Rap 1-Mediated Protein Transport in Oral Cancer

描述（由申请人提供）：在过去的40年里，口腔癌的积极手术和放射治疗使身体和情绪衰弱，并没有改善预后（5年生存率<50%）。由于癌症是不受控制的细胞增殖的终点，阐明正常和恶性口腔角质形成细胞中控制细胞增殖的信号级联对于确定特异性治疗靶点至关重要。在口腔癌中，这些信号机制相对来说还不明确，但一个令人兴奋和重要的研究领域是由rap1A和rap1B触发的信号级联，这两种ras样蛋白已被证明在间充质细胞中具有致癌和/或肿瘤抑制特性。在之前的研究中，我们发现rap1GAP使rap1失活可以刺激非恶性角质形成细胞的增殖，但抑制口腔癌细胞的增殖。Rap1GAP使95%相同的rap1A和rap1B失活，两者都在正常和恶性角质形成细胞中表达。尽管rap1A和rap1B与几种细胞的生长有关，但尚未探索这些蛋白在同一细胞中的相互作用。此外，我们的实验室最近发现rap1在恶性角质形成细胞的细胞核中强烈表达，血清中的生长因子诱导核易位。因此，rap1A和rap1B可能与转运蛋白和效应蛋白相互作用来调节增殖。核心假设是，在口腔癌中，rap1介导的核转运被破坏，促增殖蛋白的核易位增强。本研究的目的是研究rap1A和rap1B在调节正常和恶性角质形成细胞增殖中的相互作用；并识别由rap1A和rap1B运输到细胞核以调节增殖的蛋白质。本研究的意义在于探索了促增殖蛋白在口腔癌中核质转运的重要新机制，从而确定了新的治疗靶点。

DESCRIPTION (provided by applicant): The aggressive surgical and radiologic treatment for oral cancer is physically and emotionally debilitating and has not improved prognosis (<50% 5 year survival) in the past four decades. Since cancer is the endpoint of uncontrolled cell proliferation, elucidation of the signaling cascade controlling cell proliferation in normal and malignant oral keratinocytes is critical to the identification of specific treatment targets. In oral cancer these signaling mechanisms are relatively uncharacterized but an exciting and significant area of research is the signaling cascade triggered by rap1A and rap1B, ras-like proteins that have been shown to have oncogenic and/or tumor suppressive properties in mesenchymal cells. In previous studies we found that inactivation of rap1 by rap1GAP, stimulated proliferation in non-malignant keratinocytes but inhibited proliferation in oral cancer. Rap1GAP inactivates rap1A and rap1B, the 95% identical isoforms, both of which are expressed in normal and malignant keratinocytes. Although rap1A and rap1B have been linked to growth in several cells, the interaction between these proteins in the same cell has not been explored. Furthermore, our laboratory recently discovered that rap1 is strongly expressed in the nucleus of malignant keratinocytes and that growth factors in serum induce nuclear translocation. Hence, it is likely that rap1A and rap1B interact with transport and effector proteins to regulate proliferation. The central hypothesis is that in oral cancer there is a disruption in rap1-mediated nuclear transport with enhanced nuclear translocation of pro-proliferative proteins. The objectives of this proposal are to investigate the interaction between rap1A and rap1B in regulating proliferation in normal and malignant keratinocytes; and to identify the proteins that are transported by rap1A and rap1B to the nucleus to regulate proliferation. The significance of this research is that it explores an important and novel mechanism for nucleocytoplasmic transport of pro-proliferative proteins in oral cancer, thereby identifying novel treatment targets.