He Guobin, Muga Stephanie, Thuillier Philippe, Lubet Ronald A, Fischer Susan M
The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA.
Mol Carcinog. 2005 Aug;43(4):198-206. doi: 10.1002/mc.20111.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand activated transcription factor. There have been suggestions that PPARgamma ligands may have utility in preventing tumor development in rodent mammary glands and colon. The recent finding that mice lacking one allele of the PPARgamma gene were significantly more susceptible to 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin carcinogenesis compared to wild-type mice highlights mouse skin as another potential organ in which PPARgamma ligands may be effective as chemopreventive agents. In this study, we assessed the effect of two PPARgamma ligands (rosiglitazone and troglitazone) on UV and DMBA/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin carcinogenesis, two of the most commonly used mouse skin carcinogenesis models. Unexpectedly, neither rosiglitazone (dietary 200 ppm) nor troglitazone (topical 100 microg) significantly inhibited UV-induced skin tumor development in SKH-1 hairless mice. Likewise, dietary rosiglitazone did not statistically significantly inhibit DMBA/TPA-induced skin tumor development. Interestingly, dietary troglitazone significantly inhibited basal level keratinocyte proliferation as shown by 5-bromo-2'-deoxyuridine (BrdU) labeling, but it had no effect on TPA-induced epidermal cell proliferation. Northern blot analysis showed that PPARgamma expression was extremely low in normal mouse epidermis and was virtually undetectable in skin tumors. Collectively, our data suggest that PPARgamma ligands may not be useful in the prevention of chemically or UV-induced skin tumors.
过氧化物酶体增殖物激活受体γ（PPARγ）是一种配体激活的转录因子。有人提出PPARγ配体可能有助于预防啮齿动物乳腺和结肠中的肿瘤发生。最近的研究发现，与野生型小鼠相比，缺乏一个PPARγ基因等位基因的小鼠对7,12-二甲基苯并[a]蒽（DMBA）诱导的皮肤癌发生明显更敏感，这表明小鼠皮肤是PPARγ配体可能作为化学预防剂有效的另一个潜在器官。在本研究中，我们评估了两种PPARγ配体（罗格列酮和曲格列酮）对紫外线和DMBA/12-O-十四烷酰佛波醇-13-乙酸酯（TPA）诱导的小鼠皮肤癌发生的影响，这是两种最常用的小鼠皮肤癌发生模型。出乎意料的是，罗格列酮（饮食中200 ppm）和曲格列酮（局部应用100微克）均未显著抑制SKH-1无毛小鼠紫外线诱导的皮肤肿瘤发生。同样，饮食中的罗格列酮对DMBA/TPA诱导的皮肤肿瘤发生也没有统计学上的显著抑制作用。有趣的是，饮食中的曲格列酮通过5-溴-2'-脱氧尿苷（BrdU）标记显示显著抑制基底角质形成细胞增殖，但对TPA诱导的表皮细胞增殖没有影响。Northern印迹分析表明，PPARγ在正常小鼠表皮中的表达极低，在皮肤肿瘤中几乎检测不到。总体而言，我们的数据表明PPARγ配体可能对预防化学或紫外线诱导的皮肤肿瘤无效。
