Figure 1.

PPARβ/δ suppresses malignant conversion by promoting HRAS-induced senescence. (a) Distribution of skin tumor types from wild-type (+/+) or Pparβ/δ-null (−/−) mice topically treated with or without GW0742 was quantified. SCC: squamous cell carcinoma. SCP: squamous cell papilloma. KA: keratoacanthoma. BBCT: benign basal cell tumor. Using a two proportion z-test, significant differences (P ≤ 0.05) were found in the percentage of squamous cell papillomas between wild-type and Pparβ/δ-null controls, the percentage of squamous cell papillomas between GW0742-treated wild-type and Pparβ/δ-null, and the percentage of squamous cell carcinomas between GW0742-treated wild-type and Pparβ/δ-null. No significant differences in the percentage of squamous cell papillomas or squamous cell carcinomas were found between control and GW0742 groups in either genotype. The percentage of squamous cell carcinomas between wild-type and Pparβ/δ-null controls was not statistically significant. However, a higher percentage of keratoacanthomas was found in control Pparβ/δ-null mice compared to wild-type. Keratoacanthomas can convert to squamous cell carcinoma in mice with prolonged promotion ⁷², signaling typically observed in Pparβ/δ-null mice ⁵. Thus, it is important to note that there are significantly more combined squamous cell carcinomas and keratoacanthomas in control and/or GW0742-treated Pparβ/δ-null mice compared to similarly treated wild-type mice. These data suggest that loss of PPARβ/δ promotes the conversion of keratoacanthomas to squamous cell carcinomas. (b, c) HRAS-expressing (+/+) or (−/−) keratinocytes were cultured in high Ca²⁺ medium for 4 weeks and Ca²⁺ resistant foci were stained with rhodamine. (b) The number and size of foci were quantified and (c) proliferating (+/+) or (−/−) cells (BrdU positive) in the foci are shown. DIC = representative photomicrograph using differential interference contrast microscopy. (d, e) HRAS-expressing (+/+) or (−/−) keratinocytes treated with or without GW0742 were either labeled with BrdU or stained for β-gal. The percentage of BrdU and β-gal positive cells was quantified. (f) β-gal staining of skin tumor samples from (+/+) or (−/−) mice isolated from one stage bioassay. Values represent the mean ± S.E.M.. *significantly different from (+/+) control (P ≤ 0.05). #significantly differerent from (−/−) control (P ≤ 0.05).