Multiple skin squamous cell carcinomas in junctional epidermolysis bullosa due to altered laminin-332 function

Paola Fortugno, Angelo Giuseppe Condorelli, Elena Dellambra, Liliana Guerra, Francesca Cianfarani, Lavinia Tinaburri, Vittoria Proto, Naomi De Luca, Francesca Passarelli, Francesca Ricci, Giovanna Zambruno, Daniele Castiglia

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number1426
JournalInternational Journal of Molecular Sciences
Volume21
Issue number4
DOIs
Publication statusPublished - Feb 2 2020

Keywords

  • Disulphide bond
  • Epidermal carcinogenesis
  • Extracellular matrix
  • LAMB3
  • Laminin assembly
  • Laminin coiled-coil domain

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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