Progression and Metastasis of Oral Tongue Cancer

描述（由申请人提供）：口腔鳞状细胞癌（SCCOC）是全球第六大癌症死亡原因。然而，对SCCOC肿瘤进展的细胞和分子机制知之甚少。在之前的资助期间，我们证明了获得失巢凋亡抗性是口腔上皮肿瘤进展的重要标志。我们的基因芯片表达分析的结果显示，失巢凋亡抵抗和敏感细胞的S100 A7蛋白，一个低分子量（11.4 kDa）的Ca 2+结合蛋白，属于S100多基因蛋白家族，差异表达失巢凋亡敏感和抵抗细胞。进一步的分析表明，S100 A7在浸润前、分化良好的SCCOC中过表达。然而，随着向浸润性癌的进展，S100 A7的表达在肿瘤发生的晚期常常下调或减少。虽然S100 A7蛋白对某些癌症的肿瘤发生是至关重要的，但鉴于其双相表达，S100 A7在SCCOC中是否发挥“致癌”或“肿瘤抑制”作用仍不清楚。我们的初步研究结果表明，尽管它在癌前病变的过度表达，S100 A7起着重要的抑制作用，通过下调肿瘤生长，EMT，肿瘤浸润/转移，至少部分通过其作为一个“新的”调节2-连环蛋白降解的SCCOC进展。因此，本申请的中心假设是S100 A7通过抑制2-连环蛋白、Twist和Snail抑制细胞增殖、运动性、EMT和侵袭，在SCCOC的发展和进展中发挥重要的“肿瘤抑制剂”作用。这一假设将在4个具体目标中进行测试，我们期望完成这4个目标中概述的方法将有助于我们确定S100 A7作为SCCOC中肿瘤抑制因子的作用，并且这些信息将增强我们对SCCOC进行临床分期并确定潜在新治疗靶点的能力。公共卫生相关性：在之前的资助期间，我们证明了获得对特定形式的细胞死亡的抗性是口腔癌生长的重要标志。这些研究使我们探索了一种特定蛋白S100 A7的功能，S100 A7是一种低分子量的钙结合蛋白，在头颈部早期癌症中表达更高，在更晚期的癌症中表达减少。在这里提出的研究中，我们将更好地定义这种蛋白质在口腔癌生长中的作用，口腔癌是美国和世界各地癌症死亡的主要原因，以确定更好的方法来分期和治疗这种通常致命的疾病。

DESCRIPTION (provided by applicant): Squamous cell carcinoma of the oral cavity (SCCOC) is the sixth leading cause of cancer deaths worldwide. However, little is known about the cellular and molecular mechanisms of SCCOC tumor progression. In the prior funding period, we demonstrated that acquisition of anoikis-resistance is an important hallmark of oral epithelial tumor progression. Results of our cDNA microarray expression analysis of anoikis-resistant and - sensitive cells revealed that the S100A7 protein, a low-molecular-weight (11.4 kDa) Ca2+binding protein that belongs to S100 multigenic protein family, is differentially expressed in anoikis-sensitive and -resistant cells. Further analyses indicated that S100A7 is overexpressed in pre-invasive, well-differentiated SCCOC. However, with the progression to invasive carcinomas, S100A7 expression is often down-regulated or diminished in the late stages of tumorigenesis. While it is evident that S100A7 protein is critical to the tumorigenesis of certain cancers, it remains unclear whether S100A7 plays an "oncogenic" or "tumor suppressive" role in SCCOC given its biphasic expression. Our preliminary results show that despite its overexpression in premalignant oral lesions, S100A7 plays an important inhibitory role in SCCOC progression by down-regulating tumor growth, EMT, tumor invasion/metastasis at least in part through its role as a "novel" regulator of 2-catenin degradation. Thus, the central hypothesis of this application is that S100A7 plays an important role as a "tumor suppressor" in SCCOC development and progression, through its inhibition of cell proliferation, motility, EMT, and invasion by inhibition of 2-catenin, Twist, and Snail. This hypothesis will be tested in 4 specific aims, and it is our expectation that completion of the approaches outlined in these 4 aims will help us to define S100A7's role as a tumor suppressor in SCCOC and that this information will enhance our ability to clinically stage SCCOC and identify potential new targets for therapy. PUBLIC HEALTH RELEVANCE: In the prior funding period, we demonstrated that acquisition of resistance to a specific form of cell death is an important hallmark of oral cancer growth. These studies led us to explore the function of a specific protein, S100A7, which is a low-molecular-weight calcium-binding protein that is more highly expressed in early staged cancers of the head and neck, with diminished expression in more advanced cancers. In the studies proposed here, we will better define the role of this protein in the growth of oral cancer, a leading cause of cancer deaths in the U.S. and around the world, in order to identify better ways to stage and treat this often deadly disease.