Fowlis D J, Flanders K C, Duffie E, Balmain A, Akhurst R J
Duncan Guthrie Institute of Medical Genetics, University of Glasgow, Yorkhill Hospitals, United Kingdom.
Cell Growth Differ. 1992 Feb;3(2):81-91.
Transforming growth factor beta (TGF-beta) inhibits proliferation of normal keratinocytes, and this response is retained, to variable extents, in benign tumors of the skin (S. Haddow, D. J. Fowlis, K. Parkinson, R. J. Akhurst, and A. Balmain, Oncogene, 6: 1465-1470, 1991). To investigate the profile of TGF-beta biosynthesis during various stages of chemical carcinogenesis of the skin, we used a combination of ribonuclease protection assay, in situ hybridization with gene-specific probes for TGF-beta 1, -beta 2, and -beta 3, and immunohistochemistry with isoform-specific antibodies against TGF-beta 1. Following 12-O-tetradecanoylphorbol-13-acetate treatment of adult mouse skin, there was a rapid induction of TGF-beta 1 protein. Intracellular TGF-beta 1 protein was localized to suprabasal keratinocytes, and the extracellular form was localized predominantly to the dermis. Despite ubiquitous induction of TGF-beta 1 protein by 12-O-tetradecanoylphorbol-13-acetate in various mouse strains, we noted strain-specific differences in the quantitative induction of TGF-beta 1 RNA. Papillomas and carcinomas induced in vivo had elevated levels of TGF-beta 1 RNA within the basal keratinocyte compartment but did not contain significant levels of TGF-beta 1 protein within the tumor. We postulate that the tumor evades TGF-beta 1-controlled negative growth regulation by altered translational and/or posttranslational processing mechanisms of this growth factor. Levels of TGF-beta 2 and -beta 3 RNA were not elevated at any stage of chemical carcinogenesis of the skin.
转化生长因子β（TGF-β）可抑制正常角质形成细胞的增殖，并且在皮肤良性肿瘤中，这种反应在不同程度上得以保留（S. 哈多、D. J. 福利斯、K. 帕金森、R. J. 阿克赫斯特和A. 巴尔曼，《癌基因》，6: 1465 - 1470，1991年）。为了研究皮肤化学致癌不同阶段中TGF-β生物合成的情况，我们结合使用了核糖核酸酶保护分析、用针对TGF-β1、-β2和-β3的基因特异性探针进行原位杂交，以及用针对TGF-β1的亚型特异性抗体进行免疫组织化学分析。用12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯处理成年小鼠皮肤后，TGF-β1蛋白迅速被诱导产生。细胞内TGF-β1蛋白定位于基底上层角质形成细胞中，而细胞外形式主要定位于真皮中。尽管在各种小鼠品系中12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯普遍诱导了TGF-β1蛋白，但我们注意到在TGF-β1 RNA的定量诱导方面存在品系特异性差异。体内诱导产生的乳头状瘤和癌在基底角质形成细胞区室中TGF-β1 RNA水平升高，但肿瘤内TGF-β1蛋白水平不高。我们推测肿瘤通过改变这种生长因子的翻译和/或翻译后加工机制来逃避TGF-β1控制的负生长调节。在皮肤化学致癌的任何阶段，TGF-β2和-β3 RNA水平均未升高。
