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: 2897110
• 负责人: DANIEL M RAMOS
• 金额: $ 7.28万
• 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/2897110
• 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) 约占口腔癌的 96% 癌症。 SCC 具有局部侵袭性以及 广泛转移；五年生存率低于50%。 瘤 侵袭和转移是一个涉及多种因素的复杂过程 肿瘤细胞和细胞外基质（ECM）之间的相互作用。 研究了层粘连蛋白和纤连蛋白等基质成分 广泛关注它们在肿瘤进展中的作用。 然而，其他 ECM 组件也发挥作用。 特别是，我们和其他人观察到 腱蛋白-C (TN-C) 表达在口腔癌中上调。 在这个 我们建议研究 TN-C 的表达及其表达方式 受体 alpha vbeta6 在口腔 SCC 进展过程中受到调节。 TN-C 是 一种大的寡聚糖蛋白，在 发育并参与形态发生运动、组织模式、 和组织修复。 TN-C 包含多个域，包括粘合域和抗域域 粘合剂，与细胞、纤连蛋白和其他 ECM 分子相互作用。 该分子有不同的亚型，这是由替代的结果造成的 mRNA 剪接。 TN-C 的一种受体是 alphavbeta6。 几条证据表明 αv 整合素亚家族对于肿瘤生长、侵袭、 和转移。 首先，最近的工作表明，反对者 alphavbeta3 抑制肿瘤血管生成。 二、alphavbeta3已展示 在垂直侵袭性黑色素瘤中上调。 第三，alphavbeta6是 最近发现在口腔鳞状细胞癌中新表达，而在正常细胞中不表达 口腔粘膜。 我们假设 TN-C 和 alphavbeta6 在疾病进展中发挥作用 通过充当肿瘤细胞运动的共刺激调节剂来治疗口腔癌， 入侵或基因表达。 该提案的具体目标是： (1) 评估生腱蛋白-C 及其受体 alphavbeta6 的表达，如 侵袭性口腔鳞状细胞癌的潜在标志物。 (2)判断是否 alphavbeta6表达的改变将改变侵入性 口腔鳞状细胞癌细胞的行为。 (3)评估肿瘤的不同阶段 入侵，使用动物模型，用于 TN-C 和 TN-C 的差异表达 αvβ6。 这些研究应该丰富我们对如何减少 充分表征的基质蛋白，如腱蛋白-C 和 alphavbeta6 受体有助于口腔癌的进展。 能够识别 那些可能最具侵袭性的口腔鳞状细胞癌肿瘤将有助于选择 最合适的治疗方式，可能会改善目前严峻的情况 这些肿瘤患者的预后。