Shibata M A, Ward J M, Green J E, Merlino G
Veterinary and Tumor Pathology Section, National Cancer Institute, Frederick, Maryland 21702-1201, USA.
Mol Carcinog. 1997 Mar;18(3):160-70. doi: 10.1002/(sici)1098-2744(199703)18:3<160::aid-mc5>3.0.co;2-j.
Transforming growth factor-alpha (TGF alpha) can stimulate keratinocyte proliferation and function as an autocrine tumor promoter in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated TGF alpha-transgenic mouse skin. In this study, we examined the effect of ectopic TGF alpha transgene expression on skin tumor growth and progression after DMBA initiation in the presence of 12-O-tetradecanoylphorbol-13-acetate (TPA). Both the multiplicity and size of skin tumors arising in TGF alpha-transgenic mice were significantly higher than those of the nontransgenic parental CD-1 strain. There were more dysplastic papillomas and squamous cell carcinomas (SCCs) in the transgenic animals as well. ProTGF alpha protein was expressed in transgenic papillomas, but mature TGF alpha was not detected. The epidermal growth factor receptor (EGFR) appeared to be downregulated and was associated with enhanced tyrosine phosphorylation of several substrates in TGF alpha-transgenic mouse tumors. Characteristic codon 61 mutations in the Ha-ras gene were found in most of the papillomas and SCCs induced by DMBA and TPA in transgenic as well as nontransgenic mice. However, no p53 gene mutations were found in any skin tumors from either transgenic or control animals. Analysis of cellular proliferation in both DMBA-TPA-induced papillomas and in skin 48 h after TPA treatment alone revealed significantly more DNA synthesis in TGF alpha-transgenic mice relative to controls. These results demonstrate that TGF alpha, through EGFR overstimulation, can act synergistically with TPA to induce the formation, growth, and development of DMBA-initiated skin tumors containing classic Ha-ras gene mutations but not p53 gene inactivation.
转化生长因子-α（TGFα）可刺激角质形成细胞增殖，并在7,12-二甲基苯并[a]蒽（DMBA）引发的TGFα转基因小鼠皮肤中作为自分泌肿瘤促进剂发挥作用。在本研究中，我们检测了在存在12-O-十四酰佛波醇-13-乙酸酯（TPA）的情况下，异位TGFα转基因表达对DMBA引发后皮肤肿瘤生长和进展的影响。TGFα转基因小鼠产生的皮肤肿瘤的数量和大小均显著高于非转基因亲代CD-1品系。转基因动物中发育异常的乳头瘤和鳞状细胞癌（SCC）也更多。前TGFα蛋白在转基因乳头瘤中表达，但未检测到成熟的TGFα。表皮生长因子受体（EGFR）似乎下调，并与TGFα转基因小鼠肿瘤中几种底物的酪氨酸磷酸化增强有关。在转基因和非转基因小鼠中，由DMBA和TPA诱导的大多数乳头瘤和SCC中都发现了Ha-ras基因的特征性密码子61突变。然而，在转基因或对照动物的任何皮肤肿瘤中均未发现p53基因突变。对DMBA-TPA诱导的乳头瘤以及单独TPA处理48小时后的皮肤中的细胞增殖分析显示，相对于对照，TGFα转基因小鼠中的DNA合成明显更多。这些结果表明，TGFα通过过度刺激EGFR，可与TPA协同作用，诱导含有经典Ha-ras基因突变但无p53基因失活的DMBA引发的皮肤肿瘤的形成、生长和发展。
