MOLECULAR BASIS OF SQUAMOUS DIFFERENTIATION AND NEOPLASIA IN SKIN & ORAL TISSUES

绝大多数发生在口腔的癌症是鳞状细胞癌。角质形成细胞生物学小组成立于1998年1月，目的是阐明鳞状细胞分化的机制以及导致肿瘤表型和恶变的生化变化。我们的工作利用了小鼠表皮的角质形成细胞以及体外和体内的方法来剖析分化和肿瘤进展的阶段。P53抑癌基因在包括口腔癌在内的大多数人类肿瘤中都存在突变或失活，我们的研究主要集中在阐明该基因产物在角质形成细胞生物学中的功能和作用机制。细胞周期蛋白依赖性激酶抑制因子WAF1是P53介导的基因转录的下游靶点，被认为是P53抑制肿瘤的效应因子。我们已经探索了WAF1基因产物在多步癌变中的作用，并通过体内和体外模型证明，WAF1的缺失不足以解释P53缺失的肿瘤的恶性表型；因此，除了WAF1基因的转录激活外，P53的其他特征对于其肿瘤抑制功能是必要的。此外，通过差异显示分析，我们发现了一个新的p53调控基因，它也是肿瘤坏死因子-α途径的一部分，并发现该基因产物的过度表达迅速诱导角质形成细胞死亡。由于P53蛋白在大多数口腔癌中是失活的，阐明这一途径将有助于阐明口腔癌发生的病因并提出新的治疗措施。角质形成细胞、鳞状细胞分化、表皮癌变、肿瘤抑制

The vast majority of cancers arising in the oral cavity are squamous cell carcinomas. The Keratinocyte Biology Group was established in January, 1998 to elucidate mechanisms of squamous cell differentiation and the biochemical alterations contributing to the neoplastic phenotype and malignant conversion. Our work has utilized keratinocytes of murine epidermis and both in vitro and in vivo approaches to dissect the stages of differentiation and neoplastic progression. The p53 tumor suppressor gene is mutated or inactivated in a majority of human cancers, including those of the oral cavity, and our studies have focused on elucidating the function and mechanism of action of this gene product in keratinocyte biology. The cyclin dependent kinase inhibitor WAF1, a downstream target of p53 mediated gene transcription, is believed to be an effector of tumor suppression by p53. We have explored the role of the WAF1 gene product in multistep carcinogenesis, and using both in vivo and in vitro models have demonstrated that loss of WAF1 is not sufficient to explain the malignant phenotype of p53 null tumors; thus, other features of p53 beside transcriptional activation of the WAF1 gene are necessary for its tumor suppressor function. In addition, by differential display analysis we have identified a novel p53 regulated gene that is also part of the TNF-alpha pathway and have found that this overexpression of this gene product rapidly induces keratinocyte cell death. Because the p53 protein is inactivated in a majority of cancers arising in the oral cavity, elucidating this pathway should help to clarify the etiology of oral carcinogenesis and suggest novel therapeutic interventions. - keratinocyte, squamous differentiation, epidermal carcinogenesis, tumor suppression