Cyclin D1 and vitamin D signaling in oral keratinocyte pathophysiology

描述(由申请人提供)：本提案的重点是细胞周期蛋白D1癌基因在口腔癌中的作用。口咽鳞状细胞癌(OSCC)是一种侵袭性肿瘤，可导致严重的死亡率和发病率。通常，这些肿瘤最初是癌前病变，然后发展为侵袭性肿瘤。然而，转化为侵袭性肿瘤的分子机制尚不完全清楚。此外，饮食制剂在改变这一过程中的作用还没有研究过。细胞周期蛋白D1癌基因在口腔鳞癌的发生发展中起重要作用。细胞周期蛋白D1是细胞周期G1-S期的关键调控因子。它通过其蛋白激酶CDK4和CDK6发挥作用，导致视网膜母细胞瘤蛋白的磷酸化，从而影响细胞周期进程。目前的研究范式认为这是细胞周期蛋白D1‘S致癌作用的主要机制。然而，越来越多的证据表明，细胞周期蛋白D1参与了转录调控。我们最近发现细胞周期蛋白D1与维生素D受体(VDR)结合并调节维生素D信号转导。这一发现特别重要，因为维生素D在角质形成细胞的增殖和分化调节中起着至关重要的作用。这项研究将研究细胞周期蛋白D1和维生素D信号通路之间的交集。这项建议的短期目标是：(1)研究细胞周期蛋白D1解除维生素D信号调控的机制；(2)研究饮食中维生素D缺乏在调节口腔癌前病变和癌症发展中的作用。长期目标是研究维生素D信号在口腔角质形成细胞生理学和病理生理学中的作用，它与致癌途径的交集及其在口腔癌发生中的意义。为了实现这些目标，提出了两个具体目标。具体目标1将研究细胞周期蛋白D1解除VDR介导的转录调控的机制。具体目标2将使用转基因小鼠模型系统来研究饮食中维生素D缺乏在调节细胞周期蛋白D1驱动的口腔癌前病变中的作用。这些研究将显著增加我们对细胞周期蛋白D1‘S致癌机制和维生素D在调节口腔癌风险中的作用的理解。鉴于美国和全球正在出现的维生素D营养状况问题，我们的研究对口腔癌管理的潜在饮食和化学预防方法具有巨大的影响。此外，细胞周期蛋白D1是几种肿瘤类型的已知癌基因，越来越多的证据表明维生素D在几种癌症中起作用。因此，我们的研究对其他几种肿瘤类型具有潜在的广泛影响。

DESCRIPTION (provided by applicant): The focus of this proposal is on the role of the cyclin D1 oncogene in oral cancer. Oropharyngeal squamous cell carcinomas (OSCC) are aggressive tumors that result in significant mortality and morbidity. Frequently, these tumors initiate as a precancerous lesion that develops to an invasive neoplasm. However, the molecular mechanisms underlying the transition to invasive neoplasia are not fully understood. Furthermore, the role of dietary agents in modifying this process has not been studied. The cyclin D1 oncogene plays an important role in OSCC development. Cyclin D1 is a key regulator of the G1-S phase of the cell cycle. Acting via its kinase partners CDK4 and CDK6, it results in phosphorylation of the retinoblastoma protein to effect cell cycle progression. The current paradigm assumes that this is the major mechanism of cyclin D1's oncogenic actions. However, there is emerging evidence that cyclin D1 participates in transcriptional control. We recently discovered that cyclin D1 binds to the vitamin D receptor (VDR) and modulates vitamin D signaling. This finding is particularly significant in that vitamin D plays an essential role in regulation of keratinocyte proliferation and differentiation. The studies described in this proposa will study the intersection between the cyclin D1 and vitamin D signaling pathways. The short-term goals of this proposal are to (1) examine the mechanism by which cyclin D1 deregulates vitamin D signaling and (2) examine role of dietary vitamin D deficiency in modulating the development of oral pre-cancer and cancer. The long-term goal is to study the contribution of vitamin D signaling in oral keratinocyte physiology and pathophysiology, its intersection with oncogenic pathways and its implications for oral carcinogenesis. To achieve these goals two Specific Aims are proposed. Specific Aim 1 will investigate the mechanism by which cyclin D1 deregulates VDR-mediated transcriptional control. Specific Aim 2 will examine the role of dietary vitamin D deficiency in modulating cyclin D1-driven oral pre-cancer using a transgenic mouse model system. These studies will significantly increase our understanding of cyclin D1's oncogenic mechanisms and vitamin D's role in modulating oral cancer risk. Given the emerging problem of vitamin D nutritional status both in the United States as well as globally, our studies have tremendous implications for potential dietary and chemopreventive approaches to oral cancer management. Furthermore, cyclin D1 is an established oncogene for several tumor types and there is growing evidence for vitamin D's role in several cancers. Thus, our studies have potentially broad implications for several other tumors types.