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Role of XPC in the human cutaneous cancer cells invasion

Abstract : Squamous cell carcinoma (SCC) is the most frequent metastatic skin cancer. His etiology is linked to exposure to ultraviolet radiation (UVR). Xeroderma pigmentosum C (XP-C) is a genetic disorder characterized by a severe susceptibility to aggressive SCCs following minimal exposure to UVR. XP-C cells are deficient in nucleotide excision repair (NER) of UV-induced DNA lesions. XP-C dermal fibroblasts expresse a phenotype resembling that of stromal fibroblasts associated to cancer cells with accumulation of reactive oxygen species and over expression of matrix metalloproteinase 1 (MMP1). We explored the effects of XP-C fibroblasts on migration and invasion of SCC cells. In organotypic skin cultures, XP-C fibroblasts promote the invasion of SCC cells. Also, scratch healing of SCC cells is enhanced with culture supernatants of XP-C fibroblasts through a mitogenic effect connected to increased ratio of SCC cells in the G2-M phase of the cell cycle. We show that XP-C fibroblasts overexpress the hepatocyte growth factor/scatter factor (HGF/SF) and activate the c-Met receptor and the p38 and JNK pathways in SCC cells. Blockage of HGF inhibits c-Met, p38 and JNK activation and prevented invasiveness of SCC cells within dermal equivalents. Spheroid assays show that XP-C fibroblasts lead SCC invasions. Our data indicate for the first time that XP-C fibroblasts are responsible for the formation of a permissive microenvironment towards SCC cells proliferation and invasion. Therapies targeting XP-C fibroblasts may be considered as a way to control aggressive cancer in XP-C patients.
Keywords : XP-C SCC HGF
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Submitted on : Tuesday, January 9, 2018 - 2:58:10 PM
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Sahar Al-Qaraghuli. Role of XPC in the human cutaneous cancer cells invasion. Human health and pathology. Université Côte d'Azur, 2017. English. ⟨NNT : 2017AZUR4037⟩. ⟨tel-01673289v2⟩

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