Molecular regulation of the invasive growth of oral cancer by YAP

描述（由申请人提供）：被诊断为口腔鳞状细胞癌（SCC）的患者继续面临显著的发病率和死亡率。虽然口腔鳞状细胞癌的危险因素是已知的，但这种可怕的恶性肿瘤的分子机制仍不清楚。特别是，口腔鳞状细胞癌侵袭性生长特性的分子基础尚不清楚。我们之前发现HGF/c-Met信号通过激活多个下游信号分子促进口腔SCC的恶性进展。我们的新研究表明yes相关蛋白（YAP）在HGF/c- met刺激的口腔SCC侵袭性生长中起作用。我们假设YAP通过调节侵袭和转移所需基因的转录，在HGF/c- met诱导的侵袭性生长中起作用。我们的建议是使用基因微阵列来鉴定YAP调控基因，并使用分子和遗传学技术来研究这些基因是否调节HGF诱导侵袭性基因。免疫组织化学将评估YAP和其他蛋白在口腔鳞状细胞癌组织中的表达。YAP受HGF刺激调控的机制也将被研究。我们的主要目的是确定YAP如何调节SCC细胞的侵袭性生长，以及YAP是否参与人类SCC的侵袭和转移。这个项目有三个具体目标。在ai1中，将研究YAP在口腔SCC侵袭性生长中的作用机制以及YAP与人类SCC的相关性。在Aim 2中，我们将阐明导致HGF调控YAP的信号事件。在Aim 3中，将研究YAP在SCC耐药中的作用。这些研究将有望为口服鳞状细胞癌的分子调控和新治疗方法的发展提供更深入的了解。

DESCRIPTION (provided by applicant): Patients diagnosed with oral squamous cell carcinoma (SCC) continue to face significant morbidity and mortality. Although the risk-factors of oral SCC are known, the molecular mechanisms responsible for this dreadful malignancy remain unclear. In particular, the molecular basis of the invasive growth properties of oral SCC is not well understood. We have previously found that HGF/c-Met signaling promotes the malignant progression of oral SCC through the activation of multiple downstream signaling molecules. Our new research suggests a role for Yes-associated protein (YAP) in HGF/c-Met-stimulated oral SCC invasive growth. We hypothesize that YAP functions in HGF/c-Met-induced invasive growth by regulating the transcription of select genes necessary for invasion and metastasis. Our proposal is to use gene microarrays to identify YAP- regulated genes and to use molecular and genetic techniques to investigate whether these genes regulate the induction of invasive genes by HGF. Immunohistochemistry will be performed to evaluate the expression of YAP and other proteins in oral SCC tissues. The mechanism whereby YAP is regulated in response to HGF stimulation will also be investigated. Our main goals are to determine how YAP regulates SCC cell invasive growth and whether YAP is involved in human SCC invasion and metastasis. There are three specific aims for this project. In Aim1, the mechanism whereby YAP functions in oral SCC invasive growth and the relevance of YAP to human SCC will be investigated. In Aim 2, the signaling events leading to YAP regulation by HGF will be elucidated. In Aim 3, a role for YAP in SCC anoikis resistance will be examined. These studies will be expected to provide greater insight into the molecular regulation of oral SCC and the development of new therapeutic approaches. PUBLIC HEALTH RELEVANCE: The research outlined in this K99/R00 award will reveal new details about the molecular basis of oral carcinogenesis. The ultimate goal of this work is to improve our understanding of the propensity of oral cancer cells to invade tissues and metastasize so as to improve our options for therapeutic intervention.