TY - JOUR
T1 - Multiple skin squamous cell carcinomas in junctional epidermolysis bullosa due to altered laminin-332 function
AU - Fortugno, Paola
AU - Condorelli, Angelo Giuseppe
AU - Dellambra, Elena
AU - Guerra, Liliana
AU - Cianfarani, Francesca
AU - Tinaburri, Lavinia
AU - Proto, Vittoria
AU - De Luca, Naomi
AU - Passarelli, Francesca
AU - Ricci, Francesca
AU - Zambruno, Giovanna
AU - Castiglia, Daniele
N1 - Funding Information:
hematoxylin served for staining and counterstaining, respectively. The uninvolved skin within each DAKOsection provided the positive control. Corporation, Carpinteria, CA, USA) and hematoxylin served for staining and counterstaining, respectively. The uninvolved skin within each section provided the positive control. 5. Conclusions 5. Conclusions The present study identified a naturally occurring LM332 mutation in a JEB-GI individual who has developed, in his adult life, over a hundred primary cutaneous SCCs. Our findings demonstrate that the mutation affects a structural determinant of LM332 stability (the C-terminal disulphide bridge) previously unrecognized in JEB pathology. Due to the intrinsic pro-tumorigenic proprieties of LM332, a subset of JEB patient with qualitative, rather than quantitative, LM332 defects may have a much higher risk than described in JEB (median of two SCC/patient) to develop multiple and higherrecurrent riskcuthantaneous SCCs redescribed inquJEBiring st(medianrict foloflow-twoup.SCC/patient) to develop multiple and recurrent cutaneous SCCs requiring strict follow-up. Author Contributions: Conceptualization, E.D. and D.C.; Funding acquisition, D.C.; Investigation, P.F., A.G.C., AE.uDth., oFr.CC.o, nLt.Tri.b, Vut.Pio.,n Ns:.DC.oLn.,c Fep.Pt.uaanlidz aFt.iRo.n; ,PEr.oDje.catn addmD.iCni.s; tFruatnidonin, gDa.Ccq.;u Siusiptieornv,isDio.Cn,.;DIn.Cv.e; sVtiigsautaiolinza, tPi.oFn.,,AA.G.G.C.C.., E.D., F.C., L.T., V.P., N.D.L., F.P. and F.R.; Project administration, D.C.; Supervision, D.C.; Visualization, A.G.C. and E.D.; Writing—original draft, E.D., G.Z. and D.C.; Writing—review and editing, A.G.C., E.D., L.G., G.Z. and D.C. D.C. All authors have read and agreed to the published version of the manuscript. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Funding: This research received no external funding. Acknowledgments: Authors acknowledge support from the Italian Ministry of Health (Ricerca Corrente 2018-a2n0d20f)r aonmd fDroEmBR DAEBInRtAer nInatteiornnaatli,ofnuanl,d feudndbeydD bEy BDREABRAAu Astruisatraian danDdE DBERBARAU KU.KI.D IDI-IIR-IRCCCCSSa annddB Baammbbiinnoo GGeessùù Children’s Hospital, IRCCS are healthcare providers of the European Reference Network (ERN)-Skin.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/2/2
Y1 - 2020/2/2
N2 - Variably reduced expression of the basement membrane component laminin-332 (α3aβ3γ2) 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 β3 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 γ2 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.
AB - Variably reduced expression of the basement membrane component laminin-332 (α3aβ3γ2) 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 β3 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 γ2 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.
KW - Disulphide bond
KW - Epidermal carcinogenesis
KW - Extracellular matrix
KW - LAMB3
KW - Laminin assembly
KW - Laminin coiled-coil domain
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U2 - 10.3390/ijms21041426
DO - 10.3390/ijms21041426
M3 - Article
C2 - 32093196
AN - SCOPUS:85079895368
VL - 21
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 4
M1 - 1426
ER -