Cell Cycle Dysregulation in Oral Cancer

口腔癌的细胞周期失调

• 批准号: 6863760
• 负责人: Philip W. Hinds
• 金额: $ 44.2万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6863760
• 关键词: RNA interference; apoptosis; athymic mouse; cell cycle; cell line; cell senescence; cyclin dependent kinase; cytogenetics; genetic regulation; kinase inhibitor; mouth neoplasms; neoplasm /cancer genetics; neoplastic growth; neoplastic transformation; pathologic process; protein protein interaction; tumor suppressor genes

DESCRIPTION (provided by applicant): Head and neck cancer is believed to originate via a multi-step process that involves the activation of oncogenes and inactivation of tumor suppressor genes, however, the specific pattern of progression and the necessary genetic alterations have not been delineated. Although treatment advances have been made in the last 30 years, little or no survival improvement has been obtained. Identifying the specific genes or proteins involved in transformation of a normal cell to a malignant cell, and the particular sequence of these genes or proteins, is necessary for the development of early detection methods, the formulation of new treatment strategies, and the prediction of patient outcome. While studies on oral tumorigenesis are specifically beneficial to head and neck cancer patients, such studies are likely to also aid the understanding of multi-step carcinogenesis in general. To translate these advantages into procedures that may be beneficial to oral cancer patients, the basic molecular changes involved in oral cancer development must be understood. To this end we investigated the mechanism of cell cycle dysregulation in oral cancer development. As with most human tumors, the common tumor suppressor p53 (but not its regulator pl4ARF) and the pRb pathway are disrupted in oral cancer cells. Most interestingly, we found that the pRb regulator cdk6 is preferentially hyperactivated in oral cancer cells by a variety of mechanisms, while the related kinase cdk4 is active at levels similar to those observed in primary cells. These data complement a number of studies in our labs and others that indicate that cdk4 and cdk6 are not equivalent in their ability to induce proliferation in all cell types and may have non-overlapping roles in tumorigenesis. Further, inhibition of both kinases by p 16INK4a can lead to a senescent state in oral cancer cell lines, indicating that continued activity of cdk4, cdk6 or both is required for tumor cell proliferation. In order to better understand the roles of these pRb pathway regulators and the process of cell cycle dysregulation in general in oral cancer, we propose three specific aims: (1) construct and deconstruct oral cancer cells by manipulating the activity of cell cycle regulators in normal oral epithelial cells and oral cancer cells respectively. This will test suspected targets for antiproliferative agents in oral cancer cells and will elucidate the consequences of dysregulation of known cell cycle regulators. (2) Reversibly inhibit cdk4, cdk6 or both in order to induce senescence and apoptosis in oral cancer cells and thus validate them as targets for therapy. (3) Determine the biological activity of CLLL7, a novel cdk4/cdk6 interacting protein encoded by a gene on chromosome 13.

描述（由申请人提供）：头颈癌被认为是通过一个多步骤过程起源的，该过程涉及癌基因的激活和肿瘤抑制基因的失活，然而，具体的进展模式和必要的遗传改变尚未被描述。虽然在过去的30年里，治疗取得了进展，但生存率几乎没有改善。鉴定参与正常细胞向恶性细胞转化的特定基因或蛋白质以及这些基因或蛋白质的特定序列对于开发早期检测方法、制定新的治疗策略以及预测患者结果是必要的。虽然关于口腔肿瘤发生的研究对头颈癌患者特别有益，但这些研究也可能有助于了解一般的多步骤致癌作用。为了将这些优势转化为可能对口腔癌患者有益的程序，必须了解口腔癌发展中涉及的基本分子变化。为此，我们研究了口腔癌发展中细胞周期失调的机制。与大多数人类肿瘤一样，口腔癌细胞中常见的肿瘤抑制因子p53（但不是其调节因子p14 ARF）和pRb途径被破坏。最有趣的是，我们发现，pRb调节cdk 6优先在口腔癌细胞中通过各种机制被过度激活，而相关激酶cdk 4的活性水平与原代细胞中观察到的水平相似。这些数据补充了我们实验室和其他实验室的一些研究，这些研究表明cdk 4和cdk 6在所有细胞类型中诱导增殖的能力并不等同，并且在肿瘤发生中可能具有非重叠的作用。此外，p16 INK 4a对两种激酶的抑制可导致口腔癌细胞系中的衰老状态，表明cdk 4、cdk 6或两者的持续活性是肿瘤细胞增殖所需的。为了更好地理解pRb通路调控因子在口腔癌中的作用和细胞周期失调的过程，我们提出了三个具体的目标：（1）通过分别操纵正常口腔上皮细胞和口腔癌细胞中细胞周期调控因子的活性来构建和解构口腔癌细胞。这将测试口腔癌细胞中抗增殖剂的可疑靶点，并阐明已知细胞周期调节剂失调的后果。(2)可逆地抑制cdk 4、cdk 6或两者，以诱导口腔癌细胞的衰老和凋亡，从而验证它们作为治疗靶点。(3)确定CLLL 7的生物活性，CLLL 7是一种由13号染色体上的基因编码的新型cdk 4/cdk 6相互作用蛋白。