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Cancer and Immunology
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Cancer and Immunology
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Biomedical Science
Abstract
Background: The fine balance of the inverse relationship between keratinocyte proliferation and differentiation is critical in maintaining epidermal homeostasis. The disruption of this balance is one of the characteristic features of skin cancer. Exposure to ultraviolet B (UVB) radiation disrupts signaling pathways involved in the maintenance of epidermal cell homeostasis, resulting in hyperplasia and skin cancer formation. One implicated signaling pathway involved in epidermal homeostasis is tyrosine phosphorylation signaling. T-cell protein tyrosine phosphatase (TC-PTP) is a tyrosine-specific intracellular non-receptor PTP and is ubiquitously expressed in embryonic and adult tissues including skin. Our previous studies showed that TC-PTP has been shown to increase UVB-induced apoptosis and inhibit cell proliferation in keratinocytes via the downregulation of signaling pathways including Flk-1/JNK and STAT3, suggesting its tumor suppressive function in skin. Cell proliferation is inversely correlated with differentiation. It implies that TC-PTP-modulated signaling may have additional protective effects by regulating epidermal differentiation, which can contribute to suppress cell proliferation. In the present work, we investigate whether TC-PTP has a role in the regulation of epidermal differentiation in response to UVB radiation.
Methods: Immortalized primary keratinocytes (IPKs) derived from either wild-type FVB mice (TC-PTP/WT) or transgenic mice (TC-PTP/OVER) that specifically overexpress TC-PTP in the epidermis were used to investigate the role of TC-PTP on UVB-induced keratinocyte differentiation. TC-PTP/WT and TC-PTP/OVER IPKs were cultured and exposed to UVB irradiation (10 mJ/cm^2). Both IPKs were collected 12, 24, 48, and 72 hours after UVB for western blot analysis to measure the expression levels of differentiation markers, including involucrin, cytokeratin 1 (CK1) and transglutaminase 1 (TG-1). Groups of TC-PTP/WT and TC- PTP/OVER mice were irradiated with a single dose of UVB (100 mJ/cm^2) to investigate the role of TC-PTP on UVB-induced epidermal differentiation. The dorsal skin of mouse was collected 24, 48, and 72 hours after UVB and fixed in 10% neutral-buffered formalin to create paraffin-embedded block of tissue. Immunofluorescent analysis was performed to investigate the expression levels of differentiation markers, including involucrin, loricrin, and CK10.
Results: Our findings indicate that the expression levels of differentiation markers were significantly increased in TC-PTP-overexpressing keratinocytes at all examined time points compared to the paired wild-type keratinocytes. Similar to this observation, the expression levels of differentiation markers were significantly higher in the epidermis of TC-PTP- overexpressing mice compared to wild-type mice, whereas the expression level of cell proliferation marker proliferating cell nuclear antigen (PCNA) was significantly lower in the epidermis of TC-PTP-overexpressing mice compared to wild-type mice. This suggests that TC- PTP overexpression enhances the differentiation response of keratinocytes to UVB radiation, which can contribute to reduce epidermal hyperplasia and cancer formation in skin.
Conclusion: These results provide new insights into the molecular mechanisms of skin differentiation and emphasize the potential regulatory role of TC-PTP in the skin's response to UVB exposure. Understanding these mechanisms could contribute to the development of therapeutic strategies for skin disorders and protection against UVB-induced damage.
Presentation Type
Poster
Recommended Citation
Marupudi, Smaran; Hensley, Jared; Shim, Lindsey; B. Hafeez, Bilal B.; and Joon Kim, Dae, "TC-PTP-mediated epidermal differentiation protects skin from ultraviolet B radiation" (2024). Research Colloquium. 70.
https://scholarworks.utrgv.edu/colloquium/2024/posters/70
Included in
TC-PTP-mediated epidermal differentiation protects skin from ultraviolet B radiation
Background: The fine balance of the inverse relationship between keratinocyte proliferation and differentiation is critical in maintaining epidermal homeostasis. The disruption of this balance is one of the characteristic features of skin cancer. Exposure to ultraviolet B (UVB) radiation disrupts signaling pathways involved in the maintenance of epidermal cell homeostasis, resulting in hyperplasia and skin cancer formation. One implicated signaling pathway involved in epidermal homeostasis is tyrosine phosphorylation signaling. T-cell protein tyrosine phosphatase (TC-PTP) is a tyrosine-specific intracellular non-receptor PTP and is ubiquitously expressed in embryonic and adult tissues including skin. Our previous studies showed that TC-PTP has been shown to increase UVB-induced apoptosis and inhibit cell proliferation in keratinocytes via the downregulation of signaling pathways including Flk-1/JNK and STAT3, suggesting its tumor suppressive function in skin. Cell proliferation is inversely correlated with differentiation. It implies that TC-PTP-modulated signaling may have additional protective effects by regulating epidermal differentiation, which can contribute to suppress cell proliferation. In the present work, we investigate whether TC-PTP has a role in the regulation of epidermal differentiation in response to UVB radiation.
Methods: Immortalized primary keratinocytes (IPKs) derived from either wild-type FVB mice (TC-PTP/WT) or transgenic mice (TC-PTP/OVER) that specifically overexpress TC-PTP in the epidermis were used to investigate the role of TC-PTP on UVB-induced keratinocyte differentiation. TC-PTP/WT and TC-PTP/OVER IPKs were cultured and exposed to UVB irradiation (10 mJ/cm^2). Both IPKs were collected 12, 24, 48, and 72 hours after UVB for western blot analysis to measure the expression levels of differentiation markers, including involucrin, cytokeratin 1 (CK1) and transglutaminase 1 (TG-1). Groups of TC-PTP/WT and TC- PTP/OVER mice were irradiated with a single dose of UVB (100 mJ/cm^2) to investigate the role of TC-PTP on UVB-induced epidermal differentiation. The dorsal skin of mouse was collected 24, 48, and 72 hours after UVB and fixed in 10% neutral-buffered formalin to create paraffin-embedded block of tissue. Immunofluorescent analysis was performed to investigate the expression levels of differentiation markers, including involucrin, loricrin, and CK10.
Results: Our findings indicate that the expression levels of differentiation markers were significantly increased in TC-PTP-overexpressing keratinocytes at all examined time points compared to the paired wild-type keratinocytes. Similar to this observation, the expression levels of differentiation markers were significantly higher in the epidermis of TC-PTP- overexpressing mice compared to wild-type mice, whereas the expression level of cell proliferation marker proliferating cell nuclear antigen (PCNA) was significantly lower in the epidermis of TC-PTP-overexpressing mice compared to wild-type mice. This suggests that TC- PTP overexpression enhances the differentiation response of keratinocytes to UVB radiation, which can contribute to reduce epidermal hyperplasia and cancer formation in skin.
Conclusion: These results provide new insights into the molecular mechanisms of skin differentiation and emphasize the potential regulatory role of TC-PTP in the skin's response to UVB exposure. Understanding these mechanisms could contribute to the development of therapeutic strategies for skin disorders and protection against UVB-induced damage.