Deficiency of protein kinase Cα in mice results in impairment of epidermal hyperplasia and enhancement of tumor formation in two-stage skin carcinogenesis
Deficiency of protein kinase Cα in mice results in impairment of epidermal hyperplasia and enhancement of tumor formation in two-stage skin carcinogenesis
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DOI：
10.1158/0008-5472.can-04-4241
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发表时间：
2005-08-15
期刊：
影响因子：
11.2
通讯作者：
Chida, K
中科院分区：
文献类型：
--
作者：
Hara, T;Saito, Y;Chida, K
我们培养了缺乏蛋白激酶C α (PKC α)的小鼠品系，并评估了该酶在上皮增生和肿瘤形成中的意义。PKC α缺陷小鼠通过单次应用7,12-二甲基苯(a)蒽（DMBA）引发肿瘤和重复应用12- o-十四烷酰基磷酸-13-乙酸（TPA）促进肿瘤发生，在两期皮肤癌中表现出对肿瘤形成的易感增加。单独DMBA或TPA治疗均未促进肿瘤形成，提示PKC α抑制肿瘤促进。然而，局部TPA治疗引起的表皮增生的严重程度明显减轻。在突变小鼠中，与野生型小鼠一样，外用TPA治疗16至24小时后，5-溴-2'-脱氧尿苷标记的表皮基底角化细胞数量增加，但在36和48小时时显著减少。皮肤创面诱导的再生上皮厚度明显减少，但未见结构损伤。增强的肿瘤形成可能与表皮增生无关。TPA处理对突变小鼠皮肤中表皮生长因子（EGF）受体配体、肿瘤生长因子α (tgf - α)和肝素结合EGF样生长因子的诱导水平显著低于野生型小鼠。PKC α可能调节基底角化细胞中这些EGF受体配体的供应，导致突变小鼠表皮增生严重程度降低。我们提出PKC α正调控表皮增生，负调控两期皮肤癌的肿瘤形成。
We generated a mouse strain lacking protein kinase C alpha (PKC alpha) and evaluated the significance of the enzyme in epithelial hyperplasia and tumor formation. PKC alpha-deficient mice exhibited increased susceptibility to tumor formation in two-stage skin carcinogenesis by single application of 7,12-dimethylbenz(a)anthracene (DMBA) for tumor initiation and repeated applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) for tumor promotion. Tumor formation was not enhanced by DMBA or TPA treatment alone, suggesting that PKC alpha suppresses tumor promotion. However, the severity of epidermal hyperplasia induced by topical TPA treatment was markedly reduced. In mutant mice, the number of 5-bromo-2'-deoxyuridine-labeled epidermal basal keratinocytes increased 16 to 24 hours after topical TPA treatment as in the case of wild-type mice, but significantly decreased at 36 and 48 hours. Furthermore, the regenerating epithelium induced by skin wound significantly decreased in thickness but was not structurally impaired. The enhanced tumor formation may not be associated with epidermal hyperplasia. The induction levels of epidermal growth factor (EGF) receptor ligands, tumor growth factor alpha (TGF-alpha), and heparin-binding EGF-like growth factor, in the skin of mutant mice by TPA treatment were significantly lower than those in the skin of wild-type mice. PKC alpha may regulate the supply of these EGF receptor ligands in basal keratinocytes, resulting in a reduced epidermal hyperplasia severity in the mutant mice. We propose that PKC alpha positively regulates epidermal hyperplasia but negatively regulates tumor formation in two-stage skin carcinogenesis.