Environmental UV exposure is a major cause of skin cancers, such as melanoma, which account for about half of all cancers in the United States. Solar UV radiation (UVR) induces DNA damage in skin cells, initiating carcinogenesis as well as other pathological processes. DNA damage response (DDR) is frequently observed in precancerous lesions and is considered a critical barrier during tumorigenesis. Expression of NK cell activating receptor NKG2D ligands (NKG2DLs) plays a critical role in anti-tumor immunosurveillance, which can be induced by genotoxic stimuli, such as UVR. A critical barrier to progress in preventing melanoma is a lack of understanding of how UVR induces NKG2DLs and how melanoma cells eventually escape this innate immune surveillance by dampening cell surface presence of NKG2DLs, resulting in cancer progression and metastasis. Our goal is to reduce the incidence and inhibit progression of skin cancers induced by UVR via antagonizing immune evasion and reinforcing anti-cancer immunity. Our central hypothesis is that UVR induces upregulation of NKG2DL expression in melanocytes by activating NF-?B and IRF3, which forms a transactivating complex on NKG2DL gene promoter region to drive transcription. Meanwhile, BRAF genetic mutation in melanoma cells drives immunoevasion by promoting oncogenic miRNA induction. Our objectives include: 1) determining the potential mechanisms controlling NKG2DL expression in melanocytes upon UVR, 2) defining the roles of UVB- activated transcription factors NF-?B /IRF3 in modulating NKG2DL transcription, and 3) determining the mechanisms by which BRAF mutant drives miRNA upregulation in melanoma cells and oncogenic miRNA- mediated immunoevasion mechanisms.
Three specific aims are proposed.
Aim 1 tests the hypothesis that UVB induces TBK1 activation in melanoma cells through binding of secreted HMGB1 to the RAGE receptor, which leads to activation of IRF3 and NF-?B.
Aim 2 tests the hypothesis that UVB activated IRF3 is indirectly recruited to NKG2DL gene promoters, thereby promoting NKG2DL transactivation upon UVR.
Aim 3 tests the hypothesis that increased onco-miRs in melanoma cells due to BRAF mutation suppresses NKG2DL induction upon UVR, and inhibiting B-Raf activity may sensitize melanoma cells to anti-tumor immunity by enhancing NKG2DL induction. Our expected outcomes include: 1) providing mechanistic insights into how the environmental genotoxic stressor UVR drives transactivation of NKG2DL genes; 2) identifying potential drug targets for enhancing NKG2DL expression in skin cells and mitigating immunoevasion, which render those precancerous cells susceptible to anti-cancer immunity; and 3) new understanding of UVR-induced NKG2DL transcription in primary melanocytes and melanoma cells as well as immune escape mechanisms in malignant cells. Our studies will have impact on: 1) understanding of how cancer cells elicit and evade immune surveillance; 2) understanding of the mechanisms by which UVR modulates expression of NKG2DLs; and 3) insights into strategies for preventing skin tumorigenesis and progression by enhancing immune surveillance.
Cellular stress response to solar UV radiation in skin cells plays a critical role in preventing initiation of skin cancers such as melanoma. Damaged skin cells at precancerous stage can express ?danger? marker such as NKG2D ligands on the cell surface which will be recognized by anti-tumor immunity, leading to their clearance. In this study, we aim to understand how the NKG2D ligands expression is regulated in skin cells exposed to environmental UV radiation and their roles in skin immune response upon UVR, which will help to develop strategies promoting tumor immune surveillance and preventing skin cancer initiation.
