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.

摘要 头颈部鳞状细胞癌(HNSCC)，包括上呼吸道癌症，是一种 全球最常见的癌症之一，据估计，20111年美国新增病例为52,000例。 虽然早期HNSCC的放射治疗和/或手术治疗在治疗上往往是成功的 原发肿瘤，许多患者发生二次原发肿瘤(SPT)或复发，导致 5年存活率约为50%，这一比率几十年来一直保持不变2。到目前为止，全跨 维甲酸(RA)及其异构体可能是治疗和治疗中研究最深入的药物 预防SPT和HNSCC复发。内源性视黄醇合成视黄酸的限速酶 (维生素A)，乙醛脱氢酶1a2(ALDH1a2)，最近被证明在 人类前列腺癌20。此外，在RNA数据集中，ALDH1a2转录水平显著降低 从500多个人类HNSCC样本中。我们的目的是研究ALDH1a2作为HNSCC抑制因子的作用 肿瘤发生学。我们假设ALDH1a2的表达通过增加HNSCC的表达抑制HNSCC的发展。 内源性RA的产生和信号转导。为了验证这一假设，我将进行一个多方面的项目 检测ALDH1a2在体内外对HNSCC的影响。在目标1中，我将确定是否 ALDH1a2的表达通过感染几个人HNSCC株而改变其致瘤表型 逆转录病毒ALDH1a2表达载体。我的初步结果表明，ALDH1a2的表达显著 在体外抑制HNSCC细胞的生长和克隆形成。在目标2中，我将创建可诱导(通过)的转基因小鼠 四环素调节)在口腔粘膜中表达ALDH1a2，然后确定这种诱导 在我们的致癌物诱导的小鼠口腔癌模型中降低口腔癌的发生率和/或严重程度 人类口腔癌的发生。此外，在这两个目标中，我将比较内源性ALDH1a2的影响 与外源性RA治疗组相比，差异有统计学意义。通过完成这些目标，我将决定是否异端 ALDH1a2的表达可以抑制口腔癌的恶性表型和发病，并确定 内源性RA的生成增加是否对口腔癌的发生有更大的抑制作用 而不是外源RA的加入。这项研究不仅将加深我们对视黄醇信号转导和 HNSCC的化学预防，但也可能为ALDH1a2作为肿瘤抑制物提供第一个证据 HNSCC的发展。