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Keratinocyte p38? loss inhibits Ras-induced tumor formation, while systemic p38? loss enhances skin inflammation in the early phase of chemical carcinogenesis in mouse skin.

ABSTRACT: p38? 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 p38? in cutaneous carcinogenesis has not been well-defined. We have reported that mice with germline loss of p38? 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 p38? gene ablation inhibited the growth of tumors generated from v-ras(Ha) -transformed keratinocytes in skin orthografts to nude mice, indicating that keratinocyte-intrinsic p38? is required for Ras-induced tumorigenesis. Gene expression profiling of v-ras(Ha) -transformed p38?-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 p38?-null skin compared with skin of wild-type mice, as assessed by measuring the expression of pro-inflammatory cytokines, including IL-1?, IL-6, IL-17, and TNF?. Additionally, p38?-null skin and p38?-null keratinocytes exhibited increased p38? activation and signaling in response to acute inflammatory challenges, suggesting a role for p38? in stimulating the elevated inflammatory response in p38?-null skin during the initial phases of the DMBA/TPA treatment compared with similarly treated p38?(+/+) skin. Altogether, our results indicate that p38? 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.

SUBMITTER: Kiss A

PROVIDER: S-EPMC6310148 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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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.

Kiss Alexi A Koppel Aaron C AC Anders Joanna J Cataisson Christophe C Yuspa Stuart H SH Blumenberg Miroslav M Efimova Tatiana T

Molecular carcinogenesis 20150308 5

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 mo ...[more]

PMID: 25753147

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Project description:Ras oncogenes (Hras, Kras and Nras) are important drivers of carcinogenesis. However, tumors with Ras mutations often show loss of the corresponding wild-type (WT) allele, suggesting that proto-oncogenic forms of Ras can function as a suppressor of carcinogenesis. In vitro studies also suggest that WT Ras proteins can suppress the tumorigenic properties of alternate mutant Ras family members, but in vivo evidence for these heterologous interactions is lacking. We have investigated the genetic interactions between different combinations of mutant and WT Ras alleles in vivo using carcinogen-induced lung and skin carcinogenesis in mice with targeted deletion of different Ras family members. The major suppressor effect of WT Kras is observed only in mutant Kras-driven lung carcinogenesis, where loss of one Kras allele led to increased tumor number and size. Deletion of one Hras allele dramatically reduced the number of skin papillomas with Hras mutations, consistent with Hras as the major target of mutation in these tumors. However, skin carcinoma numbers were very similar, suggesting that WT Hras functions as a suppressor of progression from papillomas to invasive squamous carcinomas. In the skin, the Kras proto-oncogene functions cooperatively with mutant Hras to promote papilloma development, although the effect is relatively small. In contrast, the Hras proto-oncogene attenuated the activity of mutant Kras in lung carcinogenesis. Interestingly, loss of Nras increased the number of mutant Kras-induced lung tumors, but decreased the number of mutant Hras-induced skin papillomas. These results show that the strongest suppressor effects of WT Ras are only seen in the context of mutation of the cognate Ras protein, and only relatively weak effects are detected on tumor development induced by mutations in alternative family members. The data also underscore the complex and context-dependent nature of interactions between proto-oncogenic and oncogenic forms of different Ras family members during tumor development.

Dataset Information

Keratinocyte p38? loss inhibits Ras-induced tumor formation, while systemic p38? loss enhances skin inflammation in the early phase of chemical carcinogenesis in mouse skin.

Publications

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.

Similar Datasets

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