Madonna Stefania, Scarponi Claudia, Morelli Martina, Sestito Rosanna, Scognamiglio Pasqualina Liana, Marasco Daniela, Albanesi Cristina
Laboratory of Experimental Immunology, IDI-IRCCS, Fondazione "Luigi M. Monti" (FLMM), Rome, Italy.
Current address: Preclinical Models and New Therapeutic Agents Unit, Regina Elena National Cancer Institute, Rome, Italy.
Oncotarget. 2017 Apr 11;8(15):24652-24667. doi: 10.18632/oncotarget.15629.
Basal cell carcinomas (BCC) and squamous-cell carcinomas (SCC) are common malignancies in humans, caused by neoplastic transformation of keratinocytes of the basal or suprabasal layers of epidermis, respectively. Tumor-infiltrating lymphocytes (TILs) are frequently found in BCC and SCC, and functionally promote epithelial carcinogenesis. TILs secreting IL-22, in particular, participate to BCC and SCC growth by inducing keratinocyte proliferation and migration, as well as the expression of inflammatory, anti-apoptotic and pro-angiogenic genes.In this study, we identified SOCS3 as a valid candidate to be manipulated for suppressing tumorigenic functions in BCC and SCC. We found that SOCS3 and SOCS1 expression was reduced in vivo, in tumor lesions of BCC and SCC, as compared to other skin inflammatory conditions such as psoriasis, despite the high number of IL-22-secreting TILs. Moreover, IL-22 was not able to induce in vitro the transcriptional expression of SOCS3 in BCC-or SCC-derived keratinocytes, contrarily to healthy cells. Aimed at rescuing SOCS3 activity in these tumor contexts, a SOCS3-derived peptide, named KIR-ESS, was synthesized, and its ability in suppressing IL-22-induced responses was evaluated in healthy and transformed keratinocytes. We found that KIR-ESS peptide efficiently suppressed the IL-22 molecular signaling in keratinocytes, by acting on STAT3 and Erk1/2 cascade, as well as on the expression of STAT3-dependent downstream genes. Interestingly, after treatment with peptide, both healthy and transformed keratinocytes could no longer aberrantly proliferate and migrate in response to IL-22. Finally, treatment of athymic nude mice bearing SCC xenografts with KIR-ESS peptide concomitantly reduced tumor growth and activated STAT3 levels. As a whole, these data provides the rationale for the use in BCC and SCC skin tumors of SOCS3 mimetics, being able to inhibit the deleterious effects of IL-22 in these contexts.
基底细胞癌（BCC）和鳞状细胞癌（SCC）是人类常见的恶性肿瘤，分别由表皮基底层或基底层上方角质形成细胞的肿瘤转化引起。肿瘤浸润淋巴细胞（TILs）在BCC和SCC中经常被发现，并在功能上促进上皮细胞癌变。特别是分泌IL-22的TILs，通过诱导角质形成细胞增殖和迁移以及炎症、抗凋亡和促血管生成基因的表达，参与BCC和SCC的生长。在本研究中，我们确定SOCS3是一个可用于抑制BCC和SCC致瘤功能的有效候选靶点。我们发现，与银屑病等其他皮肤炎症性疾病相比，尽管分泌IL-22的TILs数量很多，但在BCC和SCC的肿瘤病变中，SOCS3和SOCS1的表达在体内降低。此外，与健康细胞相反，IL-22在体外不能诱导BCC或SCC来源的角质形成细胞中SOCS3的转录表达。为了在这些肿瘤环境中挽救SOCS3的活性，合成了一种名为KIR-ESS的SOCS3衍生肽，并在健康和转化的角质形成细胞中评估了其抑制IL-22诱导反应的能力。我们发现，KIR-ESS肽通过作用于STAT3和Erk1/2级联以及STAT3依赖性下游基因的表达，有效抑制了角质形成细胞中的IL-22分子信号传导。有趣的是，用该肽处理后，健康和转化的角质形成细胞都不再对IL-22产生异常增殖和迁移反应。最后，用KIR-ESS肽治疗携带SCC异种移植物的无胸腺裸鼠，同时降低了肿瘤生长并激活了STAT3水平。总体而言，这些数据为在BCC和SCC皮肤肿瘤中使用SOCS3模拟物提供了理论依据，因为它们能够在这些情况下抑制IL-22的有害作用。
