Abstract 4650: TOPK is a prognostic marker and therapeutic target in skin carcinogenesis

Abstract

Abstract Solar ultraviolet (sUV) is linked to development of cutaneous squamous cell carcinoma (cSCC) as a non-melanoma skin cancer (NMSC). Actinic keratosis (AK), induced by sUV irradiation, acts as precursor to cutaneous squamous cell carcinoma (cSCC) and is a pre-malignant skin lesion characterized with an abnormal proliferation of atypical keratinocytes confined to the epidermis of the skin. Therefore, to identify the major signaling molecules in the prevention, development and metastasis of cSCC is a critically important task. Here, we suggested a promising protein target, T-LAK cell-originated protein kinase (TOPK) as an active form of MEK1 continuously phosphorylating downstream targets, which appears to be critical in mediating skin carcinogenesis. We detected high levels of total and phosphorylated TOPK protein expression in SCC, and phosphorylated TOPK levels were also markedly higher in AKs and SCCs from patients compared to matched normal skin. Inflammation is known to contribute to tumor development and thus we examined the effect of a 2-minimal erythema dose (MED) of solar stimulated light (SSL) exposure in clinical human skin samples. Our results indicated that acute SSL irradiation increased epidermal thickness as a feature of inflammation and also enhanced total protein and phosphorylation levels of TOPK in human skin in a time-dependent manner. TOPK phosphorylation in human precancerous HaCaT keratinocytes was also increased by SSL irradiation in a dose- and time-dependent manner. Interestingly, TOPK knockout (TOPK-/-) SKH1 (Crl: SKH1-Hrhr) hairless mice showed no tumors on SSL-exposed skin tissues. In contrast, wild-type (TOPK+/+) control SKH1 hairless mice treated with SSL showed increased tumor volume and number. Furthermore, TOPK-/- mice showed base levels of epidermal thickness similar to the SSL-unexposed control group and the Ki-67 proliferation marker was decreased in SSL-exposed TOPK-/- mouse skin compared to SKH1 TOPK+/+ mice. Notably, levels of the anti-apoptotic protein Bcl-2 were decreased in TOPK-/- mice, compared to SSL-treated TOPK+/+ mice. Moreover, our results indicated that phosphorylated and total TOPK protein levels in SCC metastasized to skin or lymph nodes were significantly higher compared to human SCC primary tumors. These results indicated that phosphorylated and total TOPK proteins are associated with both SCC development and metastasis. Thus, molecular targeting of TOPK could be an effective approach in the clinic to treat or prevent cSCC. Citation Format: Eunmiri Roh. TOPK is a prognostic marker and therapeutic target in skin carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4650.