Tumour Suppressor Neuron Navigator 3 and Matrix Metalloproteinase 14 are Co-expressed in Most Melanomas but Downregulated in Thick Tumours
DOI:
https://doi.org/10.2340/actadv.v103.298Keywords:
melanoma, NAV3, MMP14, copy number changeAbstract
Melanoma is a highly metastatic tumour originating from neural crest-derived melanocytes. The aim of this study was to analyse the expression of neuron navigator 3 (NAV3) in relation to membrane type-1 matrix metalloproteinase MMP14, a major regulator of invasion, in 40 primary melanomas, 15 benign naevi and 2 melanoma cell lines. NAV3 copy number changes were found in 18/27 (67%) primary melanomas, so that deletions dominated (16/27 of samples, 59%). NAV3 protein was found to be localized at the leading edge of migrating melanoma cells in vitro. Silencing of NAV3 reduced both melanoma cell migration in 2-dimensional conditions, as well as sprouting in 3-dimensional collagen I. NAV3 protein expression correlated with MMP14 in 26/37 (70%) primary melanomas. NAV3 and MMP14 were co-expressed in all tumours with Breslow thickness < 1 mm, in 11/23 of mid-thickness tumours (1–5 mm), but in only 1/6 samples of thick (> 5 mm) melanomas. Altogether, NAV3 number changes are frequent in melanomas, and NAV3 and MMP14, while expressed in all thin melanomas, are often downregulated in thicker tumours, suggesting that the lack of both NAV3 and MMP14 favours melanoma progression.
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Rager EL, Bridgeford EP, Ollila DW. Cutaneous melanoma: update on prevention, screening, diagnosis, and treatment. Am Fam Physician 2005; 72: 269-276.
Leonardi G, Candido S, Falzone L, Spandidos DA, Libra M. Cutaneous melanoma and the immunotherapy revolution (Review). Int J Oncol 2020; 57: 609-618.
https://doi.org/10.3892/ijo.2020.5088 DOI: https://doi.org/10.3892/ijo.2020.5088
van Haren J, Draegestein K, Keijzer N, Abrahams JP, Grosveld F, Peeters PJ, et al. Mammalian Navigators are microtubule plus-end tracking proteins that can reorganize the cytoskeleton to induce neurite-like extensions. Cell Motil Cytoskeleton 2009; 66: 824-838.
https://doi.org/10.1002/cm.20370 DOI: https://doi.org/10.1002/cm.20370
Bleeker FE, Lamba S, Rodolfo M, Scarpa A, Leenstra S, Vandertop WP, et al. Mutational profiling of cancer candidate genes in glioblastoma, melanoma and pancreatic carcinoma reveals a snapshot of their genomic landscapes. Hum Mutat 2009; 30: E451-459.
https://doi.org/10.1002/humu.20927 DOI: https://doi.org/10.1002/humu.20927
Carlsson E, Ranki A, Sipilä L, Karenko L, Abdel-Rahman WM, Ovaska K et al. Potential role of a navigator gene NAV3 in colorectal cancer. Br J Cancer 2012; 106: 517-524.
https://doi.org/10.1038/bjc.2011.553 DOI: https://doi.org/10.1038/bjc.2011.553
Coy JF, Wiemann S, Bechmann I, Bächner D, Nitsch R, Kretz O, et al. Pore membrane and/or filament interacting like protein 1 (POMFIL1) is predominantly expressed in the nervous system and encodes different protein isoforms. Gene 2002; 290: 73-94.
https://doi.org/10.1016/S0378-1119(02)00567-X DOI: https://doi.org/10.1016/S0378-1119(02)00567-X
Hahtola S, Burghart E, Jeskanen L, Karenko L, Abdel-Rahman WM, Polzer B, et al. Clinicopathological characterization and genomic aberrations in subcutaneous panniculitis-like T-cell lymphoma. J Invest Dermatol 2008a; 128: 2304-2309.
https://doi.org/10.1038/jid.2008.6 DOI: https://doi.org/10.1038/jid.2008.6
Hahtola S, Burghart E, Puputti M, Karenko L, Abdel-Rahman WM, Väkevä L, et al. Cutaneous T-cell lymphoma-associated lung cancers show chromosomal aberrations differing from primary lung cancer. Genes Chromosomes Cancer 2008b; 47: 107-117.
https://doi.org/10.1002/gcc.20513 DOI: https://doi.org/10.1002/gcc.20513
Karenko L, Hahtola S, Päivinen S, Karhu R, Syrjä S, Kähkönen M, et al. Primary Cutaneous T-Cell Lymphomas Show a Deletion or Translocation Affecting NAV3, the Human UNC-53 Homologue. Cancer Res 2005; 65: 8101-8110.
https://doi.org/10.1158/0008-5472.CAN-04-0366 DOI: https://doi.org/10.1158/0008-5472.CAN-04-0366
Nord H, Hartmann C, Andersson R, Menzel U, Pfeifer S, Piotrowski A, et al. Characterization of novel and complex genomic aberrations in glioblastoma using a 32K BAC array. Neuro Oncol 2009; 11: 803-818.
https://doi.org/10.1215/15228517-2009-013 DOI: https://doi.org/10.1215/15228517-2009-013
Soon PSH, Gill AJ, Benn DE, Clarkson A, Robinson BG, McDonald KL, et al. Microarray gene expression and immunohistochemistry analyses of adrenocortical tumors identify IGF2 and Ki-67 as useful in differentiating carcinomas from adenomas. Endocr Relat Cancer 2009; 16: 573-583.
https://doi.org/10.1677/ERC-08-0237 DOI: https://doi.org/10.1677/ERC-08-0237
Wood LD, Parsons DW, Jones S, Lin J, Sjöblom T, Leary RJ, et al. The genomic landscapes of human breast and colorectal cancers. Science 2007; 318: 1108-1013.
https://doi.org/10.1126/science.1145720 DOI: https://doi.org/10.1126/science.1145720
Zhang L, Luo M, Yang H, Zhu S, Cheng X, Qing C. Next-generation sequencing-based genomic profiling analysis reveals novel mutations for clinical diagnosis in Chinese primary epithelial ovarian cancer patients. J Ovarian Res 2019; 12: 19.
https://doi.org/10.1186/s13048-019-0494-4 DOI: https://doi.org/10.1186/s13048-019-0494-4
Aly J, Lewis T, Parikh T, Britten J, Malik M, Catherino W. NAV3, a tumor suppressor gene, is decreased in uterine leiomyoma tissue and cells. Reprod Sci 2020; 27: 925-934.
https://doi.org/10.1007/s43032-019-00096-3 DOI: https://doi.org/10.1007/s43032-019-00096-3
Carlsson E, Krohn K, Ovaska K, Lindberg P, Häyry V, Maliniemi P et al. Neuron navigator 3 alterations in nervous system tumors associate with tumor malignancy grade and prognosis. Genes Chromosomes Cancer 2013; 52: 191-201.
https://doi.org/10.1002/gcc.22019 DOI: https://doi.org/10.1002/gcc.22019
Cohen-Dvashi H, Ben-Chetrit N, Russell R, Carvalho S, Lauriola M, Nisani S, et al. Navigator-3, a modulator of cell migration, may act as a suppressor of breast cancer progression. EMBO Mol Med 2015; 7: 299-314.
https://doi.org/10.15252/emmm.201404134 DOI: https://doi.org/10.15252/emmm.201404134
Uboveja A, Satija Y, Siraj F, Sharma I, Saluja D. p73 - NAV3 axis plays a critical role in suppression of colon cancer metastasis. Oncogenesis 2020; 9: 12.
https://doi.org/10.1038/s41389-020-0193-4 DOI: https://doi.org/10.1038/s41389-020-0193-4
Napoli S, Scuderi C, Gattuso G, Di Bella V, Candido S, Basile MS, et al. Functional roles of matrix metalloproteinases and their inhibitors in melanoma. Cells 2020; 9: 1151.
https://doi.org/10.3390/cells9051151 DOI: https://doi.org/10.3390/cells9051151
Szabova L, Chrysovergis K, Yamada SS, Holmbeck K. MT1-MMP is required for efficient tumor dissemination in experimental metastatic disease. Oncogene 2008; 27: 3274-3281.
https://doi.org/10.1038/sj.onc.1210982 DOI: https://doi.org/10.1038/sj.onc.1210982
Hofmann UB, Houben R, Bröcker E-B, Becker JC. Role of matrix metalloproteinases in melanoma cell invasion. Biochimie 2005; 87: 307-314.
https://doi.org/10.1016/j.biochi.2005.01.013 DOI: https://doi.org/10.1016/j.biochi.2005.01.013
Raeeszadeh-Sarmazdeh M, Do LD, Hritz BG. Metalloproteinases and their inhibitors: potential for the development of new therapeutics. Cells 2020; 9: 1313.
https://doi.org/10.3390/cells9051313 DOI: https://doi.org/10.3390/cells9051313
Wolf K, Mazo I, Leung H, Engelke K, von Andrian UH, Deryugina EI, et al. Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis. J Cell Biol 2003; 160: 267-277.
https://doi.org/10.1083/jcb.200209006 DOI: https://doi.org/10.1083/jcb.200209006
Castro-Castro A, Janke C, Montagnac G, Paul-Gilloteaux P, Chavrier P. ATAT1/MEC-17 acetyltransferase and HDAC6 deacetylase control a balance of acetylation of alpha-tubulin and cortactin and regulate MT1-MMP trafficking and breast tumor cell invasion. Eur J Cell Biol 2012; 91: 950-960.
https://doi.org/10.1016/j.ejcb.2012.07.001 DOI: https://doi.org/10.1016/j.ejcb.2012.07.001
Maliniemi P, Carlsson E, Kaukola A, Ovaska K, Niiranen K, Saksela O et al. NAV3 copy number changes and target genes in basal and squamous cell cancers. Exp Dermatol 2011; 20: 926-931.
https://doi.org/10.1111/j.1600-0625.2011.01358.x DOI: https://doi.org/10.1111/j.1600-0625.2011.01358.x
Ranki A, Väkevä L, Sipilä L, Krohn K. Molecular markers associated with clinical response to bexarotene therapy in cutaneous T-cell lymphoma. Acta Derm Venereol 2011; 91: 568-573.
https://doi.org/10.2340/00015555-1114 DOI: https://doi.org/10.2340/00015555-1114
Tatti O, Gucciardo E, Pekkonen P, Holopainen T, Louhimo R, Repo P, et al. MMP16 mediates a proteolytic switch to promote cell-cell adhesion, collagen alignment, and lymphatic invasion in melanoma. Cancer Res 2015; 75: 2083-2094.
https://doi.org/10.1158/0008-5472.CAN-14-1923 DOI: https://doi.org/10.1158/0008-5472.CAN-14-1923
Cobb JP, Walker DG. Studies on human melanoma cells in tissue culture. I. Growth characteristics and cytology. Cancer Res 1960; 20: 858-867.
Cepeda MA, Pelling JJ, Evered CL, Williams KC, Freedman Z, Stan I, et al. Less is more: low expression of MT1-MMP is optimal to promote migration and tumourigenesis of breast cancer cells. Mol Cancer 2016; 15: 65.
https://doi.org/10.1186/s12943-016-0547-x DOI: https://doi.org/10.1186/s12943-016-0547-x
Friedl P. Prespecification and plasticity: shifting mechanisms of cell migration. Curr Opin Cell Bio 2004; 16: 14-23.
https://doi.org/10.1016/j.ceb.2003.11.001 DOI: https://doi.org/10.1016/j.ceb.2003.11.001
Sabeh F, Ota I, Holmbeck K, Birkedal-Hansen H, Soloway P, Balbin M, et al. Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP. J Cell Biol 2004; 167: 769-781.
https://doi.org/10.1083/jcb.200408028 DOI: https://doi.org/10.1083/jcb.200408028
Raza S, Jokl E, Pritchett J, Martin K, Su K, Simpson K. SOX9 is required for kidney fibrosis and activates NAV3 to drive renal myofibroblast function. Sci Signal 2021; 14: eabb4282.
https://doi.org/10.1126/scisignal.abb4282 DOI: https://doi.org/10.1126/scisignal.abb4282
Cheng PF, Shakhova O, Widmer DS, Eichhoff OM, Zingg D, Frommel SC, et al. Methylation-dependent SOX9 expression mediates invasion in human melanoma cells and is a negative prognostic factor in advanced melanoma. Genome Biol 2015; 16: 42.
https://doi.org/10.1186/s13059-015-0594-4 DOI: https://doi.org/10.1186/s13059-015-0594-4
Hofmann U, Westphal J, Van Muijen G, Ruiter D. Matrix metalloproteinases in human melanoma. J Invest Dermatol 2000; 115: 337-344.
https://doi.org/10.1046/j.1523-1747.2000.00068.x DOI: https://doi.org/10.1046/j.1523-1747.2000.00068.x
Remacle A, Cieplak P, Nam D, Shiryaev S, Ge X, Strongin A. Selective function-blocking monoclonal human antibody highlights the important role of membrane type-1 matrix metalloproteinase (MT1-MMP) in metastasis. Oncotarget 2017; 8: 2781-2799.
https://doi.org/10.18632/oncotarget.13157 DOI: https://doi.org/10.18632/oncotarget.13157
Cowden Dahl KD, Zeineldin R, Hudson LG. PEA3 is necessary for optimal epidermal growth factor receptor-stimulated matrix metalloproteinase expression and invasion of ovarian tumor cells. Mol Cancer Res 2007; 5: 413-421.
https://doi.org/10.1158/1541-7786.MCR-07-0019 DOI: https://doi.org/10.1158/1541-7786.MCR-07-0019
Overland A, Insel P. Heterotrimeric G proteins directly regulate MMP14/membrane type-1 matrix metalloprotease: a novel mechanism for GPCR-EGFR transactivation. J Biol Chem 2015; 290: 9941-9947.
https://doi.org/10.1074/jbc.C115.647073 DOI: https://doi.org/10.1074/jbc.C115.647073
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Copyright (c) 2023 Olga Bugaeva, Pilvi Maliniemi, Wenche S. Prestvik, Eeva Leivo, Nicolas Kluger, Alexander Salava, Sanna Virtanen, Kirsi Jäntti, Olli Saksela, Kaisa Lehti, Paula Kujala, Kaj Krohn, Annamari Ranki
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