Role of Long Intergenic Noncoding RNA in UVB-induced Apoptosis and Skin Cancer

长基因间非编码 RNA 在 UVB 诱导的细胞凋亡和皮肤癌中的作用

• 批准号: 9273531
• 负责人: Robert C Smart
• 金额: $ 33.58万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9273531
• 关键词: Address; Alleles; Alzheimer' s Disease; Apoptosis; Apoptotic; Biological Markers; Cell Culture System; Cell Cycle Arrest; Cell Death; Cells; Cessation of life; Chronic; Chronic Disease; Code; DNA; DNA Damage; Data; Defect; Development; Disease; Environment; Environmental Health; Environmental Risk Factor; Etiology; Experimental Models; Exposure to; Fibroblasts; Future; Gene Expression; Genetic Models; Genetic Transcription; Grant; Heart Diseases; Human; Human Genome; Inbred HRS Mice; Induced Mutation; Intergenic DNA; Intergenic Sequence; Junk DNA; Knock-in Mouse; Knockout Mice; Lead; Malignant Neoplasms; Molecular; Mus; Mutation; Oncogenic; Outcome Study; Pathogenesis; Pathway interactions; Play; Prognostic Marker; Proteins; RNA; Regulation; Reporting; Role; Screening for cancer; Skin; Skin Cancer; Skin Carcinoma; Sunlight; System; TP53 gene; Time; Transcript; Tumor Suppressor Proteins; UVB induced; Ultraviolet B Radiation; Untranslated RNA; cancer cell; disorder prevention; gain of function mutation; genome wide association study; human disease; in vivo; keratinocyte; molecular targeted therapies; mouse model; mutant; prototype; public health relevance; response; restoration; trait

 DESCRIPTION (provided by applicant): Only ~3% of the human genome encodes protein and the remaining 97% is referred to as noncoding DNA. Initially, much of the intergenic noncoding sequence was referred to as "junk DNA" as it was considered to have no function. However, many intergenic sequences can be transcribed into RNA. In fact, ~85% of the human genome is transcribed into RNA. RNAs that lack protein coding function are referred to as noncoding RNAs and of these the long noncoding RNAs (lncRNAs >200 nt) represent the majority. LncRNAs are one of the largest and most diverse classes of cellular transcripts with over 10,000 transcripts. Only a few lncRNAs have been studied to date but emerging evidence indicates lncRNAs have key roles in regulating gene expression and are associated with human diseases such as cancer, Alzheimer's and heart disease. It is critical to determine whether associations of lncRNAs with specific diseases are functionally significant and to develop mouse genetic models to define and characterize the function of lncRNAs in disease in vivo. Such studies could lead to development of prognostic markers and molecular targets for therapy. Given that the etiology of most chronic human diseases involves interactions with the environment, it is also important to determine if environmental factors can impact the expression, activity and function of lncRNAs to contribute to disease. Nonmelanoma skin cancer (NMSC) is the most common cancer in the US. The majority of NMSC is caused by UVB radiation from sunlight. p53 plays a key role in the response of skin keratinocytes to UVB- induced DNA damage by inducing cell cycle arrest and apoptosis. In NMSC, UVB-induced mutation of p53 allows keratinocytes upon successive UVB exposures to evade apoptosis and cell cycle arrest. These defects have a critical role in NMSC development. LincRNA-p21 is an lncRNA and a direct transcriptional target of p53 and is reported to induce apoptosis in mouse fibroblasts in culture. We reasoned that lincRNA-p21 could have a critical role in UVB-induced apoptosis in keratinocytes and its loss in the evasion of apoptosis and the pathogenesis of skin cancer. Our preliminary data show lincRNA-p21 is highly inducible by UVB and has a key role in UVB-induced apoptosis in keratinocytes. We plan to define the regulation and function of lincRNA-p21 in keratinocytes and to develop mouse genetic models to define the molecular function of lincRNA-p21 in controlling keratinocyte gene expression, apoptosis and skin cancer in response to UVB radiation. The central hypotheses are; i) lincRNA-p21 is induced by UVB in keratinocytes through a p53-dependent pathway to trigger apoptotic cell death and ii) lincRNA-p21 functions as a tumor suppressor in NMSC whereby the loss of lincRNA-p21 expression allows both mutant p53 and non-mutant p53 keratinocytes to evade UVB-induced apoptosis leading to skin cancer. If correct, these studies will reveal for the first time that; i) a lncRNA an function as a tumor suppressor in vivo in a mouse model, ii) an environmental factor can control the expression, activity and function of a lncRNA and iii) a lncRNA has a key role in an environmentally-induced disease.

 描述(申请人提供)：只有~3%的人类基因组编码蛋白质，其余的97%被称为非编码DNA。最初，许多基因间的非编码序列被称为“垃圾DNA”，因为它被认为没有功能。然而，许多基因间序列可以转录成RNA。事实上，大约85%的人类基因组被转录成RNA。缺乏蛋白质编码功能的RNA被称为非编码RNA，在这些RNA中，长的非编码RNA(LncRNAs&gt；200nt)代表了大部分。LncRNAs是最大和最多样化的细胞转录本之一，有超过10,000个转录本。到目前为止，只有几个lncRNAs被研究过，但越来越多的证据表明，lncRNAs在调节基因表达方面具有关键作用，并与癌症、阿尔茨海默氏症和心脏病等人类疾病有关。关键是要确定lncRNAs与特定疾病的关联是否在功能上有意义，并建立小鼠遗传模型来定义和表征lncRNAs在体内疾病中的功能。这样的研究可能导致开发预后标记物和治疗的分子靶点。鉴于大多数慢性人类疾病的病因学涉及与环境的相互作用，确定环境因素是否可以影响lncRNAs的表达、活性和功能以促进疾病也是重要的。非黑素瘤皮肤癌(NMSC)是美国最常见的癌症。NMSC的大部分是由太阳光的UVB辐射引起的。P53通过诱导细胞周期停滞和细胞凋亡，在皮肤角质形成细胞对UVB诱导的DNA损伤的反应中起关键作用。在NMSC中，UVB诱导的p53突变允许角质形成细胞在连续的UVB暴露下逃避细胞凋亡和细胞周期停滞。这些缺陷对NMSC的发展起着至关重要的作用。LincRNA-p21是一种lncRNA，是P53的直接转录靶点，据报道可诱导培养的小鼠成纤维细胞凋亡。我们推测，lincRNA-p21可能在UVB诱导角质形成细胞的凋亡中起关键作用，并在逃避细胞凋亡和皮肤癌的发病机制中发挥重要作用。我们的初步数据表明，lincRNA-p21是UVB高度诱导的，并且在UVB诱导角质形成细胞的凋亡中起关键作用。我们计划确定lincRNA-p21在角质形成细胞中的调控和功能，并建立小鼠遗传模型，以确定lincRNA-p21在调控角质形成细胞基因表达、细胞凋亡和皮肤癌中的分子功能。中心假设是：i)lincRNA-p21是由UVB通过P53依赖的途径在角质形成细胞中诱导细胞死亡，以及ii)LincRNA-p21在NMSC中作为肿瘤抑制因子，从而使突变型P53和非突变型P53角质形成细胞都能逃避UVB诱导的细胞凋亡，从而导致皮肤癌。如果正确，这些研究将首次揭示：i)lncRNA在小鼠模型中具有肿瘤抑制作用，ii)环境因素可以控制lncRNA的表达、活性和功能，iii)lncRNA在环境诱导的疾病中发挥关键作用。