retinoids regulate a variety of importantcellular processes during normal development, help maintainhomeostasis, and also exert anti-cancer activities in a numberof types of cancer cells [23-28]. Vitamin A can transformed intoisomers such as all-trans-retinoic acid (ATRA), 9-cis retinoicacid (9-cis-RA) or 13-cis-retinoic acid (13-cis-RA) reversibly,resulting in slightly different receptor binding propertiesand hence biological activities. Retinoids are essential for themaintenance of epithelial differentiation which can be oxidatedto retinoic acid (RA) as an agent in chemoprevention of epithelialcarcinogenesis [29]. RA regulates gene transcription through twonuclear receptor super family, retinoic acid receptors (RARs) andretinoid X receptors (RXRs) which with significant anti-cancereffects [29-31]. RARs as well as RXRs has three main subtypes α,β, and γ, and each receptor has an N-terminal A/B region whichcontains an autonomous transcriptional activation functioncalled AF-1, a central DNA-binding domain (the C region), anda C-terminal E region which containing a ligand binding domainand a ligand-dependent activation function-2 (AF-2). Thesereceptors are ligand-dependent DNA binding transcriptionfactors. Retinoids have been investigated in preclinical modelsfor a long time, by now clinical data have already supported thepotential of these compounds in cancer prevention and treatment[32]. Such as retinoic acid is being increasingly included in boththerapeutic schemes and chemo preventive for a series of tumourdiseases [32-34] and inhibit invasion and metastasis in diversetypes of cancer such as in breast cancer cells and HCC [35-38].Several reports have demonstrated that RA treatment caused asignificant decrease in MMPs expression in breast cells and alsoin colon cancer cells, they suggest that it may contribute to thecell migration and invasion decrease [39-40]. In general, RA isbelieved to inhibit carcinogenesis by blocking the promotionof initiated or transformed cells by three mechanisms: such asarrest of tumour growth and/or differentiation, induction ofapoptosis [41]. RA alone can suppress proliferation of HNSCCSCs and glioma in vitro and in vivo [42-44]. Many reports havebeen showed that RA and its receptors can inhibit invasion andmetastasis by regulating Wnt/β-catenin signaling pathway andblocking the transformation in a fibroblastic phenotype of cancerprogression.Cross talk between RA and Wnt protein in cancer cellsThe Wnt signaling pathway has been extensively studiedJ Cancer Biol Res 4(3): 1086 (2016)which is related to cancer metastasis. Many reports havesuggested that dysregulation of Wnt signaling can lead to cancerinitiation and progression in a wide group of human tissues [4,79]. Wnt family genes comprise 19 members which are classifiedas non-canonical Wnts and canonical Wnts. Non-canonicalWnt ligands Wnt4, Wnt5a and Wnt11 activate Wnt/planar cellpolarity (PCP) and Wnt/Ca2 pathways whereas canonical Wntligands including Wnt1, Wnt2, Wnt3, Wnt8a, Wnt8b, Wnt10a andWnt10b, activate the β-catenin and translocate it into nucleus toinduce its target genes [45]. And various evidences indicatingthat downstream components of the Wnt signaling pathway areover activated in many metastatic tumors [46]. The potentialfor Wnt signaling to cooperate with RA signaling pathways wasrevealed in a recent research demonstrating cross-talk betweenthe two pathways. Researchers have found that non-canonicalWnt signals can repress β-catenin/TCF activity downstreamof β-catenin, in parallel, evidence has been shown that RA canrepresses β-catenin/TCF activity in embryonal carcinoma (EC)NTERA-2 clone D1 (NT2) cells and that this is accompanied byincreased expression of non-canonical Wnt protein Wnt-4 andWnt-11 [47], both of which inhibit endogenous β-catenin/TCFactivity. Wnt-1 is the oncogenic driver because this signalingpathway is hyperactivated in a high percentage of human cancer[48]. As in genuine cross-talk, some studies have demonstratedthat retinoic acid-responsive gene stra6 could induced by Wnt1, and this process is strictly dependent upon retinoic acidreceptor activity, while other genes such as tumor necrosis factorfamily 4-1BB ligan, ephrin B1 , autotaxinand ISLR synergisticallyinduced by ATRA plus Wnt can be activated independentlyby Wnt signaling [49]. Moreover, up-regulation of stra6 genetranscription also happened in RA given to transplantedmammary tumors, derived from Wnt1 transgenic animals orcolon cancer xenografts (lacking functional APC) [50]. Genomicanalysis by Li laboratory found a major shift in expression of Wntand RXR-α pathway genes (up and down, respectively) coincidentwith the transition from hepatoblasts to hepatocytes, whichcategorized HCC cells into two subtypes (high Wnt, low RXR-αand low Wnt, high RXR-α) [51]. These data imply that retinoidsmay be useful for increasing the efficacy of therapeutic targetedat oncogenic targets of Wnt transformed cells.RA Regulates Wnt/β-catenin signaling pathway invarious cancer cellsThe Wnt signaling pathway plays a critical role in geneexpression, cell adhesionand is pivotal to every stage of cancerprogression, including initiation, development, and metastasis[20,52-56]. A principal executioner of Wnt pathway is β-cateninand suppression of β-catenin may be a good target for inhibitionof Wnt pathway. There are three different ways to degradeof cytosolic β-catenin: (1) by the serine/threonine kinase,glycogen synthase kinase (GSK)-3β, which is part of the Wntsignaling pathway, (2) by the p53/Siah-1 pathway, and (3) bya nuclear hormone receptor-mediated degradation pathway[21]. Some reports proved treatment with ATRA can decreasethe phosphorylation of GSK-3β which causes the cytosolicβ-catenin destruction complex to become stabilized, allowingfor the disruption of β-catenin in the cytosol, decrease cellularproliferation, and increase the expression of pro-apoptoticproteins in cancer cells [57]. Thus, RA increase of GSK-3β2/9

Luo et al. (2016)Email: Central Bringing Excellence in Open Accessfunction leads to a disruption in the equilibrium of β-cateninconcentration in nucleus and decreased Wnt signaling. As iswidely known that cross-talk between the PI3K/Akt pathwayand the Wnt/β-catenin signaling pathway occurs with GSK-3β(The relationships of RA regulates the function of GSK-3β andPI3K/Akt are shown in (Figure 1)). ATRA has been shown toinhibit PI3K activity and decrease the phosphorylation of GSK-3βwhich means the cytoplasmic β-catenin can be phosphorylatedby disruption complex and weaken Wnt/β-catenin signaling,then decrease cell invasion and metastasis at last [58]. Thephosphorylated form of GSK-3β also results in the increasedaccumulation of snail which is the repressor of E-cadherin,decreasing cell-cell adhesion through E-cadherin [59]. Inadditionally, retinoids have been shown to alter PTEN activity inmany cancers, such as smooth muscle cells, neuroblastoma andglioblastoma cells, promyelocytes, leukemia cells, fibroblasts,and breast, endometrial, and HCC [60-69]. Increases of PTENand consequent decreases of Akt and eventually decreaseβ-catenin in the cytosol. As described previous, the second wayfor RA regulates β-catenin is through the p53/Siah-1 pathway.Mutations of the tumor suppressor gene p53 are the mostcommon mutations found in human cancers [70], this loss ofp53 function during a defined step such as K-ras and the Wnt/βcatenin signaling pathway may already be dysregulated. Siah1 is a p53-inducible protein that binds ubiquitin-conjugatingenzymes and degrades both mutant and wild-type β-cateninresult in a decrease in TCF/LEF reporter activity and theconsequent reduction the levels of β-catenin target genes cyclinD1 and c-Myc [71]. Because Siah-1 expression is regulated by p53,the loss of p53 inhibits Siah-1 expression and activity, preventingthe p53/Siah-1 pathway activity to cause β-catenin degradation[72]. A high percentage of evidences have proved that retinoicacid treatment in various different cell types induces p53 mRNAand protein expression, increased p53 expression resulted inincreased degradation of β-catenin and a decrease in TCF/LEFactivity(The relationship of RA regulates the function of P53 isshown in (Figure1) [73-76]. Another research has demonstratedthat the β-catenin/TCF pathway was playing some role in theaction of retinoic acid, treatment with retinoic acid, in fact, doesstimulate the stabilization of β-catenin levels and retinoic acidprompts an activation of LEF-TCF-sensitive transcription in F9teratocarcinoma cells. This cross-regulation between retinoidsignaling and the Wnt/β-catenin pathways is focused on theformation of primitive endoderm, so the mechanism is differentfrom carcinoma [77]. Thus, the relationship between RA and Wntpathways is variable, contextual and cell type specific.Retinoic acid receptors RAR and RXR regulateβ-cateninRetinoic acid receptors (RARs) and retinoid X receptors(RXRs) are members of the nuclear receptor superfamily. All threeRAR subtypes (α, β and γ) can be activated by ATRA or 9-cis RA,Figure 1 RA regulates β-catenin with PTEM and P53 signaling pathways1) RA alter PTEN activity , inhibit PI3K/Akt activity and decrease the phosphorylation of GSK-3β which causes the cytosolic β-catenin destructioncomplex(GSK-3β, APC, CK-1 and AXIN) to become stabilized, allowing for the disruption of β-catenin in the cytosol and inhibit gene expression innucleus.2) RA induces p53 expression, and activates the p53/Siah-1 pathway to degrade β-catenin resulted in increased degradation of β-catenin and adecrease in TCF/LEF activity.3) RA inhibits the phosphorylation of GSK-3β results in the decreased accumulation of snail andincreasing cell-cell adhesion through E-cadherinand β-catenin.J Cancer Biol Res 4(3): 1086 (2016)3/9

Luo et al. (2016)Email: Central Bringing Excellence in Open Accessand function as heterodimers with retinoid-X receptors (RXRs)to enhance or drive the expression of target genes [78]. However,the specific receptor which mediates these effects varies withdifferent cell lines. Both RARs and RXRs can bind responseelements as RAR-RXR heterodimers or RXR homodimers, even athigh protein concentrations [79,80]. More evidences have shownthat β-catenin interact directly with RAR or RXR in a retinoiddependent manner (The mechanisms of RAR and RXR regulateβ-catenin is shown in (Figure 2). RAR can compete with TCF forβ-catenin binding suggest that direct regulation of β-catenin/TCFsignaling is one mechanism whereby RA influences development,cell differentiation and cancer [81].In general, retinoid receptors either inhibit β-cateninmediated gene transcription, as in the case of RAR, or decreaseβ-catenin protein levels, as in the case of RXR [82]. When treatedwith 9-cis-RA, a ligand for both RAR and RXR is recruitedto enhance β-catenin protein stability in breast cancers cellSKBR3 which express low endogenous levels of β-catenin [8385]. But 9-cis–RA treatment do reduce β-catenin/TCF/LEFmediated gene transcription in the same cell SKBR3 as well asMCF-7, CaCo-2 and HS578t [81]. With a down-regulated RARβexpression, RA resulted ineffective to reduce cellular migration,suggesting that tumour cells could silence RARβ to facilitate theescape of the tumour triggering the metastatic process. RARγacts as a tumor suppressor or oncogene in different cancers,depending on the cell-specific context [86-90]. RARγ plays asa tumor suppressor of the Hippo-Yap pathway in colorectaltumorigenesis and metastasis, where its expression correlatesinversely with tumor size, TNM stage, and distant metastasis[91]. But in cholangiocarcinoma (CCA) and HCC, RARγ is apivotal oncogene which was frequently over expressed andresulting in poor differentiation, and poor prognosis [89,92].Researchers have found that RA treatment up regulated RARγand down regulated phosphorylated β-catenin which escapefrom the degraded complex, means RARγ up regulating totalβ-catenin, then increased cyclinD1, P-P glycoprotein, PCNA andMMP9 which plays a critical role in early CCA metastasis [93]. Inpresent studies, the only know molecular mechanism of tumorrevealed that RARγ interacted with β-catenin and led to β-cateninnuclear translocation is in CCA, whether RARγ suppressesthe level of β-catenin in other cancers is still unknown. Theseresults showed that RARγ upregulated β-catenin in nucleartranslocation and subsequently lead to the activation of Wnt/βcatenin pathway. The paradoxical roles of RAR in the regulationof β-catenin might depend on its particular cellular location. Asdescribed previous, Wnt-1 promotes the up-regulation of RARγ,which could potentiate the response of the cell to retinoids andincrease the expression of retinoic acid-responsive gene Stra6in many cancers [50]. These consequences indicate retinoidsin various cancer models has been inconsistent, yielding bothsuppression and enhancement of tumor progression dependingon genetic background and tumor type also by differentadministration protocol [94]. In additionally, Xiao et al foundthat retinoid X receptor (RXR) can mediated APC-independentpathway in the regulation of β-catenin in APC- and p53-mutatedcolorectal cancer cells, and results have been found that RXRαand β-catenin have been shown to directly interact in nucleus,which proved retinoids can increase β catenin degradation bya nuclear hormone receptor-mediated degradation pathway[82,95]. Revealing despite mutations in the p53 and APCproteins that regulate β-catenin protein degradation only bythe RXR-mediated pathway remains functional in these humancolon cancer cell lines [21]. Further evidence shows that retinolincreases migration of β-catenin and RXRα from the nucleusinto the cytosol concomitant with the β-catenin-RXRα bindingcomplex, the provement demonstrated that cytosolic RXRα isproteasomally degraded, and more important, the evidenceshows that the RXRα and β-catenin binding is required for theproteosome degradation of β-catenin (As is shown in (Figure 2))[96]. These results are consistent with a transrepression model ofβ-catenin inhibition, which depends on the high-level expressionFigure 2 The mechanisms of RAR and

Wnt/β-catenin signaling pathway, the non canonical planar cell polarity (PCP) pathway, and the Wnt/Ca2 pathway [3]. A critical and most studied Wnt pathway is canonical Wnt signaling and is the primary subject of this review. Many reports have suggested that over expressed of

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