Progression and Metastasis of Oral Tongue Cancer

描述(申请人提供)：TP53是所有癌症中最常见的体细胞突变基因，在高达85%的口腔舌鳞状细胞癌(SCCOT)病例中发生改变。虽然一些TP53突变会导致野生型p53功能的丧失，但许多TP53突变已被发现具有促进侵袭、转移、基因组不稳定性和癌细胞增殖的功能获得(GOF)。然而，特定突变是否会导致GOF的确定，以及突变的P53 GOF活性所涉及的机制仍然是未知的。我们的长期目标是了解TP53突变在促进SCCOT侵袭性方面的作用，并基于这些信息，为SCCOT患者设计和开发有效和精确的癌症治疗方法。本研究的目的是了解不同的TP53突变对SCCOT患者临床预后的影响，并进一步探讨突变型p53 GOF活性促进肿瘤进展和转移的机制。我们的中心假设是，我们新开发的EAp53评分系统发现的高危p53突变与突变的p53 GOF活性有关，后者有助于疾病的进展、转移和不良的临床结果，突变的p53通过以转录依赖和非依赖的方式抑制AMPK介导的信号传导，通过正向调节癌基因转录因子、FOXM1‘S的表达和刺激粘着斑激酶(FAK)来实现癌基因功能。这一假设是基于我们最近令人兴奋的初步数据而提出的。这项拟议研究的基本原理是，拟议研究的成功完成将确立EAp53分层在预测临床结果或SCCOT患者方面的临床意义，并将提供对P53突变的GOF的机械性见解。以强大的初步数据为指导，这一假说将通过追求三个特定目标来验证：1)目的1：证明EAp53能够确定与HNSCC患者不良临床结局相关的P53突变，并证明高危P53突变与体内外突变的P53功能获得活性之间的相关性；2)目的2：证明高危突变的P53 GOF活性通过转录依赖和转录非依赖的机制抑制AMPK信号转导导致侵袭性肿瘤细胞的生长和转移；3)目标3：证明TP53密码子72多态性调控突变P53介导的AMPK抑制GOF活性，促进肿瘤侵袭细胞的生长和转移。我们建议的研究是创新的，因为研究GOF突变p53的机制和方法以前还没有报道过。我们建议的研究也具有重要意义，因为它不仅增强了我们对突变型p53在介导SCCOT疾病进展中的作用的理解，而且使我们能够基于TP53突变状态更好地预测和治疗具有高疾病进展和复发风险的HNSCC患者。

DESCRIPTION (provided by applicant): TP53 is the most commonly somatically mutated gene in all cancers, and is altered in as many as 85% of squamous cell carcinoma of the oral tongue (SCCOT) cases. While some TP53 mutations lead to a loss of wild-type p53 function, many TP53 mutations have been identified to confer gain of functions (GOF) that promote invasion, metastasis, genomic instability, and cancer cell proliferation. However, the determination of whether a specific mutation will lead to GOF, and the mechanisms involved in mutant p53 GOF activity remain elusive. Our long-term goal is to understand the role of TP53 mutations in promoting aggressiveness of SCCOT, and based on this information, to design and develop effective and precise cancer therapies for SCCOT patients. The objective of this proposal is to understand the impact of different TP53 mutations on the clinical outcomes of SCCOT patients, and to further investigate the mechanisms involved in mutant p53 GOF activity that promote tumor progression and metastasis. Our central hypothesis is that high-risk p53 mutations identified by our newly-developed EAp53 scoring system are associated with mutant p53 GOF activity that contributes to disease progression, metastasis and adverse clinical outcomes, and that mutant p53s achieve gain oncogenic function through positive regulation of the oncogenic transcription factor, FoxM1's expression and stimulation of focal adhesion kinase (FAK) through inhibition of AMPK-mediated signaling in both transcription-dependent and -independent manners. This hypothesis has been formulated on the basis of our recent exciting preliminary data. The rationale for the proposed study is that successful completion of proposed studies will establish clinical significance of EAp53 stratification in predicting clinic outcomes or SCCOT patients, and will provide mechanistic insights into GOF of p53 mutations. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Aim 1: Demonstrate the ability of EAp53 to identify p53 mutations associated with adverse clinical outcomes for HNSCC patients, and correlate high-risk p53 mutations with both in vitro and in vivo mutant p53 gain-of-function activity; 2) Aim 2: Demonstrate that high-risk mutant p53 GOF activity inhibits AMPK signaling leading to invasive tumor cell growth and metastasis through transcription-dependent and transcription-independent mechanisms, and 3) Aim 3: Demonstrate that the TP53 codon 72 polymorphism modulates the GOF activity of mutant p53-mediated AMPK inhibition and promotes tumor invasive cell growth and metastasis. Our proposed study is innovative given that the proposed mechanisms and the approaches for studying GOF mutp53 have not been reported before. Our proposed study is also significant since it not only enhances our understanding of the role of mutant p53 in mediating SCCOT disease progression, but also enables us to better prognosticate and treat HNSCC patients at high risk for disease progression and recurrence based on TP53 mutational status.