{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:15:42Z","timestamp":1792034142474,"version":"4.4.0"},"reference-count":37,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,2,20]],"date-time":"2020-02-20T00:00:00Z","timestamp":1582156800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Variably reduced expression of the basement membrane component laminin-332 (\u03b13a\u03b23\u03b32) causes junctional epidermolysis bullosa generalized intermediate (JEB-GI), a skin fragility disorder with an increased susceptibility to squamous cell carcinoma (SCC) development in adulthood. Laminin-332 is highly expressed in several types of epithelial tumors and is central to signaling pathways that promote SCC tumorigenesis. However, laminin-332 mutations and expression in individuals affected by JEB-GI and suffering from recurrent SCCs have been poorly characterized. We studied a JEB-GI patient who developed over a hundred primary cutaneous SCCs. Molecular analysis combined with gene expression studies in patient skin and primary keratinocytes revealed that the patient is a functional hemizygous for the p.Cys1171* mutant allele which is transcribed in a stable mRNA encoding for a \u03b23 chain shortened of the last two C-terminal amino acids (Cys1171-Lys1172). The lack of the Cys1171 residue involved in the C-terminal disulphide bond to \u03b32 chain did not prevent assembly, secretion, and proteolytic processing of the heterotrimeric molecule. Immunohistochemistry of SCC specimens revealed accumulation of mutant laminin-332 at the epithelial-stromal interface of invasive front. We conclude that the C-terminal disulphide bond is a structural element crucial for laminin-332 adhesion function in-vivo. By saving laminin-332 amount, processing, and signaling role the p.Cys1171* mutation may allow intrinsic pro-tumorigenic properties of the protein to be conveyed, thus contributing to invasiveness and recurrence of SCCs in this patient.<\/jats:p>","DOI":"10.3390\/ijms21041426","type":"journal-article","created":{"date-parts":[[2020,2,21]],"date-time":"2020-02-21T08:59:47Z","timestamp":1582275587000},"page":"1426","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Multiple Skin Squamous Cell Carcinomas in Junctional Epidermolysis Bullosa Due to Altered Laminin-332 Function"],"prefix":"10.3390","volume":"21","author":[{"given":"Paola","family":"Fortugno","sequence":"first","affiliation":[{"name":"Laboratory of Molecular and Cell Biology, IDI-IRCCS, via Monti di Creta 104, 00167 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1502-5852","authenticated-orcid":false,"given":"Angelo Giuseppe","family":"Condorelli","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, viale di San Paolo 15, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4329-3312","authenticated-orcid":false,"given":"Elena","family":"Dellambra","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cell Biology, IDI-IRCCS, via Monti di Creta 104, 00167 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliana","family":"Guerra","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cell Biology, IDI-IRCCS, via Monti di Creta 104, 00167 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Cianfarani","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cell Biology, IDI-IRCCS, via Monti di Creta 104, 00167 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lavinia","family":"Tinaburri","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cell Biology, IDI-IRCCS, via Monti di Creta 104, 00167 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittoria","family":"Proto","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cell Biology, IDI-IRCCS, via Monti di Creta 104, 00167 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"De Luca","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cell Biology, IDI-IRCCS, via Monti di Creta 104, 00167 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Passarelli","sequence":"additional","affiliation":[{"name":"Pathology Unit, IDI-IRCCS, via Monti di Creta 104, 00167 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7665-5471","authenticated-orcid":false,"given":"Francesca","family":"Ricci","sequence":"additional","affiliation":[{"name":"Pathology Unit, IDI-IRCCS, via Monti di Creta 104, 00167 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Zambruno","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, viale di San Paolo 15, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3501-6742","authenticated-orcid":false,"given":"Daniele","family":"Castiglia","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cell Biology, IDI-IRCCS, via Monti di Creta 104, 00167 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"122","DOI":"10.4161\/cam.23132","article-title":"Laminin 332 processing impacts cellular behavior","volume":"7","author":"Rousselle","year":"2013","journal-title":"Cell Adh. 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