MIF antagonist (CPSI-1306) protects against UVB-induced squamous cell carcinoma.
MIF antagonist (CPSI-1306) protects against UVB-induced squamous cell carcinoma.
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DOI：
10.1158/1541-7786.mcr-14-0255-t
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发表时间：
2014-09
期刊：
影响因子：
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通讯作者：
Oberyszyn TM
中科院分区：
文献类型：
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作者：
Nagarajan P;Tober KL;Riggenbach JA;Kusewitt DF;Lehman AM;Sielecki T;Pruitt J;Satoskar AR;Oberyszyn TM
巨噬细胞移动抑制因子（MIF）是一种同源三聚体促炎细胞因子，与慢性炎症性疾病和恶性肿瘤（包括皮肤鳞状细胞癌（SCC））有关。为了确定MIF抑制是否可以减少UVB光诱导的炎症和鳞状细胞癌的发生，使用了破坏同源三聚化的小分子MIF抑制剂（CPSI-1306）。为了检查CPSI-1306对急性UVB诱导的皮肤变化的作用，在UVB暴露之前用CPSI-1306全身性处理Skh-1无毛小鼠5天。除了降低皮肤厚度和髓过氧化物酶（MPO）活性外，CPSI-1306预处理增加角质形成细胞凋亡和p53表达，降低增殖和磷酸化组蛋白变体H2 AX（γ-H2 AX），并增强环丁烷嘧啶二聚体的修复。为了检查CPSI-1306对鳞状细胞癌发生的作用，将小鼠暴露于UVB 10周，然后用CPSI-1306处理8周。CPSI-1306显著降低了非荷瘤皮肤中UVB相关p53病灶的密度，同时降低了表皮Ki 67增殖指数。除了减缓肿瘤发展的速率之外，CPSI-1306还降低了每只小鼠的平均肿瘤负荷。尽管CPSI-1306治疗的小鼠仅发展乳头状瘤，但在载体治疗的小鼠中，近三分之一的乳头状瘤进展为微侵袭性SCC。因此，MIF抑制是预防急性和慢性UVB暴露的有害皮肤效应的有希望的策略。
Macrophage migration inhibitory factor (MIF) is a homotrimeric proinflammatory cytokine implicated in chronic inflammatory diseases and malignancies, including cutaneous squamous cell carcinomas (SCC). To determine whether MIF inhibition could reduce UVB light–induced inflammation and squamous carcinogenesis, a small-molecule MIF inhibitor (CPSI-1306) was utilized that disrupts homotrimerization. To examine the effect of CPSI-1306 on acute UVB-induced skin changes, Skh-1 hairless mice were systemically treated with CPSI-1306 for 5 days before UVB exposure. In addition to decreasing skin thickness and myeloperoxidase (MPO) activity, CPSI-1306 pretreatment increased keratinocyte apoptosis and p53 expression, decreased proliferation and phosphohistone variant H2AX (γ-H2AX), and enhanced repair of cyclobutane pyrimidine dimers. To examine the effect of CPSI-1306 on squamous carcinogenesis, mice were exposed to UVB for 10 weeks, followed by CPSI-1306 treatment for 8 weeks. CPSI-1306 dramatically decreased the density of UVB-associated p53 foci in non–tumor-bearing skin while simultaneously decreasing the epidermal Ki67 proliferation index. In addition to slowing the rate of tumor development, CPSI-1306 decreased the average tumor burden per mouse. Although CPSI-1306–treated mice developed only papillomas, nearly a third of papillomas in vehicle-treated mice progressed to microinvasive SCC. Thus, MIF inhibition is a promising strategy for prevention of the deleterious cutaneous effects of acute and chronic UVB exposure.