Abstract 1313: IL-17RC, but not PLK4 inhibitor centrinone, plays a critical role in the development of skin papilloma and psoriasis in mouse models

Abstract

Introduction: Hyperproliferation of epidermis is a histopathological hallmark of skin disorders, such as skin cancers and psoriasis. Polo-like kinase 4 (PLK4) is a master regulator of centriole replication and its overexpression has been identified in non-melanoma skin cancers. The aberrant proliferation of epidermal keratinocytes provoked by interleukin-17 (IL-17) leads to psoriasis. Thus, targeting centriole replication and IL-17 signaling simultaneously has been speculated as a potential therapeutic strategy. We hypothesized that inhibition of centriole duplication might enhance the blockade of epidermal proliferation through Il-17rc knockout. Methods: To investigate cooperation between IL-17 signaling and centriole duplication in the proliferation of epidermis, we used 37 mice to establish a two-stage model of skin carcinogenesis and 69 mice to establish imiquimod-induced psoriasis model in wild-type (WT), IL-17 receptor A (T779A) knock-in (Il-17ra(T779A)-KI) and IL-17 receptor C knock-out (Il-17rc-KO) C57BL/6J mouse strains. Results: During our 13-week monitor of the two-stage skin carcinogenesis model, we found that Il-17ra(T779A)-KI mice showed significantly decreased tumor incidence, tumor multiplicity, and tumor volume, compared to the wild-type mice. Il-17rc-KO mice didn’t develop any skin papilloma. The skin papilloma formed never progressed into squamous carcinoma based on our immunohistochemical (IHC) staining of laminin and cytokeratin 8. However, centrinone, a selective inhibitor of PLK4, didn’t affect skin papilloma formation or epidermal thickening. In our psoriasis model, we found that the thickness of the epidermis of Il-17rc-KO mice was dramatically decreased, compared to WT and Il-17ra(T779A)-KI mice. There was no significant difference between WT and Il-17ra(T779A)-KI mice, in terms of psoriasis formation and the thickness of the epidermis. Centrinone didn’t stall the thickening of the epidermis in the psoriasis model. IHC staining showed significantly increased Ki-67+ basal keratinocytes in the untreated skin of Il-17ra(T779A)-KI male mice, but not in female mice, compared to WT mice. In imiquimod-treated skin, the percentage of Ki-67+ basal keratinocytes significantly decreased in Il-17ra(T779A)-KI mice, compared to WT mice. The percentage of Ki-67+ basal keratinocytes was also dramatically decreased in Il-17rc-KO mice, compared to WT and Il-17ra(T779A)-KI mice. Conclusion: Our findings suggest that the proliferation of keratinocytes is not stalled by PLK4 inhibitor centrinone but is inhibited by Il-17rc-KO. Il-17ra(T779A)-KI significantly inhibits skin papilloma formation, but only slightly decreases epidermal thickening in the psoriasis model. However, in the untreated normal skin, Il-17ra(T779A)-KI increases keratinocyte proliferation based on Ki-67 staining. Citation Format: Ben Jin, Yongfeng Zhang, Haiyan D. Miller, Ling He, Zongbing You. IL-17RC, but not PLK4 inhibitor centrinone, plays a critical role in the development of skin papilloma and psoriasis in mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1313.