{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T04:19:58Z","timestamp":1777177198632,"version":"3.51.4"},"reference-count":45,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2023,11,28]],"date-time":"2023-11-28T00:00:00Z","timestamp":1701129600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003549","name":"Hungarian Scientific Research Fund","doi-asserted-by":"publisher","award":["OTKA125509"],"award-info":[{"award-number":["OTKA125509"]}],"id":[{"id":"10.13039\/501100003549","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Micro-environmental factors, including stromal and immune cells, cytokines, and circulating hormones are well recognized to determine cancer progression. Melanoma cell growth was recently shown to be suppressed by cholecystokinin\/gastrin (CCK) receptor antagonists, and our preliminary data suggested that melanoma patients with Helicobacter gastritis (which is associated with elevated serum gastrin) might have an increased risk of cancer progression. Therefore, in the present study, we examined how gastrin may act on melanoma cells. In 89 melanoma patients, we found a statistically significant association between circulating gastrin concentrations and melanoma thickness and metastasis, which are known risk factors of melanoma progression and prognosis. Immunocytochemistry using a validated antibody confirmed weak to moderate CCK2R expression in both primary malignant melanoma cells and the melanoma cell lines SK-MEL-2 and G361. Furthermore, among the 219 tumors in the Skin Cutaneous Melanoma TCGA Pan-Cancer dataset showing gastrin receptor (CCKBR) expression, significantly higher CCKBR mRNA levels were linked to stage III\u2013IV than stage I\u2013II melanomas. In both cell lines, gastrin increased intracellular calcium levels and stimulated cell migration and invasion through mechanisms inhibited by a CCK2 receptor antagonist. Proteomic studies identified increased MMP-2 and reduced TIMP-3 levels in response to gastrin that were likely to contribute to the increased migration of both cell lines. However, the effects of gastrin on tumor cell invasion were relatively weak in the presence of the extracellular matrix. Nevertheless, dermal fibroblasts\/myofibroblasts, known also to express CCK2R, increased gastrin-induced cancer cell invasion. Our data suggest that in a subset of melanoma patients, an elevated serum gastrin concentration is a risk factor for melanoma tumor progression, and that gastrin may act on both melanoma and adjacent stromal cells through CCK2 receptors to promote mechanisms of tumor migration and invasion.<\/jats:p>","DOI":"10.3390\/ijms242316851","type":"journal-article","created":{"date-parts":[[2023,11,28]],"date-time":"2023-11-28T06:45:35Z","timestamp":1701153935000},"page":"16851","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Elevated Serum Gastrin Is Associated with Melanoma Progression: Putative Role in Increased Migration and Invasion of Melanoma Cells"],"prefix":"10.3390","volume":"24","author":[{"given":"Akos Janos","family":"Varga","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 7BE, UK"},{"name":"Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Istvan Balazs","family":"Nemeth","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2119-9501","authenticated-orcid":false,"given":"Lajos","family":"Kemeny","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janos","family":"Varga","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laszlo","family":"Tiszlavicz","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Szeged, 6725 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dinesh","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 7BE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven","family":"Dodd","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 7BE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alec W. M.","family":"Simpson","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 7BE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tunde","family":"Buknicz","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rob","family":"Beynon","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7BE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deborah","family":"Simpson","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7BE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9164-065X","authenticated-orcid":false,"given":"Tibor","family":"Krenacs","sequence":"additional","affiliation":[{"name":"Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graham J.","family":"Dockray","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 7BE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Varro","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 7BE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1146\/annurev.physiol.63.1.119","article-title":"The gastrins: Their production and biological activities","volume":"63","author":"Dockray","year":"2001","journal-title":"Annu. Rev. Physiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3120","DOI":"10.1038\/onc.2014.255","article-title":"Progastrin a new pro-angiogenic factor in colorectal cancer","volume":"34","author":"Najib","year":"2015","journal-title":"Oncogene"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"G712","DOI":"10.1152\/ajpgi.00406.2011","article-title":"Clathrin mediates endocytosis of progastrin and activates MAPKs: Role of cell surface annexin A2","volume":"302","author":"Sarkar","year":"2012","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3696","DOI":"10.18632\/oncotarget.12467","article-title":"Transgenic and gene knockout mice in gastric cancer research","volume":"8","author":"Jiang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1042\/bj20020068","article-title":"Gastrin-stimulated gastric epithelial cell invasion: The role and mechanism of increased matrix metalloproteinase 9 expression","volume":"365","author":"Wroblewski","year":"2002","journal-title":"Biochem. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.fsc.2012.11.007","article-title":"Melanoma","volume":"21","author":"Ingraffea","year":"2013","journal-title":"Facial Plast. Surg. Clin. N. Am."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"10123","DOI":"10.1158\/0008-5472.CAN-07-3127","article-title":"Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts","volume":"67","author":"Zeisberg","year":"2007","journal-title":"Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1038\/nm.2753","article-title":"Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET","volume":"18","author":"Peinado","year":"2012","journal-title":"Nat. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1038\/nm.3394","article-title":"Microenvironmental regulation of tumor progression and metastasis","volume":"19","author":"Quail","year":"2013","journal-title":"Nat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.ejca.2015.09.014","article-title":"Association of TIMP3 expression with vessel density, macrophage infiltration and prognosis in human malignant melanoma","volume":"53","author":"Das","year":"2016","journal-title":"Eur. J. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/nature22071","article-title":"Whole-genome landscapes of major melanoma subtypes","volume":"545","author":"Hayward","year":"2017","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1046\/j.1523-1747.2000.00068.x","article-title":"Matrix metalloproteinases in human melanoma","volume":"115","author":"Hofmann","year":"2000","journal-title":"J. Investig. Dermatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1002\/path.1080","article-title":"Identification of activated matrix metalloproteinase-2 (MMP-2) as the main gelatinolytic enzyme in malignant melanoma by in situ zymography","volume":"197","author":"Kurschat","year":"2002","journal-title":"J. Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1093\/carcin\/bgp248","article-title":"MMP13 as a stromal mediator in controlling persistent angiogenesis in skin carcinoma","volume":"31","author":"Lederle","year":"2010","journal-title":"Carcinogenesis"},{"key":"ref_16","first-page":"1071","article-title":"Cutaneous melanoma: From pathogenesis to therapy (Review)","volume":"52","author":"Leonardi","year":"2018","journal-title":"Int. J. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1593\/neo.05379","article-title":"Gastrin exerts pleiotropic effects on human melanoma cell biology","volume":"7","author":"Mathieu","year":"2005","journal-title":"Neoplasia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"100153","DOI":"10.1016\/j.xjidi.2022.100153","article-title":"Cholecystokinin Receptor Antagonist Suppresses Melanoma Growth by Inducing Apoptosis of Tumor Cells","volume":"2","author":"Funakoshi","year":"2022","journal-title":"JID Innov."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e13683","DOI":"10.14814\/phy2.13683","article-title":"Matrix metalloproteinase (MMP)-7 in Barrett\u2019s esophagus and esophageal adenocarcinoma: Expression, metabolism, and functional significance","volume":"6","author":"Garalla","year":"2018","journal-title":"Physiol. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e13394","DOI":"10.14814\/phy2.13394","article-title":"Cell cycle dependent expression of the CCK2 receptor by gastrointestinal myofibroblasts: Putative role in determining cell migration","volume":"5","author":"Varga","year":"2017","journal-title":"Physiol. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5191","DOI":"10.3748\/wjg.v20.i18.5191","article-title":"History of Helicobacter pylori, duodenal ulcer, gastric ulcer and gastric cancer","volume":"20","author":"Graham","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5461","DOI":"10.3748\/wjg.v20.i18.5461","article-title":"Helicobacter pylori associated chronic gastritis, clinical syndromes, precancerous lesions, and pathogenesis of gastric cancer development","volume":"20","author":"Watari","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1074\/mcp.TIR117.000516","article-title":"Stable Isotope Dynamic Labeling of Secretomes (SIDLS) Identifies Authentic Secretory Proteins Released by Cancer and Stromal Cells","volume":"17","author":"Hammond","year":"2018","journal-title":"Mol. Cell. Proteom."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"D377","DOI":"10.1093\/nar\/gks1118","article-title":"PANTHER in 2013: Modeling the evolution of gene function, and other gene attributes, in the context of phylogenetic trees","volume":"41","author":"Mi","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1152\/physrev.00014.2005","article-title":"Cholecystokinin and gastrin receptors","volume":"86","author":"Dufresne","year":"2006","journal-title":"Physiol. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1007\/s12672-017-0311-8","article-title":"Expression of the Cholecystokinin-B Receptor in Neoplastic Gastric Cells","volume":"9","author":"Nordrum","year":"2018","journal-title":"Horm Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1093\/jnci\/93.9.678","article-title":"Recent trends in cutaneous melanoma incidence among whites in the United States","volume":"93","author":"Jemal","year":"2001","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"32122","DOI":"10.1074\/jbc.M005754200","article-title":"Human colorectal cancers express a constitutively active cholecystokinin-B\/gastrin receptor that stimulates cell growth","volume":"275","author":"Hellmich","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1111\/j.1582-4934.2009.00859.x","article-title":"CCK(2) receptor splice variant with intron 4 retention in human gastrointestinal and lung tumours","volume":"14","author":"Waser","year":"2010","journal-title":"J. Cell. Mol. Med."},{"key":"ref_30","first-page":"125","article-title":"The effects of long-term therapy with proton pump inhibitors on meal stimulated gastrin","volume":"46","author":"Helgadottir","year":"2014","journal-title":"Dig. Liver Dis. Off. J. Ital. Soc. Gastroenterol. Ital. Assoc. Study Liver"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"642","DOI":"10.3855\/jidc.2923","article-title":"Prevalence of Helicobacter pylori cagA and vacA genes in Cypriot patients","volume":"7","author":"Krashias","year":"2013","journal-title":"J. Infect. Dev. Ctries."},{"key":"ref_32","first-page":"827","article-title":"Suspension culture of a pigment-producing cell line derived from a human malignant melanoma","volume":"41","author":"Oettgen","year":"1968","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"10498","DOI":"10.18632\/oncotarget.14443","article-title":"Investigating the utility of human melanoma cell lines as tumour models","volume":"8","author":"Vincent","year":"2017","journal-title":"Oncotarget"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1126\/science.aad0501","article-title":"Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq","volume":"352","author":"Tirosh","year":"2016","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Eom, S., Lee, S., Lee, J., Yeom, H.D., Lee, S.G., and Lee, J. (2022). DDX3 Upregulates Hydrogen Peroxide-Induced Melanogenesis in Sk-Mel-2 Human Melanoma Cells. Molecules, 27.","DOI":"10.3390\/molecules27207010"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"150s","DOI":"10.1038\/jid.1993.68","article-title":"Tyrosinase gene transcription and its control by melanogenic inhibitors","volume":"100","author":"Ando","year":"1993","journal-title":"J. Investig. Dermatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1186\/bcr1980","article-title":"Inflammation and breast cancer: Metalloproteinases as common effectors of inflammation and extracellular matrix breakdown in breast cancer","volume":"10","author":"Hojilla","year":"2008","journal-title":"Breast Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3853","DOI":"10.1007\/s00018-011-0763-x","article-title":"Matrix metalloproteinases in tumorigenesis: An evolving paradigm","volume":"68","author":"Hua","year":"2011","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1038\/sj.bjc.6690763","article-title":"Matrix metalloproteinases in human melanoma cell lines and xenografts: Increased expression of activated matrix metalloproteinase-2 (MMP-2) correlates with melanoma progression","volume":"81","author":"Hofmann","year":"1999","journal-title":"Br. J. Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1136\/gut.50.6.827","article-title":"Gastrin-cholecystokinin(B) receptor expression in AGS cells is associated with direct inhibition and indirect stimulation of cell proliferation via paracrine activation of the epidermal growth factor receptor","volume":"50","author":"Varro","year":"2002","journal-title":"Gut"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"14824","DOI":"10.1074\/jbc.M113.451336","article-title":"Transforming growth factor-beta1 (TGF-beta1)-stimulated fibroblast to myofibroblast differentiation is mediated by hyaluronan (HA)-facilitated epidermal growth factor receptor (EGFR) and CD44 co-localization in lipid rafts","volume":"288","author":"Midgley","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1016\/j.celrep.2014.09.027","article-title":"Cellular heterogeneity in the mouse esophagus implicates the presence of a nonquiescent epithelial stem cell population","volume":"9","author":"DeWard","year":"2014","journal-title":"Cell Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1038\/bjc.2016.93","article-title":"The role of chemerin and ChemR23 in stimulating the invasion of squamous oesophageal cancer cells","volume":"114","author":"Kumar","year":"2016","journal-title":"Br. J. Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1158\/1541-7786.MCR-13-0535","article-title":"Insidious changes in stromal matrix fuel cancer progression","volume":"12","author":"Miles","year":"2014","journal-title":"Mol. Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6633","DOI":"10.1158\/0008-5472.CAN-11-0034","article-title":"HB-EGF and PDGF mediate reciprocal interactions of carcinoma cells with cancer-associated fibroblasts to support progression of uterine cervical cancers","volume":"71","author":"Murata","year":"2011","journal-title":"Cancer Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/23\/16851\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:32:09Z","timestamp":1760131929000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/23\/16851"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,28]]},"references-count":45,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["ijms242316851"],"URL":"https:\/\/doi.org\/10.3390\/ijms242316851","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,28]]}}}