Project 2: Tumor Suppessive Role of ACER1 in Skin Cancer

项目2：ACER1在皮肤癌中的抑癌作用

• 批准号: 8742660
• 负责人: CUNGUI MAO
• 金额: $ 21.54万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8742660
• 关键词: Accounting; Acetates; Animal Model; Anthracenes; Apoptosis; Biological Markers; Cancer Biology; Cancer Etiology; Cell Cycle; Cell Line; Cell Proliferation; Cells; Ceramidase; Ceramides; Cessation of life; Chemoprevention; Chronic; Development; Diagnosis; Disease; Down-Regulation; Enzymes; Epidermis; Family; Gene Expression; Gene Expression Profiling; Genes; Goals; Growth; Head and Neck Cancer; Head and neck structure; High Prevalence; Human; Hydrolysis; Laboratories; Lipids; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Mammals; Measures; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Normal tissue morphology; Oral; Pathogenesis; Pathway interactions; Play; Premalignant; Prevention; Prevention approach; Preventive; Process; Recurrence; Refractory; Regulation; Research; Role; Saccharomyces cerevisiae; Signal Transduction Pathway; Skin; Skin Cancer; Skin Carcinogenesis; Skin Carcinoma; Sphingolipids; Sphingosine; Squamous Cell; Squamous cell carcinoma; Staging; Testing; Tetradecanoylphorbol Acetate; Therapeutic; Tissues; Transgenes; Tumor Burden; Tumor Promoters; Tumor Promotion; Tumor Suppressor Proteins; Ultraviolet Rays; United States; Yeasts; base; cancer diagnosis; cancer therapy; care burden; combat; dimethylbenzanthracene; early onset; health economics; in vitro Model; insight; keratinocyte; keratinocyte differentiation; lipid mediator; member; mortality; mouse alkaline ceramidase; mouse model; novel; novel strategies; outcome forecast; overexpression; senescence; skin cancer prevention; skin squamous cell carcinoma; sphingosine 1-phosphate; sphingosine kinase; sphingosine-1-phosphate lyase; tumor; tumor initiation; tumorigenesis

PROJECT SUMMARY Cutaneous squamous cell carcinoma (CSCC), the most aggressive non-melanoma skin cancer, is the second most common cancer in the USA and worldwide. Head and neck SCC (HNSCC) is a leading cause of cancer deaths worldwide and accounts for 3-5% of all cancers in USA. Together, these cancers (SCC) contribute substantially to morbidity and mortality. Our long-term goal is to develop novel approaches to SCC prevention and treatment based on a deep understanding of its pathogenesis. The specific goal of this application is to define a novel tumor suppressive role for alkaline ceramidase 1 (ACER1), a member in the alkaline ceramidase family that we identified initially from the yeast Saccharomyces cerevisiae and then from mammals, in SCC development and progression. SCC arises from keratinocytes or squamous cells through a multistage process including tumor promotion. Tumor promotion alters the expression of genes controlling cell proliferation, differentiation, and apoptosis and identification of such genes offers targets for chemoprevention and/or therapy. Through gene expression profiling, we find that 12-O-tetradecanoylphorbol-13-acetate (TPA), the classic tumor promoter, inhibits the expression of ACER1 in normal epidermal keratinocytes. Importantly, we demonstrate that overexpression of the human ACER1 transgene in the mouse epidermis increases tumor latency and reduces tumor burden in the two-stage skin carcinogenesis model initiated with 7,12- dimethylbenz(a)anthracene (DMBA) and promoted with TPA, suggesting that ACER1 downregulation contributes to tumor promotion. Consistent with this notion, we show that ACER1 expression is markedly suppressed in SCC cell lines and tissues and that restoring ACER1 expression inhibits the proliferation of SCC cells, suggesting that ACER1 downregulation leads to the hyperproliferation of premalignant and malignant keratinocytes, thereby promoting SCC development. Based on these important findings, we hypothesize that ACER1 acts as a tumor suppressor in SCC and that its downregulation promotes skin tumorigenesis by promoting epidermal keratinocyte hyperproliferation. As a further corollary, we hypothesize that rectifying the ACER1 mediated pathway will inhibit skin tumorigenesis. These hypotheses will be tested by two specific aims. In Aim 1, we will define the tumor suppressive role for ACER1 in SCC using both in vitro model of tumor promotion and animal models of skin tumorigenesis and establish that dysregulation of the ACER1/sphingolipid pathway is a predictive biomarker for early onset SCC. In Aim 2 we will define the cellular and molecular mechanisms by which the ACER1/sphingolipid pathway functions as a tumor suppressor in SCC. The proposed research will provide not only insights into the role of the ACER1/sphingolipid pathway in SCC suppression but also an intellectual framework for skin cancer prevention and treatment.

项目摘要 皮肤鳞状细胞癌（CSCC）是最具侵略性的非黑色素瘤皮肤癌，是第二种 在美国和全球最常见的癌症。头和颈SCC（HNSCC）是癌症的主要原因 全球死亡，占美国所有癌症的3-5％。这些癌症（SCC）一起贡献 基本上是发病率和死亡率。我们的长期目标是开发新颖的SCC预防方法 以及基于对其发病机理的深刻理解的治疗。此应用的具体目标是 定义碱性神经酶1（ACER1）的新型肿瘤抑制作用，碱性成员 我们最初从酿酒酵母中发现的神经酰胺酶家族，然后是 哺乳动物，在SCC开发和进展中。 SCC来自角质形成细胞或鳞状细胞通过 多阶段过程，包括肿瘤促进。肿瘤促进改变控制细胞的基因的表达 这种基因的增殖，分化和凋亡和鉴定提供了化学预防的靶标 和/或治疗。通过基因表达谱分析，我们发现12-O-四烷酰基-13-乙酸酯（TPA）， 经典肿瘤启动子抑制正常表皮角质形成细胞中ACER1的表达。重要的是， 我们证明了小鼠表皮中人ACER1转基因的过表达增加肿瘤 潜伏期和减轻了以7,12--启动的两级皮肤致癌模型中的肿瘤负担 Dimethylbenz（A）蒽（DMBA）并用TPA促进，表明ACER1下调 促进肿瘤。与这个概念一致，我们表明ACER1表达明显 在SCC细胞系和组织中抑制，恢复ACER1表达抑制了SCC的增殖 细胞，表明ACER1下调会导致预抗剂和恶性肿瘤的过度增殖 角质形成细胞，从而促进SCC开发。基于这些重要发现，我们假设 ACER1充当SCC中的肿瘤抑制剂，其下调可通过 促进表皮角质形成细胞高增殖。作为进一步的推论，我们假设这是纠正的 ACER1介导的途径将抑制皮肤肿瘤发生。这些假设将通过两个具体目标来检验。 在AIM 1中，我们将使用两种体外肿瘤模型来定义SCC中ACER1的肿瘤抑制作用 皮肤肿瘤发生的促进和动物模型，并确定ACER1/鞘脂的失调 途径是早期发作SCC的预测生物标志物。在AIM 2中，我们将定义细胞和分子 ACER1/鞘脂途径在SCC中充当肿瘤抑制剂的机制。这 拟议的研究不仅将提供有关ACER1/鞘脂途径在SCC中的作用的见解。 抑制是预防皮肤癌和治疗的智力框架。