ALDH1a2 (RALDH2) in a Murine Oral Cavity Squamous Cell Carcinoma Model

小鼠口腔鳞状细胞癌模型中的 ALDH1a2 (RALDH2)

• 批准号: 8649168
• 负责人: Abigail Kathryn Horstmann
• 金额: $ 4.3万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8649168
• 关键词: Abbreviations; Affect; Aftercare; All-Trans-Retinol; Apoptosis; Attenuated; Automobile Driving; Biological Assay; Carcinogens; Cell Differentiation process; Cells; Chemoprevention; Cytochrome P450; Cytokeratin; Cytokeratin-14 Staining Method; Data; Data Set; Deoxycytidine; Development; Dietary intake; Doxycycline; Early treatment; Employee Strikes; Enzymes; Epidermal Growth Factor Receptor; Exhibits; Genes; Goals; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; High Pressure Liquid Chromatography; Human; In Vitro; Incidence; Knowledge; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Modeling; Molecular; Monitor; Mus; Nitroquinolines; Operative Surgical Procedures; Oral cavity; Oral mucous membrane structure; Oxides; Patients; Phenotype; Polymerase Chain Reaction; Prevention; Primary Neoplasm; Production; Prostate; Protein Isoforms; RNA; RXR; Radiation therapy; Recurrence; Regulation; Research; Response Elements; Retinaldehyde; Retinoic Acid Receptor; Retinoic Acid Response Element; Retinoids; Retroviral Vector; Risk; Role; Sampling; Severities; Signal Pathway; Signal Transduction; Staging; Stratum Basale; Survival Rate; System; Testing; Tetanus Helper Peptide; Tetracycline Control; Tetracyclines; Time; Tissues; Trans-Activators; Transcript; Transgenic Mice; Transgenic Organisms; Tretinoin; Tumor Suppressor Proteins; United States; Upper aerodigestive tract cancer; Vitamin A; Western Blotting; Work; aldehyde dehydrogenase 1A2; base; cancer prevention; cancer therapy; carcinogenesis; cell growth; cell motility; experience; expression vector; in vivo; inhibitor/antagonist; lecithin-retinol acyltransferase; malignant phenotype; mouse model; mouth squamous cell carcinoma; oral carcinogenesis; oral cavity epithelium; prevent; promoter; public health relevance; receptor; tumor; tumorigenesis; tumorigenic

Abstract Head and neck squamous cell carcinomas (HNSCC), including cancers of the upper aerodigestive tract, are one of the most common cancers worldwide, with an estimated 52,000 new cases in the United States in 20111. While treatment of early-stage HNSCC with radiation therapy and/or surgery is often successful in treating primary tumors, many patients develop second primary tumors (SPT) or experience recurrence, resulting in a 5-year survival rate of approximately 50%, a rate which has remained constant for decades2. To date, all-trans retinoic acid (RA) and its isoforms are perhaps the most thoroughly studied agents in the treatment and prevention of SPT and HNSCC recurrence. The rate-limiting enzyme in endogenous RA synthesis from retinol (vitamin A), aldehyde dehydrogenase 1a2 (ALDH1a2), has recently been shown to act as a tumor suppressor in human prostate cancer20. Moreover, ALDH1a2 transcript levels were dramatically reduced in RNA data sets from over 500 human HNSCC samples. We aim to investigate the role of ALDH1a2 as an inhibitor of HNSCC tumorigenesis. We hypothesize that ALDH1a2 expression inhibits the development of HNSCC by increasing endogenous RA production and signaling. To test this hypothesis, I will conduct a multi-faceted project examining the effect of ALDH1a2 expression on HNSCC both in vitro and in vivo. In Aim 1, I will determine if ALDH1a2 expression alters the tumorigenic phenotype of several human HNSCC lines by infecting them with a retroviral ALDH1a2 expression vector. My preliminary results indicate that ALDH1a2 expression significantly inhibits HNSCC cell growth and clonogenicity in vitro. In Aim 2 I will create transgenic mice that inducibly (via tetracycline regulation) express ALDH1a2 in the oral mucosa, and then determine whether this induction reduces the incidence and/or severity of oral cavity carcinogenesis in our carcinogen-induced murine model of human oral carcinogenesis. Furthermore, in both aims I will compare the effects of endogenous ALDH1a2 expression to those of treatment with exogenous RA. By completing these aims I will determine if ectopic ALDH1a2 expression can inhibit the malignant phenotype and onset of oral cavity cancer, and ascertain whether enhanced production of endogenous RA is more inhibitory with respect to oral cavity carcinogenesis than addition of exogenous RA. This research will not only further our understanding of retinoid signaling and chemoprevention in HNSCC, but may also provide the first evidence for ALDH1a2 as an inhibitor of tumor development in HNSCC.

抽象的 头部和颈部鳞状细胞癌（HNSCC），包括上层机场消化道的癌症，是一个 在全球最常见的癌症中，在20111年，美国有52,000例新病例。 虽然通过放射治疗和/或手术治疗早期HNSCC通常在治疗方面成功 原发性肿瘤，许多患者发生第二个原发性肿瘤（SPT）或经历复发，导致 5年生存率约为50％，这种率一直保持恒定数十年2。迄今为止，全能 视黄酸（RA）及其同工型也许是治疗中最彻底研究的药物 预防SPT和HNSCC复发。视黄醇内源性RA合成中的速率限制酶 （维生素A），醛脱氢酶1A2（ALDH1A2），最近已被证明是在 人前列腺癌20。此外，在RNA数据集中，ALDH1A2转录水平大大降低 来自500多个人类HNSCC样品。我们旨在研究Aldh1a2作为HNSCC抑制剂的作用 肿瘤发生。我们假设ALDH1A2表达通过增加而抑制HNSCC的发展 内源性RA产生和信号传导。为了检验这一假设，我将进行一个多方面的项目 检查ALDH1A2表达对体外和体内HNSCC的影响。在AIM 1中，我将确定是否 Aldh1a2表达通过用A感染几种人类HNSCC线的致瘤表型 逆转录病毒ALDH1A2表达载体。我的初步结果表明aldh1a2表达显着 在体外抑制HNSCC细胞生长和克隆原性。在AIM 2中，我将创建可诱导的转基因小鼠（通过 四环素调节）在口服粘膜中表达ALDH1A2，然后确定是否诱导 在我们的致癌鼠模型中降低口腔癌的发生率和/或严重程度 人口腔癌变。此外，在这两个目的中，我都将比较内源性aldh1a2的影响 表达外源性RA治疗的表达。通过完成这些目标，我将确定是否异位 ALDH1A2表达可以抑制口腔癌的恶性表型和发作，并确定 相对于口腔癌发生，增强内源性RA的产生是否更具抑制作用 而不是添加外源性RA。这项研究不仅将进一步了解类类类动物信号传导和 HNSCC中的化学预防，但也可能提供ALDH1A2作为肿瘤抑制剂的第一个证据 HNSCC的开发。