REGULATED EXPRESSION OF TENASCIN AND AVB6 IN ORAL CANCER

口腔癌中腱蛋白和 AVB6 的调控表达

• 批准号: 2015297
• 负责人: DANIEL M RAMOS
• 金额: $ 11.02万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2015297
• 关键词: athymic mouse; biomarker; cell growth regulation; disease /disorder model; gene expression; genetic regulation; glycoprotein structure; human tissue; immunocytochemistry; integrins; metastasis; monoclonal antibody; neoplasm /cancer classification /staging; neoplasm /cancer invasiveness; neoplastic cell; neoplastic growth; neoplastic process; oral pharyngeal neoplasm; receptor expression; squamous cell carcinoma; tenascin; tissue /cell culture

Squamous cell carcinoma (SCC) accounts for approximately 96% or all oral cancers. SCC has a tendency to be locally invasive as well as to metastasize widely; the five-year survival rates are less than 50%. Tumor invasion and metastasis is a complex process involving multiple interactions between tumor cells and the extracellular matrix (ECM). Matrix components such as laminin and fibronectin have been studied extensively regarding their roles in tumor progression. However, other ECM components also play a role. In particular, we and others have observed that tenascin-C (TN-C) expression is upregulated in oral cancer. In this project we propose to investigate how the expression of TN-C and its receptor, alpha vbeta6, are regulated during oral SCC progression. TN-C is a large oligomeric glycoprotein that is transiently expressed during development and is involved in morphogenetic movements, tissue patterning, and tissue repair. TN-C contains multiple domains, both adhesive and anti- adhesive, that interact with cells, fibronectin, and other ECM molecules. There are different isoforms of the molecule, which result from alternative mRNA splicing. One receptor for TN-C is alphavbeta6. Several lines of evidence suggest that the alphav integrin subfamily is important for tumor growth, invasion, and metastasis. First, recent work has demonstrated that antagonists to alphavbeta3 inhibit tumor angiogenesis. Second, alphavbeta3 has been shown to be upregulated in vertically invasive melanoma. Third, alphavbeta6 was recently found to be neo-expressed in oral SCC, while absent from normal oral mucosa. We hypothesize that TN-C and alphavbeta6 play a role in the progression of oral cancer by acting as co-stimulatory modulators of tumor cell motility, invasion, or gene expression. The specific aims of this proposal are; (1) To assess the expression of tenascin-C and its receptor, alphavbeta6, as potential markers for invasive oral SCC. (2) To determine whether alterations in the expression of alphavbeta6 will modify the invasive behavior of oral SCC cells. (3) To evaluate different stages of tumor invasion, using an animal model, for differential expression of TN-C and alphavbeta6. These studies should enrich our understanding of how less- well-characterized matrix proteins like tenascin-C and the alphavbeta6 receptor contribute to oral cancer progression. Being able to identify those oral SCC tumors likely to be most invasive will help in selecting the most appropriate treatment modality and may improve the currently grim prognosis of patients with these tumors.

鳞状细胞癌(SCC)约占96%或全部口腔癌 癌症。鳞状细胞癌有局部侵袭性的倾向，以及 转移范围广；五年存活率不到50%。肿瘤 侵袭和转移是一个复杂的过程，涉及多个 肿瘤细胞与细胞外基质之间的相互作用。 对层粘连蛋白和纤维连接蛋白等基质成分进行了研究 广泛关注它们在肿瘤进展中的作用。然而，其他ECM 组件也起到了作用。特别是，我们和其他人观察到 TN-C在口腔癌中的表达上调。在这 我们计划研究TN-C及其受体的表达如何 受体αvbeta6在口腔鳞状细胞癌进展过程中受到调节。TN-C IS 一种大的寡聚体糖蛋白，在 发育并参与形态发生运动、组织构图、 和组织修复。TN-C含有多个结构域，既有粘性的，也有防粘性的 粘合剂，与细胞、纤维连接蛋白和其他ECM分子相互作用。 分子有不同的异构体，它们是由交替产生的 信使核糖核酸剪接 TN-C的一个受体是αvbeta6。有几行证据表明 整合素α亚家族对肿瘤的生长、侵袭、 和转移。首先，最近的研究表明，拮抗剂可以 αvbeta3抑制肿瘤血管生成。第二，Alphavbeta3已经显示出来了 在垂直侵袭性黑色素瘤中上调。第三，Alphavbeta6是 最近发现在口腔鳞癌中有新的表达，而在正常的口腔鳞癌中没有表达 口腔粘膜。 我们假设TN-C和Alphavbeta6在糖尿病的进展中起作用。 口腔癌作为肿瘤细胞运动的共刺激调节器， 入侵，或基因表达。这项建议的具体目的是：(1) 检测Tenascin-C及其受体Alphavbeta6、AS的表达 侵袭性口腔鳞癌的潜在标志物。(2)确定是否 αvbeta6表达的改变将改变侵袭性 口腔鳞状细胞癌细胞的行为。(3)评价肿瘤的不同分期 侵袭性，使用动物模型，以差异表达TN-C和 阿尔法贝塔6.这些研究应该会丰富我们对如何减少- 特性良好的基质蛋白，如Tenascin-C和Alphavbeta6 受体参与口腔癌的进展。能够辨别出 那些可能是最具侵袭性的口腔鳞癌肿瘤将有助于选择 最合适的治疗方式，并可能改善目前的严峻 这些肿瘤患者的预后。