Possible Roles of Proinflammatory Signaling in Keratinocytes Through Aryl Hydrocarbon Receptor Ligands for the Development of Squamous Cell Carcinoma

Abstract

Aryl hydrocarbon receptor (AhR) provides a deeper insight into the pathogenesis of cutaneous squamous cell carcinoma (cSCC). AhR ligands, such as 6-formylindolo[3,2-b] carbazole (FICZ), and 7,12-Dimethylbenz[a]anthracene (DMBA), constitute major substrates for the cytochrome P450 (CYP) family, and influence the expression of various cytokine genes, including IL-17 and IL-23 -related genes via the AhR. On the other hand, proinflammatory cytokines could drive tumor progression through the TRAF-ERK5 signaling pathway in cSCC. From the above findings, we hypothesized that AhR ligands might enhance the mRNA expression of proinflammatory cytokines via the AhR, leading to the development of cSCC. The purpose of this study was to investigate (1) the immunomodulatory effects of FICZ and DMBA on normal human keratinocytes (NHKCs), focusing on IL-17, and related cytokines/chemokines (IL-23, IL-36γ, and CCL20), (2) the expression of these factors in AhR-dependent pathways using a two-stage chemically induced skin carcinogenesis mouse model, and (3) the expression of these factors in lesion-affected skin in cSCC. Both FICZ and DMBA augmented the expression of CYP1A1, p19, CCL20, and IL-36γ mRNA in NHKCs in vitro . Moreover, the mRNA expression of these proinflammatory factors, as well as IL-17, in mouse cSCC is significantly decreased in the AhR-(fl/fl) Krt5-(Cre) mice compared to wild type mice, leading to a decrease in the number of developed cSCC lesions. Furthermore, CCL20, IL-23, as well as IL-17, are detected in the lesion-affected skin of cSCC patients. Our study demonstrates a possible mechanism for the development of cSCC involving AhR-mediated signaling by epidermal keratinocytes and recruitment of Th17 cells.

Plasminogen activating inhibitor‐1 promotes angiogenesis in cutaneous angiosarcomas

“…35 In addition, CXCL5 is a chemokine that attracts CXCR2+ macrophages and neutrophils, 35 and also increases the expression of PD-L1 on cancer fibroblasts, leading to the maintenance of the immunosuppressive microenvironment in cancer-bearing hosts. 36 CCL20 is a chemokine that attracts CCR6+ lymphocytes including Th17, and it is increased in skin cancers such as cutaneous squamous cell carcinoma 37 and extramammary Paget's disease 38…”

Interleukin‐38 promotes skin tumorigenesis in an IL‐1Rrp2‐dependent manner

“…In particular, important carcinogenic or tumor suppressor changes may increase cell survival and proliferation, impair DNA repair and checkpoint activation, and induce inflammation in vivo (Ming et al , 2014). DMBA is a typical mutagenic agent belongs to polyaromatic hydrocarbons (PAHs) which are accessible to humans and the analogous mutations are also common in human cancers (Sato et al , 2020). Hence, we investigated the DNA damage in keratinocytes 24 h after the treatment of DMBA.…”

Stromal Factors as a Target for Immunotherapy in Melanoma and Non-Melanoma Skin Cancers

“…Recent reports suggested the significance of IL-17 in developing skin cancers such as cSCC and EMPD through the recruitment of TANs [ 80 , 95 , 96 , 97 ]. As a previous report suggested, IL-17 promotes the development of cSCC by keratinocyte proliferation through sustained activation of the TRAF4-ERK5 axis [ 95 ].…”

“…As a previous report suggested, IL-17 promotes the development of cSCC by keratinocyte proliferation through sustained activation of the TRAF4-ERK5 axis [ 95 ]. More recently, 7,12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) were reported to induce the development of cSCC in the mouse by the enhancement of the IL-23/IL-17 signaling pathway [ 97 ]. This pathway may be correlated with the development of EMPD [ 80 ].…”

“…This pathway may be correlated with the development of EMPD [ 80 ]. Notably, aryl hydrocarbon receptor (AhR) signals could trigger IL-23/IL-17 signals in both cSCC and EMPD [ 80 , 97 ]. These reports suggest that AhR ligands could induce IL-17 not only in skin inflammatory disease (e.g., psoriasis vulgaris), but also in non-melanoma skin cancers.…”