PROGRESSION OF CHEMICAL INDUCED SKIN TUMORS

化学诱导的小鼠皮肤肿瘤的初步研究表明 在鳞状细胞癌(SCC)的肿瘤进展中， 变异型低分化肿瘤，称为梭形细胞癌 (SPCC)，可出现以侵袭性增强和 转移潜能。我们已经开发出了与 同一双相(SCC/SPCC)主节点的SCC和SPCC组件 小鼠肿瘤，为了通过差异显示来鉴定基因 干预从SCC到SPCC的转换。特别是，我们专注于 人和大鼠同源基因的缺失表达 PACE4在鳞状细胞癌细胞系中的表达及其在匹配的SPCC中的过表达 细胞系。由于PACE4是几种蛋白质加工酶之一 被称为原蛋白转换酶(PC)，其中一些具有假定的作用 在激活对癌症发展至关重要的底物时， 在这一应用中，我们建议研究PC在肿瘤中的功能 进步。需要检验的中心假设是，PACE4和 另一种PC，通过激活特定的靶点，如基质，FURIN 金属蛋白酶(MMPs)可增强SCC细胞的侵袭性，从而 构成了导致一系列事件的重要组成部分 晚期恶性表型，最终出现在SPCC。 为了实现这一目标，我们计划：1)调查是否 PACE4的表达是小鼠肿瘤的一个重要特征 化学致癌的方案以及这种表达是否 与增强的侵袭/转移行为和/或丢失密切相关 区分；2)确定Furin是否参与该过程 3)研究外源基因表达对肿瘤生长的影响 PC-cDNA在获得侵袭/转移表型中的作用 乳头状瘤和低级别非转移性鳞癌细胞株；4)研究 PC在培养系统中激活MMPs中的作用以及 在原发肿瘤中；5)确定可能的翻译价值 这些发现是通过研究PC在人类干细胞中的作用和6) 通过克隆和克隆启动PC上调原因的研究 PACE4启动子区域测序及启动子-报告基因的创建 转基因小鼠评估正常组织和 诱导的SCCs。

Preliminary studies on chemically-induced mouse skin tumors have shown that during tumor progression of squamous cell carcinomas (SCC), a variant poorly-differentiated neoplasm, called spindle cell carcinoma (SPCC), can arise that is characterized by enhanced invasiveness and metastatic potential. We have developed cell lines that correspond to the SCC and SPCC components of the same biphasic (SCC/SPCC) primary mouse tumor, in order to identify by differential display genes that intervene in the switch from SCC to SPCC. In particular, we focused on the absence of expression of a gene homologous to the human and rat PACE4 in the SCC cell line and its overexpression in the matched SPCC cell line. Since PACE4 is one of the several protein processing enzymes known as proprotein convertases (PCs), some of which have putative roles in activating substrates that are essential for cancer development, in this application we propose to investigate the function of PCs in tumor progression. The central hypothesis to be tested is that PACE4 and another PC, furin by activating specific targets such as matrix metalloproteinases (MMPs) enhance the invasiveness of SCC cells, thus constituting important components of the chain of events leading to an advanced malignant phenotype, culminating in the SPCC. In order to achieve this objective, we plan to: 1) investigate whether PACE4 expression is a significant feature of mouse tumors induced by protocols of chemical carcinogenesis and whether this expression is closely related to enhanced invasive/metastatic behavior and/or loss of differentiation; 2) determine whether furin participates in the process of tumor progression; 3) investigate the effect of exogenous expression of PC cDNAs on the acquisition of the invasive/metastatic phenotype of papilloma and low grade non-metastatic SCC cell lines; 4) investigate the role of PCs in the activation of MMPs in culture systems as well as in primary tumors; 5) determine the probable translational value of these findings by investigating the role of PCs in human SCCs and 6) initiate studies on the cause of PC upregulation by cloning and sequencing the PACE4 promoter region and create promoter-reporter transgenic mice to evaluate gene regulation in normal tissues and induced SCCs.