{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T18:50:39Z","timestamp":1771267839034,"version":"3.50.1"},"reference-count":50,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2020,10,21]],"date-time":"2020-10-21T00:00:00Z","timestamp":1603238400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,10,21]],"date-time":"2020-10-21T00:00:00Z","timestamp":1603238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Sveu\u010dili\u0161te u Rijeci","award":["Uniri-biomed-18-274)."],"award-info":[{"award-number":["Uniri-biomed-18-274)."]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Virchows Arch"],"published-print":{"date-parts":[[2021,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Metallothioneins (MTs) are phylogenetically old cysteine-rich proteins, which are implicated in a variety of physiological and pathological processes. Their growth-regulating, anti-apoptotic and anti-inflammatory functions have been attributed not only to intracellular free radical scavenging and to zinc and copper regulation but also to the ability of secreted MT to bind on surface lipoprotein receptor-megalin\/LRP2, which enables the endocytosis of MT-I\/II and a wide range of other functionally distinct ligands. In the present study, we analysed the expression pattern of both proteins in 55 cases of premalignant transformation of cervical squamous cells, i.e. in low- and high-grade squamous intraepithelial lesion (LSIL and HSIL). The data showed that in LSIL (cervical intraepithelial neoplasia CIN1; <jats:italic>N<\/jats:italic>\u2009=\u200925) MTs were present only in basal and parabasal cells and that megalin was only weakly expressed. In HSIL (CIN2; <jats:italic>N<\/jats:italic>\u2009=\u200915 and CIN 3\/carcinoma in situ; <jats:italic>N<\/jats:italic>\u2009=\u200915), however, overexpression and co-localization of MT with megalin were found in the entire hyperplastic epithelium. Moreover, megalin immunoreactivity appeared on the glandular epithelium and vascular endothelium, as well as on lymphatic cells in stroma. Besides, multiple megalin-positive cells expressed phosphorylated Akt1, implying that MT- and\/or megalin-dependent prosurvival signal transduction pathways might contribute to the development of severe cervical dysplasia. The data emphasize the diagnostic power of combined MT\/megalin analysis in pre-cancer screening.<\/jats:p>","DOI":"10.1007\/s00428-020-02947-w","type":"journal-article","created":{"date-parts":[[2020,10,21]],"date-time":"2020-10-21T04:05:47Z","timestamp":1603253147000},"page":"735-746","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Expression profiles of metallothionein-I\/II and megalin\/LRP-2 in uterine cervical squamous lesions"],"prefix":"10.1007","volume":"478","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8174-5124","authenticated-orcid":false,"given":"Hrvoje","family":"Jakovac","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikola","family":"Sta\u0161i\u0107","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maja","family":"Kra\u0161evi\u0107","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2995-0766","authenticated-orcid":false,"given":"Nives","family":"Jonji\u0107","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3331-9320","authenticated-orcid":false,"given":"Biserka","family":"Rado\u0161evi\u0107-Sta\u0161i\u0107","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,10,21]]},"reference":[{"key":"2947_CR1","doi-asserted-by":"publisher","first-page":"435","DOI":"10.3390\/biom4020435","volume":"4","author":"G Isani","year":"2014","unstructured":"Isani G, Carpene E (2014) Metallothioneins, unconventional proteins from unconventional animals: a long journey from nematodes to mammals. Biomolecules 4:435\u2013457. https:\/\/doi.org\/10.3390\/biom4020435","journal-title":"Biomolecules"},{"key":"2947_CR2","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1007\/s00018-002-8454-2","volume":"59","author":"P Coyle","year":"2002","unstructured":"Coyle P, Philcox JC, Carey LC, Rofe AM (2002) Metallothionein: the multipurpose protein. Cell Mol Life Sci 59:627\u2013647. https:\/\/doi.org\/10.1007\/s00018-002-8454-2","journal-title":"Cell Mol Life Sci"},{"key":"2947_CR3","doi-asserted-by":"publisher","first-page":"4813","DOI":"10.1021\/ja01574a064","volume":"79","author":"M Margoshes","year":"1957","unstructured":"Margoshes M, Vallee B (1957) A cadmium protein from equine kidney cortex. J Am Chem Soc 79:4813\u20134814. https:\/\/doi.org\/10.1021\/ja01574a064","journal-title":"J Am Chem Soc"},{"key":"2947_CR4","doi-asserted-by":"publisher","first-page":"1079","DOI":"10.1007\/s00775-011-0800-0","volume":"16","author":"W Maret","year":"2011","unstructured":"Maret W (2011) Redox biochemistry of mammalian metallothioneins. J Biol Inorg Chem 16:1079\u20131086. https:\/\/doi.org\/10.1007\/s00775-011-0800-0","journal-title":"J Biol Inorg Chem"},{"key":"2947_CR5","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1096\/fj.00-0641fje","volume":"15","author":"K Zangger","year":"2001","unstructured":"Zangger K, Oz G, Haslinger E, Kunert O, Armitage I (2001) Nitric oxide selectively releases metals from the amino-terminal domain of metallothioneins: potential role at inflammatory sites. FASEB J 15:1303\u20131305. https:\/\/doi.org\/10.1096\/fj.00-0641fje","journal-title":"FASEB J"},{"key":"2947_CR6","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1385\/MN:23:1:53","volume":"23","author":"Y Li","year":"2001","unstructured":"Li Y, Cam J, Bu G (2001) Low-density lipoprotein receptor family: endocytosis and signal transduction. Mol Neurobiol 23:53\u201367. https:\/\/doi.org\/10.1385\/MN:23:1:53","journal-title":"Mol Neurobiol"},{"key":"2947_CR7","doi-asserted-by":"publisher","first-page":"269","DOI":"10.3389\/fphys.2012.00269","volume":"3","author":"C Spuch","year":"2012","unstructured":"Spuch C, Ortolano S, Navarro C (2012) LRP-1 and LRP-2 receptors function in the membrane neuron. Trafficking mechanisms and proteolytic processing in Alzheimer\u2019s disease. Front Physiol 3:269. https:\/\/doi.org\/10.3389\/fphys.2012.00269","journal-title":"Front Physiol"},{"key":"2947_CR8","doi-asserted-by":"publisher","first-page":"15349","DOI":"10.1074\/jbc.M708446200","volume":"283","author":"RS Chung","year":"2008","unstructured":"Chung RS, Penkowa M, Dittmann J, King CE, Bartlett C, Asmussen JW, Hidalgo J, Carrasco J, Leung YKJ, Walker AK, Fung SJ, Dunlop SA, Fitzgerald M, Beazley LD, Chuah MI, Vickers JC, West AK (2008) Redefining the role of metallothionein within the injured brain: extracellular metallothioneins play an important role in the astrocyte-neuron response to injury. J Biol Chem 283:15349\u201315358. https:\/\/doi.org\/10.1074\/jbc.M708446200","journal-title":"J Biol Chem"},{"key":"2947_CR9","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1111\/j.1471-4159.2007.05036.x","volume":"104","author":"M Ambj\u00f8rn","year":"2008","unstructured":"Ambj\u00f8rn M, Asmussen JW, Lindstam M, Gotfryd K, Jacobsen C, Kiselyov VV, Moestrup SK, Penkowa M, Bock E, Berezin V (2008) Metallothionein and a peptide modeled after metallothionein, EmtinB, induce neuronal differentiation and survival through binding to receptors of the low-density lipoprotein receptor family. J Neurochem 104:21\u201337. https:\/\/doi.org\/10.1111\/j.1471-4159.2007.05036.x","journal-title":"J Neurochem"},{"key":"2947_CR10","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1007\/s00775-011-0817-4","volume":"16","author":"AK West","year":"2011","unstructured":"West AK, Leung JYK, Chung RS (2011) Neuroprotection and regeneration by extracellular metallothionein via lipoprotein-receptor-related proteins. JBIC J Biol Inorg Chem 16:1115\u20131122. https:\/\/doi.org\/10.1007\/s00775-011-0817-4","journal-title":"JBIC J Biol Inorg Chem"},{"key":"2947_CR11","doi-asserted-by":"publisher","first-page":"2926","DOI":"10.1002\/jnr.22118","volume":"87","author":"JW Asmussen","year":"2009","unstructured":"Asmussen JW, Von Sperling ML, Penkowa M (2009) Intraneuronal signaling pathways of metallothionein. J Neurosci Res 87:2926\u20132936. https:\/\/doi.org\/10.1002\/jnr.22118","journal-title":"J Neurosci Res"},{"key":"2947_CR12","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1007\/s00018-011-0790-7","volume":"69","author":"JYK Leung","year":"2012","unstructured":"Leung JYK, Bennett WR, Herbert RP, West AK, Lee PR, Wake H, Fields RD, Chuah MI, Chung RS (2012) Metallothionein promotes regenerative axonal sprouting of dorsal root ganglion neurons after physical axotomy. Cell Mol Life Sci 69:809\u2013817. https:\/\/doi.org\/10.1007\/s00018-011-0790-7","journal-title":"Cell Mol Life Sci"},{"key":"2947_CR13","doi-asserted-by":"publisher","first-page":"1092","DOI":"10.1074\/jbc.M115.668996","volume":"291","author":"LM Landowski","year":"2016","unstructured":"Landowski LM, Pavez M, Brown LS, Gasperini R, Taylor BV, West AK, Foa L (2016) Low-density lipoprotein receptor-related proteins in a novel mechanism of axon guidance and peripheral nerve regeneration. J Biol Chem 291:1092\u20131102. https:\/\/doi.org\/10.1074\/jbc.M115.668996","journal-title":"J Biol Chem"},{"key":"2947_CR14","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.neuroscience.2018.07.009","volume":"388","author":"H Jakovac","year":"2018","unstructured":"Jakovac H, Grubi\u0107 Kezele T, Rado\u0161evi\u0107-Sta\u0161i\u0107 B (2018) Expression profiles of metallothionein I\/II and megalin in cuprizone model of de-and remyelination. Neuroscience 388:69\u201386. https:\/\/doi.org\/10.1016\/j.neuroscience.2018.07.009","journal-title":"Neuroscience"},{"key":"2947_CR15","doi-asserted-by":"publisher","first-page":"e85346","DOI":"10.1371\/journal.pone.0085346","volume":"9","author":"J Gumulec","year":"2014","unstructured":"Gumulec J, Raudenska M, Adam V, Kizek R, Masarik M (2014) Metallothionein - immunohistochemical cancer biomarker: a meta-analysis. PLoS One 9:e85346. https:\/\/doi.org\/10.1371\/journal.pone.0085346","journal-title":"PLoS One"},{"key":"2947_CR16","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1111\/j.1365-2559.2004.01922.x","volume":"45","author":"SE Theocharis","year":"2004","unstructured":"Theocharis SE, Margeli AP, Klijanienko JT, Kouraklis GP (2004) Metallothionein expression in human neoplasia. Histopathol 45:103\u2013118. https:\/\/doi.org\/10.1111\/j.1365-2559.2004.01922.x","journal-title":"Histopathol"},{"key":"2947_CR17","doi-asserted-by":"publisher","first-page":"360","DOI":"10.2174\/138920309788922243","volume":"10","author":"T Eckschlager","year":"2009","unstructured":"Eckschlager T, Adam V, Hrabeta J, Figova K, Kizek R (2009) Metallothioneins and cancer. Curr Protein Pept Sci 10:360\u2013375. https:\/\/doi.org\/10.2174\/138920309788922243","journal-title":"Curr Protein Pept Sci"},{"key":"2947_CR18","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.proghi.2008.10.001","volume":"44","author":"MO Pedersen","year":"2009","unstructured":"Pedersen MO, Larsen A, Stoltenberg M, Penkowa M (2009) The role of metallothionein in oncogenesis and cancer prognosis. Prog Histochem Cytochem 44:29\u201364. https:\/\/doi.org\/10.1016\/j.proghi.2008.10.001","journal-title":"Prog Histochem Cytochem"},{"key":"2947_CR19","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1111\/pcmr.12352","volume":"28","author":"R Andersen","year":"2015","unstructured":"Andersen R, Hammer K, Hager H, Christensen J, Ludvigsen M, Honor\u00e9 B, Thomsen M, Madsen M (2015) Melanoma tumors frequently acquire LRP2\/megalin expression, which modulates melanoma cell proliferation and survival rates. Pigment Cell Melanoma Res 28:267\u2013280. https:\/\/doi.org\/10.1111\/pcmr.12352","journal-title":"Pigment Cell Melanoma Res"},{"key":"2947_CR20","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1515\/bmc-2012-0049","volume":"4","author":"S Atrian","year":"2013","unstructured":"Atrian S, Capdevila M (2013) Metallothionein-protein interactions. BioMol Concepts 4:143\u2013160. https:\/\/doi.org\/10.1515\/bmc-2012-0049","journal-title":"BioMol Concepts"},{"key":"2947_CR21","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/j.mrfmmm.2003.07.013","volume":"533","author":"MG Cherian","year":"2003","unstructured":"Cherian MG, Jayasurya A, Bay BH (2003) Metallothioneins in human tumors and potential roles in carcinogenesis. Mutat Res 533:201\u2013209. https:\/\/doi.org\/10.1016\/j.mrfmmm.2003.07.013","journal-title":"Mutat Res"},{"key":"2947_CR22","doi-asserted-by":"publisher","first-page":"1571","DOI":"10.1002\/jcb.21381","volume":"102","author":"EA Ostrakhovitch","year":"2007","unstructured":"Ostrakhovitch EA, Olsson PE, von Hofsten J, Cherian MG (2007) P53 mediated regulation of metallothionein transcription in breast cancer cells. J Cell Biochem 102:1571\u20131583. https:\/\/doi.org\/10.1002\/jcb.21381","journal-title":"J Cell Biochem"},{"key":"2947_CR23","doi-asserted-by":"publisher","first-page":"314","DOI":"10.3109\/10428190903518329","volume":"51","author":"M Pedersen","year":"2010","unstructured":"Pedersen M, Hansen P, Nielsen S, Penkowa M (2010) Metallothionein-I + II and receptor megalin are altered in relation to oxidative stress in cerebral lymphomas. Leuk Lymphoma 51:314\u2013328. https:\/\/doi.org\/10.3109\/10428190903518329","journal-title":"Leuk Lymphoma"},{"key":"2947_CR24","first-page":"855","volume":"6","author":"JA Raleigh","year":"2000","unstructured":"Raleigh JA, Chou SC, Calkins-Adams DP, Ballenger CA, Novotny DB, Varia MA (2000) A clinical study of hypoxia and metallothionein protein expression in squamous cell carcinomas. Clin Cancer Res 6:855\u2013862","journal-title":"Clin Cancer Res"},{"key":"2947_CR25","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1111\/aji.12120","volume":"70","author":"M Walentowicz-Sadlecka","year":"2013","unstructured":"Walentowicz-Sadlecka M, Koper A, Krystyna G, Koper K, Basta P, Mach P, Skret-Magierlo J, Dutsch-Wicherek M, Sikora J, Grabiec M, Kazmierczak W, Wicherek L (2013) The analysis of metallothionein immunoreactivity in stromal fibroblasts and macrophages in cases of uterine cervical carcinoma with respect to both the local and distant spread of the disease. Am J Reprod Immunol 70:253\u2013261. https:\/\/doi.org\/10.1111\/aji.12120","journal-title":"Am J Reprod Immunol"},{"key":"2947_CR26","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1097\/00004347-199801000-00006","volume":"17","author":"WG McCluggage","year":"1998","unstructured":"McCluggage WG, Maxwell P, Bharucha H (1998) Immunohistochemical detection of metallothionein and MIB1 in uterine cervical squamous lesions. Int J Gynecol Pathol 17:29\u201335 https:\/\/scite.ai\/reports\/10.1097\/00004347-199801000-00006","journal-title":"Int J Gynecol Pathol"},{"key":"2947_CR27","doi-asserted-by":"publisher","first-page":"69","DOI":"10.3322\/caac.20107","volume":"61","author":"A Jemal","year":"2011","unstructured":"Jemal A, Bray F, Center M, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69\u201390. https:\/\/doi.org\/10.3322\/caac.20107","journal-title":"CA Cancer J Clin"},{"key":"2947_CR28","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1385\/BTER:114:1:249","volume":"114","author":"H Jakovac","year":"2006","unstructured":"Jakovac H, Grebic D, Mrakovcic-Sutic I, Tota M, Broznic D, Marinic J, Tomac J, Milin C, Radosevic-Stasic B (2006) Metallothionein expression and tissue metal kinetics after partial hepatectomy in mice. Biol Trace Elem Res 114:249\u2013268. https:\/\/doi.org\/10.1385\/BTER:114:1:249","journal-title":"Biol Trace Elem Res"},{"key":"2947_CR29","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.jasi.2015.05.001","volume":"64","author":"P Jawanjal","year":"2015","unstructured":"Jawanjal P, Salhan S, Dhawan I, Rath G (2015) Comparative analysis of p53 and p21 proteins in normal cervix and HPV associated precancerous and cancerous lesions of cervix. J Anat Soc India 64:3\u201311. https:\/\/doi.org\/10.1016\/j.jasi.2015.05.001","journal-title":"J Anat Soc India"},{"key":"2947_CR30","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1016\/j.cell.2007.06.009","volume":"129","author":"B Manning","year":"2007","unstructured":"Manning B, Cantley L (2007) AKT\/PKB signaling: navigating downstream. Cell 129:1261\u20131274. https:\/\/doi.org\/10.1016\/j.cell.2007.06.009","journal-title":"Cell"},{"key":"2947_CR31","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1046\/j.1365-2559.1999.00579.x","volume":"34","author":"WG McCluggage","year":"1999","unstructured":"McCluggage WG, Maxwell P, Hamilton PW, Jasani B (1999) High metallothionein expression is associated with features predictive of aggressive behaviour in endometrial carcinoma. Histopathology 34:51\u201355. https:\/\/doi.org\/10.1046\/j.1365-2559.1999.00579.x","journal-title":"Histopathology"},{"key":"2947_CR32","first-page":"567","volume":"26","author":"M Dutsch-Wicherek","year":"2005","unstructured":"Dutsch-Wicherek M, Popiela TJ, Klimek M, Rudnicka-Sosin L, Wicherek L, Oudinet JP, Skladzien J, Tomaszewska R (2005) Metallothionein stroma reaction in tumor adjacent healthy tissue in head and neck squamous cell carcinoma and breast adenocarcinoma. Neuro Endocrinol Lett 26:567\u2013574","journal-title":"Neuro Endocrinol Lett"},{"key":"2947_CR33","doi-asserted-by":"publisher","first-page":"219","DOI":"10.2174\/1874609811003030219","volume":"3","author":"X Alvira-Botero","year":"2010","unstructured":"Alvira-Botero X, Carro E (2010) Clearance of amyloid-\u03b2 peptide across the choroid plexus in Alzheimer\u2019s disease. Curr Aging Sci 3:219\u2013229. https:\/\/doi.org\/10.2174\/1874609811003030219","journal-title":"Curr Aging Sci"},{"key":"2947_CR34","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1007\/s00221-007-1032-y","volume":"183","author":"M Fitzgerald","year":"2007","unstructured":"Fitzgerald M, Nairn P, Bartlett CA, Chung RS, West AK, Beazley LD (2007) Metallothionein-IIA promotes neurite growth via the megalin receptor. Exp Brain Res 183:171\u2013180. https:\/\/doi.org\/10.1007\/s00221-007-1032-y","journal-title":"Exp Brain Res"},{"key":"2947_CR35","doi-asserted-by":"publisher","first-page":"2108495","DOI":"10.1155\/2016\/2108495","volume":"2016","author":"L Auderset","year":"2016","unstructured":"Auderset L, Landowski LM, Foa L, Young KM (2016) Low density lipoprotein receptor related proteins as regulators of neural stem and progenitor cell function. Stem Cells Int 2016:2108495\u20132108416. https:\/\/doi.org\/10.1155\/2016\/2108495","journal-title":"Stem Cells Int"},{"key":"2947_CR36","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1111\/j.1365-2559.1993.tb01198.x","volume":"23","author":"B Zelger","year":"1993","unstructured":"Zelger B, Hittmair A, Schir M, \u00d6Fner C, \u00d6Fner D, Fritsch PO, B\u00f6cker W, Jasani B, Schmid KW (1993) Immunohistochemically demonstrated metallothionein expression in malignant melanoma. Histopathol 23:257\u2013264. https:\/\/doi.org\/10.1111\/j.1365-2559.1993.tb01198.x","journal-title":"Histopathol"},{"key":"2947_CR37","first-page":"27","volume":"144","author":"G Weinlich","year":"2009","unstructured":"Weinlich G (2009) Metallothionein-overexpression as a prognostic marker in melanoma. G Ital Dermatol Venereol 144:27\u201338","journal-title":"G Ital Dermatol Venereol"},{"key":"2947_CR38","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.taap.2009.03.026","volume":"238","author":"CD Klaassen","year":"2009","unstructured":"Klaassen CD, Liu J, Diwan BA (2009) Metallothionein protection of cadmium toxicity. Toxicol Appl Pharmacol 238:215\u2013220. https:\/\/doi.org\/10.1016\/j.taap.2009.03.026","journal-title":"Toxicol Appl Pharmacol"},{"key":"2947_CR39","doi-asserted-by":"publisher","first-page":"1922","DOI":"10.1242\/jcs.065912","volume":"123","author":"CR Gajera","year":"2010","unstructured":"Gajera CR, Emich H, Lioubinski O, Christ A, Beckervordersandforth-Bonk R, Yoshikawa K, Bachmann S, Christensen EI, G\u00f6tz M, Kempermann G, Peterson AS, Willnow TE, Hammes A (2010) LRP2 in ependymal cells regulates BMP signaling in the adult neurogenic niche. J Cell Sci 123:1922\u20131930. https:\/\/doi.org\/10.1242\/jcs.065912","journal-title":"J Cell Sci"},{"key":"2947_CR40","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1128\/mcb.21.4.1185-1195.2001","volume":"21","author":"Y Li","year":"2001","unstructured":"Li Y, van Kerkhof P, Marzolo MP, Strous GJ, Bu G (2001) Identification of a major cyclic AMP-dependent protein kinase A phosphorylation site within the cytoplasmic tail of the low-density lipoprotein receptor-related protein: implication for receptor-mediated endocytosis. Mol Cell Biol 21:1185\u20131195. https:\/\/doi.org\/10.1128\/mcb.21.4.1185-1195.2001","journal-title":"Mol Cell Biol"},{"key":"2947_CR41","doi-asserted-by":"publisher","first-page":"18736","DOI":"10.1074\/jbc.M201979200","volume":"277","author":"P May","year":"2002","unstructured":"May P, Reddy Y, Herz J (2002) Proteolytic processing of low density lipoprotein receptor-related protein mediates regulated release of its intracellular domain. J Biol Chem 277:18736\u201318743. https:\/\/doi.org\/10.1074\/jbc.M201979200","journal-title":"J Biol Chem"},{"key":"2947_CR42","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1002\/jnr.20774","volume":"83","author":"G Wicher","year":"2006","unstructured":"Wicher G, Larsson M, Svenningsen \u00c5F, Gyllencreutz E, Rask L, Aldskogius H (2006) Low density lipoprotein receptor-related protein-2\/megalin is expressed in oligodendrocytes in the mouse spinal cord white matter. J Neurosci Res 83:864\u2013873. https:\/\/doi.org\/10.1002\/jnr.20774","journal-title":"J Neurosci Res"},{"key":"2947_CR43","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1016\/S0092-8674(00)80675-3","volume":"2000","author":"M Brown","year":"2000","unstructured":"Brown M, Ye J, Rawson R, Goldstein J (2000) Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 2000:391\u2013398. https:\/\/doi.org\/10.1016\/S0092-8674(00)80675-3","journal-title":"Cell"},{"key":"2947_CR44","first-page":"1","volume":"4","author":"MY Lee","year":"2012","unstructured":"Lee MY, Shen MR (2012) Epithelial-mesenchymal transition in cervical carcinoma. Am J Transl Res 4:1\u201313","journal-title":"Am J Transl Res"},{"key":"2947_CR45","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1111\/his.12057","volume":"62","author":"CJR Stewart","year":"2013","unstructured":"Stewart CJR, McCluggage WG (2013) Epithelial\u2013mesenchymal transition in carcinomas of the female genital tract. Histopathol 62:31\u201343. https:\/\/doi.org\/10.1111\/his.12057","journal-title":"Histopathol"},{"key":"2947_CR46","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1152\/physiol.00022.2012","volume":"27","author":"EI Christensen","year":"2012","unstructured":"Christensen EI, Birn H, Storm T, Weyer K, Nielsen R (2012) Endocytic receptors in the renal proximal tubule. Physiology (Bethesda) 27:223\u2013236. https:\/\/doi.org\/10.1152\/physiol.00022.2012","journal-title":"Physiology (Bethesda)"},{"key":"2947_CR47","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1146\/annurev.nutr.21.1.407","volume":"21","author":"S Moestrup","year":"2001","unstructured":"Moestrup S, Verroust PJ (2001) Megalin- and cubilin-mediated endocytosis of protein-bound vitamins, lipids, and hormones in polarized epithelia. Annu Rev Nutr 21:407\u2013428. https:\/\/doi.org\/10.1146\/annurev.nutr.21.1.407","journal-title":"Annu Rev Nutr"},{"key":"2947_CR48","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1038\/s41591-018-0014-x","volume":"24","author":"M Binnewies","year":"2018","unstructured":"Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M et al (2018) Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med 24:541\u2013550. https:\/\/doi.org\/10.1038\/s41591-018-0014-x","journal-title":"Nat Med"},{"key":"2947_CR49","doi-asserted-by":"publisher","first-page":"771","DOI":"10.3389\/fimmu.2019.00771","volume":"10","author":"A Bruno","year":"2019","unstructured":"Bruno A, Mortara L, Baci D, Noonan DM, Albini A (2019) Myeloid derived suppressor cells interactions with natural killer cells and pro-angiogenic activities: roles in tumor progression. Front Immunol 10:771. https:\/\/doi.org\/10.3389\/fimmu.2019.00771","journal-title":"Front Immunol"},{"key":"2947_CR50","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1007\/s10875-009-9298-4","volume":"29","author":"E Mocchegiani","year":"2009","unstructured":"Mocchegiani E, Giacconi R, Cipriano C, Malavolta M (2009) NK and NKT cells in aging and longevity: role of zinc and metallothioneins. J Clin Immunol 29:416\u2013425. https:\/\/doi.org\/10.1007\/s10875-009-9298-4","journal-title":"J Clin Immunol"}],"container-title":["Virchows Archiv"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00428-020-02947-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00428-020-02947-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00428-020-02947-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T23:40:35Z","timestamp":1634773235000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00428-020-02947-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,21]]},"references-count":50,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021,4]]}},"alternative-id":["2947"],"URL":"https:\/\/doi.org\/10.1007\/s00428-020-02947-w","relation":{},"ISSN":["0945-6317","1432-2307"],"issn-type":[{"value":"0945-6317","type":"print"},{"value":"1432-2307","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,21]]},"assertion":[{"value":"8 July 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 September 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 October 2020","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 October 2020","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All subjects gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of Clinical Hospital Centre and Medical Faculty in Rijeka.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"The authors declare that they have no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}