Rittié Laure, Kansra Sanjay, Stoll Stefan W, Li Yong, Gudjonsson Johann E, Shao Yuan, Michael Lowell E, Fisher Gary J, Johnson Timothy M, Elder James T
Department of Dermatology, University of Michigan Medical Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0932, USA.
Am J Pathol. 2007 Jun;170(6):2089-99. doi: 10.2353/ajpath.2007.060537.
In this study, we examined ErbB1 signaling in human basal and squamous cell carcinomas (BCC and SCC) of the skin in vivo. We used enzyme-linked immunosorbent assay, laser capture microdissection-coupled real-time reverse transcriptase-polymerase chain reaction, and immunohistochemistry to assess expression and activation levels of ErbB1 protein, ligands, and potential downstream effectors, in BCC and SCC tumors, stroma, and adjacent epidermis. Although total ErbB1 protein and mRNA were similar in cancerous and normal skin, we found that ErbB1 activation (phospho-Tyr(1068)) was greater in bulk SCC versus BCC or normal skin. In addition, three ErbB1 ligand transcripts (amphiregulin, heparin-binding epidermal growth factor-like growth factor, and transforming growth factor-alpha) were up-regulated in tumor cells of SCC but not BCC. Expression of these ligands was also increased in asymptomatic epidermis adjacent to both SCC and BCC, relative to normal skin. Interestingly, betacellulin transcript levels were inversely regulated compared with the other ligands. Consistently, downstream ErbB1 effectors (Erk1/2 and Akt) were activated in tumor cells of SCC but not of BCC and in adjacent epidermis of both BCC and SCC. These results demonstrate that ErbB1 signaling is hyperactive in tumor cells of SCC but not of BCC and in nearby asymptomatic epidermis of both tumor types. Our results suggest that targeting ErbB1 signaling might be of benefit in the treatment of SCC.
在本研究中,我们在体内检测了人皮肤基底细胞癌和鳞状细胞癌(BCC和SCC)中的ErbB1信号传导。我们使用酶联免疫吸附测定、激光捕获显微切割结合实时逆转录聚合酶链反应以及免疫组织化学来评估BCC和SCC肿瘤、基质及相邻表皮中ErbB1蛋白、配体和潜在下游效应分子的表达及激活水平。尽管癌性皮肤和正常皮肤中的总ErbB1蛋白及mRNA相似,但我们发现,与BCC或正常皮肤相比,大块SCC中的ErbB1激活(磷酸化Tyr(1068))程度更高。此外,三种ErbB1配体转录物(双调蛋白、肝素结合表皮生长因子样生长因子和转化生长因子-α)在SCC的肿瘤细胞中上调,但在BCC中未上调。相对于正常皮肤,这些配体在与SCC和BCC相邻的无症状表皮中的表达也增加。有趣的是,β细胞ulin转录水平与其他配体呈反向调节。一致地,下游ErbB1效应分子(Erk1/2和Akt)在SCC的肿瘤细胞中被激活,但在BCC中未被激活,且在BCC和SCC的相邻表皮中均被激活。这些结果表明,ErbB1信号传导在SCC的肿瘤细胞中高度活跃,但在BCC中不活跃,且在两种肿瘤类型附近的无症状表皮中也高度活跃。我们的结果表明,靶向ErbB1信号传导可能对SCC的治疗有益。