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

口腔中产生的绝大多数癌症是鳞状细胞癌。角质形成细胞生物学研究组成立于1998年1月，旨在阐明鳞状细胞分化的机制以及导致肿瘤表型和恶性转化的生化改变。我们的工作利用小鼠表皮的角质形成细胞和体外和体内的方法来解剖分化和肿瘤进展的阶段。p53肿瘤抑制基因在大多数人类癌症中突变或失活，包括口腔癌，我们的研究集中在阐明该基因产物在角质形成细胞生物学中的作用和机制。细胞周期蛋白依赖性激酶抑制剂WAF 1是p53介导的基因转录的下游靶点，被认为是p53抑制肿瘤的效应物。我们已经探讨了WAF 1基因产物在多步骤致癌作用中的作用，并使用体内和体外模型证明，WAF 1的丢失不足以解释p53无效肿瘤的恶性表型;因此，除了WAF 1基因的转录激活外，p53的其他功能对其肿瘤抑制功能是必要的。此外，通过差异显示分析，我们已经鉴定了一种新的p53调节基因，该基因也是TNF-α途径的一部分，并发现该基因产物的过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，阐明这一途径有助于阐明口腔癌发生的病因，并提出新的治疗干预措施。- 角质形成细胞，鳞状分化，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