Expression of Laminin γ2 Proteolytic Fragments in Murine Skin Following Exposure to Sulfur Mustard

Abstract

Laminin-332 is a basement membrane protein composed of three genetically distinct polypeptide chains that actively promote both skin epidermal cell adhesion and migration. Proteolytic fragments of the laminin γ2 chain stimulate migration and scattering of keratinocytes and cancer cells. Sulfur mustard (SM) is a bifunctional alkylating agent that induces separation of basal keratinocytes from the dermal-epidermal junction and invokes a strong inflammatory response leading to delayed wound repair. In the present studies, the role of laminin γ2 in SM-induced skin injury and wound repair was investigated using the mouse ear vesicant model. We found that laminin γ2 chain mRNA was preferentially upregulated in mouse ear skin exposed to SM. In situ hybridization confirmed overexpression of laminin γ2 transcript. Western blot analysis showed increased protein expression of the full-length proform of laminin γ2 and smaller processed fragments of laminin γ2 in skin exposed to SM. Dual immunofluorescence labeling indicated that laminin γ2 fragments are prevalent in suprabasal keratinocytes behind the leading edge in areas of hyperplasia in injured skin. In addition, co-expression of laminin γ2 and the senescent marker, p16 INK4a was found to overlap with the hyperplastic migratory epithelial sheet. This observation is similar to hypermotile keratinocytes reported in invasive carcinoma cells. Overall, our studies indicate that laminin γ2 is preferentially expressed in skin post SM exposure and that protein expression appears to become progressively more fragmented. The laminin γ2 fragments may play a role in regulating SM-induced skin wound repair. Anat

Invasion-Associated Reorganization of Laminin 332 in Oral Squamous Cell Carcinomas: The Role of the Laminin γ2 Chain in Tumor Biology, Diagnosis, and Therapy

“…In humans, MT1-MMP cleavage leads to the generation of a 100 kDa fragment, γ2 , and a 85 kDa fragment, γ2x, as well as two smaller DIII fragments [104]. Comparable cleavage patterns have also been observed in mice [105]. The generation of further, functionally relevant Lng2-derived fragments during keratinocyte or carcinoma cell migration cannot be excluded.…”

Alcohol promotes epithelial mesenchymal transformation-mediated premetastatic niche formation of colorectal cancer by activating interaction between laminin-γ2 and integrin-β1

“…Reports have indicated that laminins are involved in the formation of the premetastatic niche[ 22 , 23 ]. Laminin-γ2 (LAMC2), a subunit of laminin-332, has been reported to be an important component in the survival dependent environment of epithelial cells in CRC and plays a key role in the regulation of tumor cell motility in premetastatic niche formation[ 24 - 27 ]. The interaction between LAMC2 and integrin-β1 (ITGB1) may stimulate the formation of premetastatic focal contacts by activating the premetastatic niche signaling, which promotes the migration of cancer cells[ 28 ].…”

Skin Models Used to Define Mechanisms of Action of Sulfur Mustard

“…36,37 Proteolysis of basement membrane components, including laminins, collagens, and other anchoring proteins by matrix metalloproteinases, contributes to the disruption of the basal cell layer, microvesication, and ulceration. 38,39 At later times, in minipig skin, aberrant epidermal proliferation and differentiation are associated with re-epithelialization including hyperplasia, hyperkeratosis, and parakeratosis. This is thought to contribute to prolonged wound healing.…”