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      Challenging role of Wnt5a and its signaling pathway in cancer metastasis (Review)

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          Abstract

          Wnt5a is a noncanonical signaling member of the wingless-related/mouse mammary tumor virus integration family, which is involved in a wide range of cellular processes, particularly in cancer development and metastasis. Accumulating evidence indicates that Wnt5a exhibits paradoxical effects in various types of cancer metastasis. Therefore, the Wnt5a signaling cascade in cancer metastasis appears to be complex and may depend on binding receptors, downstream effectors, exogenous inhibitors and tumor microenvironments, as well as the extracellular matrix, particularly cell/tissue-tropic contexts. The aim of the present study was to summarize the previous findings on the roles of Wnt5a and the potential mechanisms in various types of cancer metastasis. Furthermore, it is reasonable to hypothesize that Wnt5a and the involved signaling pathways may become molecular targets in the treatment of cancer metastasis.

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          Molecular classification of cutaneous malignant melanoma by gene expression profiling.

          M. Bittner, P. Meltzer, Y. Chen … (2000)
          The most common human cancers are malignant neoplasms of the skin. Incidence of cutaneous melanoma is rising especially steeply, with minimal progress in non-surgical treatment of advanced disease. Despite significant effort to identify independent predictors of melanoma outcome, no accepted histopathological, molecular or immunohistochemical marker defines subsets of this neoplasm. Accordingly, though melanoma is thought to present with different 'taxonomic' forms, these are considered part of a continuous spectrum rather than discrete entities. Here we report the discovery of a subset of melanomas identified by mathematical analysis of gene expression in a series of samples. Remarkably, many genes underlying the classification of this subset are differentially regulated in invasive melanomas that form primitive tubular networks in vitro, a feature of some highly aggressive metastatic melanomas. Global transcript analysis can identify unrecognized subtypes of cutaneous melanoma and predict experimentally verifiable phenotypic characteristics that may be of importance to disease progression.
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            The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway.

            Isao Oishi, Hiroaki Suzuki, Nobuyuki Onishi … (2003)
            Ror2 is an orphan receptor, belonging to the Ror family of receptor tyrosine kinases. Although Ror2 has been shown to play crucial roles in developmental morphogenesis, the precise signalling events that Ror2 mediates remain elusive. Since Ror2 possesses an extracellular cysteine-rich domain (CRD) that resembles the Wnt-binding sites of the Frizzled (Fz) proteins, it is conceivable that Ror2 interacts with members of the Wnt family. Both Ror2-/- and Wnt5a-/- mice exhibit dwarfism, facial abnormalities, short limbs and tails, dysplasia of lungs and genitals, and ventricular septal defects. In vitro binding assay revealed that Wnt5a binds to the CRD of Ror2. Furthermore, Ror2 associates via its CRD with rFz2, a putative receptor for Wnt5a. Interestingly, Wnt5a and Ror2 activate the non-canonical Wnt pathway, as assessed by activation of JNK in cultured cells and inhibition of convergent extension movements in Xenopus. Our findings indicate that Wnt5a and Ror2 interact physically and functionally. Ror2 may thus act as a receptor for Wnt5a to activate non-canonical Wnt signalling.
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              The Wnt5A/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition.

              Brian Nickoloff, Ashani T Weeraratna, Samudra K. Dissanayake … (2007)
              We have shown that Wnt5A increases the motility of melanoma cells. To explore cellular pathways involving Wnt5A, we compared gain-of-function (WNT5A stable transfectants) versus loss-of-function (siRNA knockdown) of WNT5A by microarray analysis. Increasing WNT5A suppressed the expression of several genes, which were re-expressed after small interference RNA-mediated knockdown of WNT5A. Genes affected by WNT5A include KISS-1, a metastasis suppressor, and CD44, involved in tumor cell homing during metastasis. This could be validated at the protein level using both small interference RNA and recombinant Wnt5A (rWnt5A). Among the genes up-regulated by WNT5A was the gene vimentin, associated with an epithelial to mesenchymal transition (EMT), which involves decreases in E-cadherin, due to up-regulation of the transcriptional repressor, Snail. rWnt5A treatment increases Snail and vimentin expression, and decreases E-cadherin, even in the presence of dominant-negativeTCF4, suggesting that this activation is independent of Wnt/beta-catenin signaling. Because Wnt5A can signal via protein kinase C (PKC), the role of PKC in Wnt5A-mediated motility and EMT was also assessed using PKC inhibition and activation studies. Treating cells expressing low levels of Wnt5A with phorbol ester increased Snail expression inhibiting PKC in cells expressing high levels of Wnt5A decreased Snail. Furthermore, inhibition of PKC before Wnt5A treatment blocked Snail expression, implying that Wnt5A can potentiate melanoma metastasis via the induction of EMT in a PKC-dependent manner.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Exp Ther Med
                Journal ID (iso-abbrev): Exp Ther Med
                Journal ID (publisher-id): ETM
                Title: Experimental and Therapeutic Medicine
                Publisher: D.A. Spandidos
                ISSN (Print): 1792-0981
                ISSN (Electronic): 1792-1015
                Publication date (Print): July 2014
                Publication date (Electronic): 11 April 2014
                Publication date PMC-release: 11 April 2014
                Volume: 8
                Issue: 1
                Pages: 3-8
                Affiliations
                [1 ]Department of Urology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
                [2 ]Department of Urology, Second Affiliated Hospital of South China University, Hengyang, Hunan 421001, P.R. China
                [3 ]Institute of Pharmacy and Pharmacology, University of South China, Hengyang, Hunan 421001, P.R. China
                [4 ]School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P.R. China
                Author notes
                Correspondence to: Dr Li Qin, Institute of Pharmacy and Pharmacology, University of South China, 28 Changsheng West Road, Hengyang, Hunan 421001, P.R. China, E-mail: qinli1977@ 123456gmail.com . Dr Duanfang Liao, School of Pharmacy, Hunan University of Chinese Medicine, 1 Xiangzui Road, Hanpu Science and Education District, Changsha, Hunan 410208, P.R. China, E-mail: dfliao66@ 123456aliyun.com
                Article
                Publisher ID: etm-08-01-0003
                DOI: 10.3892/etm.2014.1676
                PMC ID: 4061222
                PubMed ID: 24944588
                SO-VID: b2911495-bca5-4bba-8204-4210a82acd8d
                Copyright © Copyright © 2014, Spandidos Publications
                License:

                This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

                History
                Date received : 27 November 2013
                Date accepted : 26 March 2014
                Categories
                Subject: Articles

                ScienceOpen disciplines: Medicine
                Keywords: wnt5a,cancer,metastasis,signaling pathway
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: wnt5a, cancer, metastasis, signaling pathway

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