298 Defective DNA Repair and Chromosomal Instability in RDEB
Recessive Dystrophic Epidermolysis Bullosa (RDEB), caused by mutations in COL7A1 leading to a reduction or loss of type VII collagen (Col7), is a severe blistering disease associated with an increased risk of developing aggressive squamous cell carcinoma. Using RNASeq global transcriptomics we identified dysregulation of genes involved in cell cycle control, DNA damage response and chromosomal instability (CIN) with loss of keratinocyte Col7. To investigate the role of Col7 in DNA damage and CIN, keratinocytes with Col7 and Col17 (type XVII collagen) knockdown were treated with UV or mitomycin-C to induce DNA damage.
Dystrophic epidermolysis bullosa (DEB) is a hereditary skin fragility disorder, characterized by trauma-induced blistering followed by soft tissue fibrosis. One of the most feared complications is the early de...
PMID: 31486079 [PubMed - as supplied by publisher]
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare skin fragility disorder characterized by deficient dermo-epidermal adhesion, due to mutations in the gene encoding collagen VII. Patients with RDEB suffer chronic wounds and inflammation that ultimately trigger fibrosis and highly aggressive squamous cell carcinoma development. We previously reported a clinical case of two siblings carrying in homozygosis the same null mutation (c.6527insC) in the COL7A1 gene, but with marked phenotypic differences with respect to the extent of mucocutaneous involvement, skin fragility and fibrosis.
Recessive Dystrophic epidermolysis bullosa (RDEB) is a skin genetic disease caused by mutations in COL7A1 (coding type VII collagen). Type VII collagen is essential to maintain the fully functional dermal-epidermal junction, and the loss of type VII collagen results in detachment of epidermis. RDEB patients, without functional type VII collagen, suffer from the repetitive blistering and have high risk of early-onset aggressive squamous cell carcinoma. Currently, no fundamental treatment is available for RDEB.
The most lethal complication of recessive dystrophic epidermolysis bullosa (RDEB) is the development of aggressive cutaneous squamous cell carcinoma (cSCCs), which lead the high mortality rates in these patients. Elevated levels of phospho-STAT3 have been found in two RDEB-derived cSCC cell lines, demonstrating that constitutive activation and dysregulation of the JAK/STAT pathway may play a role in RDEB-cSCC pathogenesis. Ruxolitininb is an FDA approved JAK1/2 inhibitor that has efficacy in myelofibroblast, human head, and neck squamous cell carcinomas, as well as lung and breast carcinomas.
Abstract Some bone lesions are reported to mimic bone metastasis on imaging tests. Herein, we report a case of a 55-year-old Japanese man who presented with a skin tumor on the left lower extremity. He also had a history of recurrent generalized cutaneous blister and erosion formation since childhood. His skin lesions were diagnosed as cutaneous squamous cell carcinoma complicated by recessive dystrophic epidermolysis bullosa. Magnetic resonance imaging of the left lower extremity detected multiple focal bone lesions mimicking bone metastases in the left femur and tibia. However, bone biopsy revealed that the bone...
CONCLUSIONS: These results provide evidence for the role of tumor cell-derived C1r and C1s in the progression of cSCC and identify them as biomarkers and putative therapeutic targets in cSCC. This article is protected by copyright. All rights reserved. PMID: 31049937 [PubMed - as supplied by publisher]
Squamous cell carcinoma (SCC) develops in more than 80% of individuals with the skin blistering disorder recessive dystrophic epidermolysis bullosa (RDEB). In contrast with UV-induced SCC, RDEB SCC has a high proliferative and metastatic rate, with five-year survival near zero. RDEB dermal fibroblasts were found with higher expression of the myofibroblast markers α-smooth muscle actin (6/8 pairs), Fibronectin (7/8 pairs), and periostin (7/8 pairs) compared to matched donors. RDEB fibroblasts were also found to have higher expression of MCP-1 (3/4 pairs) and TGFβ1 (3/4 pairs), indicative of increased TGFβ1 secretion.
Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a devastating skin blistering disease for which there is still no available cure. Although RDEB is characterized by blisters caused by minimal trauma, non-healing wounds, recurrent infections, pseudosyndactyly, squamous cell carcinoma and others, one of the most challenging symptoms to treat in these patients is fibrosis. Healing takes place with an obvious scarring phenotype and RDEB can be viewed as a fibrotic disorder characterized by excessive ECM deposition, accumulation of collagen fibers, increase tissue stiffness and TGF β signaling.
Dystrophic epidermolysis bullosa (DEB) is a one of the most severe form of EB caused by mutations in COL7A1 (coding type VII collagen). DEB patients, without functional type VII collagen, suffer from the repetitive blistering and have high risk of early-onset aggressive squamous cell carcinoma. Recently, we found that a fragment of HMGB1 activates an endogenous tissue regeneration mechanism and ameliorates the DEB related manifestations in a DEB model mouse. This HMGB1 treatment model in the DEB mouse serves as a unique opportunity to investigate on how the skin can lose the integrity by loss of a single protein and how th...