Wang Qiushi, Roh Eunmiri, Khan Asad U, Dickinson Sally E, Wondrak Georg T, Bode Ann M, Curiel-Lewandrowski Clara, Zhang Tianshun
The Hormel Institute, University of Minnesota, Austin, Minnesota, USA.
The Hormel Institute, University of Minnesota, Austin, Minnesota, USA; Department of Cosmetic Science, Kwangju Women's University, Gwangju, Republic of Korea.
J Invest Dermatol. 2025 Aug 12. doi: 10.1016/j.jid.2025.07.021.
Nonmelanoma skin cancers are primarily caused by solar UV exposure and represent the most common cancers in the United States. PRPK (p53-related protein kinase) is a protein kinase that is involved in multiple cancers, including colon cancer, myeloma, and hepatocellular carcinoma. In this study, we generated epidermal-specific PRPK-knockout mice using CRISPR/Cas9 technology in SKH1 hairless mice with loxP-flanked PRPK alleles, crossed with keratin 14-Cre (K14.Cre) mice. Our findings reveal that epidermal-specific deletion of PRPK significantly suppresses tumor growth in solar-simulated light-induced nonmelanoma skin cancer. Knocking down PRPK significantly suppresses cutaneous squamous cell carcinoma cell growth by inducing G1 phase arrest and promoting apoptosis. Mechanistically, PRPK deletion inhibits proliferating cell nuclear antigen and PD-L1 expression as well as the expression of transcription factors c-Myc, c-Jun, NF-κB, and activator protein-1, which mediate PD-L1 expression. Using a 3-dimensional culture system, we further demonstrate that PRPK deletion suppresses cutaneous squamous cell carcinoma cell growth. Flow cytometry analysis indicates that PRPK deletion enhances CD8 T-cell infiltration. This is accompanied by significant reductions in IL-6, MIP-2, and VEGF levels, reprogramming the tumor microenvironment to support CD8 T-cell infiltration. In summary, our study demonstrates that PRPK deletion suppresses solar UV-induced photocarcinogenesis by inhibiting PD-L1 expression and enhancing CD8 T-cell infiltration, highlighting its potential as a therapeutic target for nonmelanoma skin cancer.
非黑素瘤皮肤癌主要由太阳紫外线照射引起，是美国最常见的癌症。PRPK（p53相关蛋白激酶）是一种蛋白激酶，参与多种癌症，包括结肠癌、骨髓瘤和肝细胞癌。在本研究中，我们利用CRISPR/Cas9技术，在带有侧翼loxP的PRPK等位基因的SKH1无毛小鼠中，与角蛋白14-Cre（K14.Cre）小鼠杂交，构建了表皮特异性PRPK基因敲除小鼠。我们的研究结果表明，表皮特异性缺失PRPK可显著抑制太阳模拟光诱导的非黑素瘤皮肤癌的肿瘤生长。敲低PRPK可通过诱导G1期阻滞和促进细胞凋亡显著抑制皮肤鳞状细胞癌细胞的生长。机制上，PRPK缺失抑制增殖细胞核抗原和PD-L1的表达，以及介导PD-L1表达的转录因子c-Myc、c-Jun、NF-κB和激活蛋白-1的表达。使用三维培养系统，我们进一步证明PRPK缺失可抑制皮肤鳞状细胞癌细胞的生长。流式细胞术分析表明，PRPK缺失可增强CD8 T细胞浸润。这伴随着IL-6、MIP-2和VEGF水平的显著降低，重新编程肿瘤微环境以支持CD8 T细胞浸润。总之，我们的研究表明，PRPK缺失通过抑制PD-L1表达和增强CD8 T细胞浸润来抑制太阳紫外线诱导的光致癌作用，突出了其作为非黑素瘤皮肤癌治疗靶点的潜力。
