Keratinocyte p38δ loss inhibits Ras-induced tumor formation, while systemic p38δ loss enhances skin inflammation in the early phase of chemical carcinogenesis in mouse skin

Abstract

p38δ expression and/or activity are increased in human cutaneous malignancies, including invasive squamous cell carcinoma (SCC) and head and neck SCC, but the role of p38δ in cutaneous carcinogenesis has not been well-defined. We have reported that mice with germline loss of p38δ exhibited a reduced susceptibility to skin tumor development compared with wild-type mice in the two-stage 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) chemical skin carcinogenesis model. Here, we report that p38δ gene ablation inhibited the growth of tumors generated from v-ras(Ha) -transformed keratinocytes in skin orthografts to nude mice, indicating that keratinocyte-intrinsic p38δ is required for Ras-induced tumorigenesis. Gene expression profiling of v-ras(Ha) -transformed p38δ-null keratinocytes revealed transcriptional changes associated with cellular responses linked to tumor suppression, such as reduced proliferation and increased differentiation, cell adhesion, and cell communications. Notably, a short-term DMBA/TPA challenge, modeling the initial stages of chemical skin carcinogenesis treatment, elicited an enhanced inflammation in p38δ-null skin compared with skin of wild-type mice, as assessed by measuring the expression of pro-inflammatory cytokines, including IL-1β, IL-6, IL-17, and TNFα. Additionally, p38δ-null skin and p38δ-null keratinocytes exhibited increased p38α activation and signaling in response to acute inflammatory challenges, suggesting a role for p38α in stimulating the elevated inflammatory response in p38δ-null skin during the initial phases of the DMBA/TPA treatment compared with similarly treated p38δ(+/+) skin. Altogether, our results indicate that p38δ signaling regulates skin carcinogenesis not only by keratinocyte cell-autonomous mechanisms, but also by influencing the interaction between between the epithelial compartment of the developing skin tumor and its stromal microenvironment.

Cell Type-Specific p38δ Targeting Reveals a Context-, Stage-, and Sex-Dependent Regulation of Skin Carcinogenesis

“…The essential role for p38δ in DMBA/TPA-induced skin tumorigenesis was subsequently confirmed by Zur et al [17]. We also reported that p38δ gene ablation inhibited the growth of squamous tumors generated from oncogenic v-ras HA -transformed keratinocytes following orthotopic grafting onto nude mice by inducing transcriptional changes linked to tumor suppression [18]. These findings suggest that keratinocyte p38δ contributes to oncogenic v-ras HA -induced tumorigenesis in a cell-autonomous manner.…”

“…Moreover, activation of p38δ has been observed in human head and neck SCC [16], suggesting a tumor-promoting function for p38δ in epithelial cancer. Consistent with this notion, significant protective effects of p38δ gene ablation have been demonstrated in several in vivo models of epithelial carcinogenesis [11,17,18].…”

“…These findings suggest that keratinocyte p38δ contributes to oncogenic v-ras HA -induced tumorigenesis in a cell-autonomous manner. Furthermore, systemic p38δ loss heightened the initial inflammatory response in pre-neoplastic murine skin following a short-term DMBA/TPA challenge [18]. The correlation between an enhanced acute inflammatory response and significant resistance to DMBA/TPA-induced skin tumor development, reported in several genetically engineered mouse models [19,20,21,22,23,24,25], underscores the critical anti-tumor role of immune/inflammatory factors in the tumor microenvironment.…”

Expression of claudin‐11 by tumor cells in cutaneous squamous cell carcinoma is dependent on the activity of p38δ

“…Cutaneous SCC cells have been shown to express p38α and p38δ MAPK isoforms, and basal activation of p38 MAPK pathway promotes cSCC cell invasion . The role for p38δ in cutaneous carcinogenesis has also been demonstrated in knockout mouse model of p38δ . Furthermore, we have previously noted that the expression of ZO‐1 is regulated by p38δ in NHEKs and cSCC cells .…”

Use of signals of positive and negative selection to distinguish cancer genes and passenger genes

“…The protein p38δ is highly expressed in all types of human breast cancers, whereas lack of p38δ resulted in reduced primary tumor size and blocked the metastatic potential to the lungs (Wada et al, 2017). The fact that mice with germline deletion of the p38δ gene are significantly protected from chemical skin carcinogenesis also suggests a cancer promoting role for the protein (Kiss et al, 2016). Interestingly, cell-selective targeted ablation of p38δ in keratinocytes and in immune (myeloid) cells on skin tumor development had different effects.…”