Research Papers:
SOCS3 inhibits the pathological effects of IL-22 in non-melanoma skin tumor-derived keratinocytes
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Abstract
Stefania Madonna1, Claudia Scarponi1, Martina Morelli1, Rosanna Sestito1,3, Pasqualina Liana Scognamiglio2, Daniela Marasco2, Cristina Albanesi1
1Laboratory of Experimental Immunology, IDI-IRCCS, Fondazione “Luigi M. Monti” (FLMM), Rome, Italy
2Department of Pharmacy, CIRPEB, University of Naples “Federico II”, Naples, Italy
3Current address: Preclinical Models and New Therapeutic Agents Unit, Regina Elena National Cancer Institute, Rome, Italy
Correspondence to:
Stefania Madonna, email: [email protected]
Cristina Albanesi, email: [email protected].
Keywords: SOCS1, SOCS3, non-melanoma skin cancers, IL-22 signaling, healthy and transformed keratinocytes
Received: July 28, 2016 Accepted: February 15, 2017 Published: February 22, 2017
ABSTRACT
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.
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PII: 15629