The role cell signalling pathways play in tnf[alpha] release from uv-irradiated skin cells
Creators: name: Muthusamy, Visalini
Publisher: name: RMIT University
Year: 2024

description: According to the WHO, three million non-melanoma skin cancers (NMSC) occur annually with one in every three cancers diagnosed is a skin cancer. In most cases, exposure to ultraviolet (UV) light seems to be the main cause in initiating and promoting skin cancer. In order to delineate how UV induces NMSC, the underlying mechanism needs to be identified. UV radiation has been shown to activate cell signalling pathways such as p38 MAPK, JNK and NFκB in keratinocytes and melanocytes. Activation of these cell signalling pathways results in many cellular responses like the release of cytokines such as TNFα and IL1α from these cells which may be implicated in skin carcinogenesis. In this study, the effect of high (1 MED) and low dose (0.1 MED) UV radiation on cell signalling pathways and cytokine release in human keratinocyte-derived cells [HEK (primary epidermal keratinocytes), HaCaT (immortalised), Colo16 (squamous carcinoma)] and human melanocyte-derived cells [HEM (primary epidermal melanocytes) and MM96L (melanoma cells)] was observed. The results indicate that HaCaT cells do not appear to be a suitable substitute to study cell signalling pathways and cytokine release in normal keratinocytes as their UV-induced responses mirrored those of Colo16 cells (squamous carcinoma cells). Therefore, these cells (HaCaT) may be better suited as a model to study solar keratoses or precancerous lesions. The key finding in this study was that normal and malignant cells exhibited different responses to UV radiation in activating cell signalling pathways which are involved in TNFα release. Since these pathways (p38 MAPK, JNK and NFκB) were regulated differently in cancerous cells, further intervention into these pathways may provide an insight on how the malignant status of these cells is maintained. As inflammation is involved in skin carcinogenesis, the finding that p38 MAPK is involved in UV-induced TNFα release may help to treat skin cancer as specific tumour-targeted inhibitors can be designed to reduce inflammation. In contrast, the malignant cells [Colo16 and MM96L (melanoma)] in this study produced low levels of TNFα which may be necessary to suppress immunosurveillance. As such, the pathways and cytokines studied in this project may have therapeutic potential but their functional roles in malignancy still needs to be further investigated. In addition the marine lipid extracts were effective in inhibiting TNFα release from HEM cells but had no effect on suppressing p38 MAPK pathway activity. This suggests that these compounds do not act through the p38 MAPK pathway to inhibit TNFα release in UVB-irradiated HEM cells. It is most likely that other mechanisms may also be involved in this process which should be investigated further. Moreover, as scymnol and MCLE (mussel crude lipid extract) exhibited potential anti-inflammatory and antioxidant properties, they may be useful supplements to add to sunscreens. This may help reduce the detrimental effects of penetrating UV radiation in the skin by protecting the cells from oxidative and/or inflammatory stress as a result of exposure to UV radiation. Therefore, further research into antioxidants and the effects of UV radiation on skin functions need to be investigated. <br><br>