Mechanisms regulating the early stages of UV-induced skin cancer

调节紫外线诱发皮肤癌早期阶段的机制

• 批准号: 10376752
• 负责人: John T. Seykora
• 金额: $ 36.23万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376752
• 关键词: Actinic keratosis; Address; Affect; American; Automobile Driving; Basic Science; Biological; Biological Assay; Biological Markers; Biopsy; Biopsy Specimen; Carcinogens; Carcinoma in Situ; Cells; Cessation of life; Chromatin; Clonal Expansion; Clone Cells; Comparative Genomic Analysis; Consumption; DNA Damage; DNA Repair; DNA Sequence Alteration; DNA analysis; DNA sequencing; Data; Development; Differentiation and Growth; Dominant-Negative Mutation; Engineering; Epidemic; Epidermis; Flow Cytometry; Frequencies; Genes; Genetic; Genetically Engineered Mouse; Genome; Genomic DNA; Goals; Growth; Harvest; Health Care Costs; Healthcare; Histologic; Human; Human Engineering; Image; Incidence; Induced Mutation; Lead; Lentivirus; Lesion; Libraries; Link; Malignant Neoplasms; Modeling; Morbidity - disease rate; Mus; Mutate; Mutation; Mutation Analysis; Neoplasm Metastasis; Nuclear; Nuclear Pore; Nuclear Pore Complex; Nuclear Pore Complex Proteins; Oncogenes; Patients; Population; Probability; Proteins; Public Health; Quality of life; RNA analysis; Reporting; Research; Role; Sampling; Signal Transduction; Skin; Skin Cancer; Skin Carcinogenesis; Squamous cell carcinoma; Strategic Planning; Surgeon; System; TP53 gene; Testing; Therapeutic; Time; Tissues; Treatment Cost; UV Radiation Exposure; UV carcinogenesis; UV induced; UV induced DNA damage; UV sensitive; Ultraviolet Rays; Xenograft Model; Xenograft procedure; aging population; cellular transduction; combat; cost effective treatment; epidermis cell; exome sequencing; genome integrity; human model; improved; in vivo; insight; keratinocyte; laser capture microdissection; loss of function mutation; mortality; mouse model; mutant; notch protein; novel; novel strategies; premalignant; rational design; response; skin squamous cell carcinoma; skin xenograft; small hairpin RNA; transcription factor; transcriptome sequencing; two photon microscopy; ultraviolet irradiation

Project Summary: Cutaneous squamous cell carcinoma (cSCC) is the second most common form of cancer with approximately 700,000 cases annually in the US leading to 3,000 deaths. The incidence of cSCC will increase given an aging population with rising cumulative UV exposure. In response to this epidemic, the Surgeon General issued a `Call to Action' detailing a plan to address the growing epidemic of UV-induced skin cancers. One component of this strategic plan to decrease UV-induced skin cancer is to perform research that defines the mechanisms of UV-induced skin cancer. The transition from keratinocyte to cSCC by UV radiation involves formation of precancerous lesions, called actinic keratoses (AKs) and carcinoma in situ (SCCIS). AKs and SCCIS are hypothesized to arise from UV-induced mutations in keratinocytes that lead to cell populations with aberrant growth and differentiation. To better understand how UV irradiation alters keratinocytes and promotes the early stages of skin cancer, we performed laser capture microdissection of SCCIS and adjacent UV-exposed epidermis, isolated genomic DNA and generated libraries for whole exome sequencing. This novel approach permits a precise comparative genomic analysis of mutations in UV-exposed epidermis and SCCIS. Our exomic sequencing data demonstrate low frequency UV-signature loss-of-function mutations in Notch in 60% of epidermal samples and heterozygous clonal mutations in 40% of SCCIS samples. Nucleoporins (Nups) were also frequently mutated in 80% of epidermal libraries and 100% of SCCIS libraries. These data show that UV-signature mutations in Notch and Nups are more common than mutations in known oncogenes such as p53 or RAS. The goal of this proposal is to show how Notch and Nup mutations promote the early stages of UV-induced skin carcinogenesis leading to SCCIS. The biological impact of UV- irradiation on Notch-deficient clones will be studied using genetically engineered mice and engineered human keratinocytes in xenograft models. The biological significance of Nup mutations in UV-irradiated skin will be determined using mice with an epidermal deficiency in the Nup Elys, which links the nuclear pore complex to chromatin. In addition, human keratinocytes will be engineered to express mutant Nups and subjected to UV-irradiation in a xenograft model. The aims of this proposal will yield novel insights into the role of Notch and Nup mutations in skin cancer and will provide important insights into designing rational approaches to treat SCCIS.

皮肤鳞状细胞癌（cSCC）是第二常见的 这种癌症在美国每年约有700，000例病例，导致3，000人死亡。 随着人口老龄化和累积紫外线的增加，cSCC的发病率将增加 exposure.为了应对这一流行病，卫生局局长发出了“行动呼吁”，详细说明了 计划解决紫外线引起的皮肤癌日益流行的问题。其中一个组成部分是 减少紫外线引起的皮肤癌的战略计划是进行研究， 紫外线诱发皮肤癌的机制。紫外线诱导角质形成细胞向鳞状细胞癌的转化 辐射涉及癌前病变的形成，称为光化性角化病（AK）， 原位癌（SCCIS）。假设AK和SCCIS是由UV诱导的 角化细胞中的突变导致细胞群体异常生长和分化。 为了更好地了解紫外线照射如何改变角质形成细胞，并促进早期阶段的 皮肤癌，我们进行激光捕获显微切割SCCIS和相邻的紫外线暴露 表皮，分离的基因组DNA和产生的文库用于全外显子组测序。这 一种新的方法允许对紫外线暴露的 表皮和SCCIS。我们的外显子组测序数据表明低频率的UV特征 在60%的表皮样本中Notch功能缺失突变， 40%的SCCIS样本中存在突变。核孔蛋白（NUPS）也经常突变，80%的人， 的表皮文库和100%的SCCIS文库。这些数据表明， Notch和Nups的突变比已知癌基因的突变更常见， p53或RAS。该提案的目标是显示Notch和Nup突变如何促进 导致SCCIS的紫外线诱导皮肤癌变的早期阶段。紫外线对生物的影响- 将使用基因工程小鼠研究Notch缺陷克隆的辐射， 在异种移植模型中的工程化人角质形成细胞。Nup的生物学意义 紫外线照射皮肤中的突变将使用表皮缺陷的小鼠来确定， Nup Elys，其将核孔复合物连接到染色质。此外，人类 角质形成细胞将被工程化以表达突变的Nups，并在一个合适的环境中经受UV照射。 异种移植模型该提案的目的将产生对Notch作用的新见解， Nup突变的皮肤癌，并将提供重要的见解，设计合理的 治疗SCCIS的方法

项目成果

Activation of STAT3 in lymphocytes associated with central centrifugal cicatricial alopecia.

与中央离心性疤痕性脱发相关的淋巴细胞中 STAT3 的激活。

• DOI: 10.1016/j.jaad.2023.01.045
• 发表时间: 2023
• 期刊: Journal of the American Academy of Dermatology
• 影响因子: 13.8
• 作者: Roche,FritzlaineC;Hedberg,MatthewL;Fischer,AndrewS;Ray,Anisa;Dentchev,Tzvete;Rice,Xavier;Taylor,SusanC;Seykora,JohnT
• 通讯作者: Seykora,JohnT

HDAC1/2 Control Proliferation and Survival in Adult Epidermis and Pre‒Basal Cell Carcinoma through p16 and p53.

• DOI: 10.1016/j.jid.2021.05.026
• 发表时间: 2022-01
• 期刊: The Journal of investigative dermatology
• 作者: Zhu X;Leboeuf M;Liu F;Grachtchouk M;Seykora JT;Morrisey EE;Dlugosz AA;Millar SE
• 通讯作者: Millar SE

Downregulation of Src-family tyrosine kinases by Srcasm and c-Cbl: A comparative analysis.

• DOI: 10.4103/jcar.jcar_13_21
• 发表时间: 2021
• 期刊: Journal of carcinogenesis
• 作者: Lee V;Griffin TD;Suzuki-Horiuchi Y;Wushanley L;Kweon Y;Marshall C;Li W;Ayli E;Haimovic A;Hines A;Seykora JT
• 通讯作者: Seykora JT

Single-Soma Deep RNA sequencing of Human DRG Neurons Reveals Novel Molecular and Cellular Mechanisms Underlying Somatosensation.

人类 DRG 神经元的单体深度 RNA 测序揭示了体感的新分子和细胞机制。

• DOI: 10.1101/2023.03.17.533207
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Yu,Huasheng;Usoskin,Dmitry;Nagi,SaadS;Hu,Yizhou;Kupari,Jussi;Bouchatta,Otmane;Cranfill,SunaLi;Gautam,Mayank;Su,Yijing;Lu,You;Wymer,James;Glanz,Max;Albrecht,Phillip;Song,Hongjun;Ming,Guo-Li;Prouty,Stephen;Seykora,John;Wu
• 通讯作者: Wu

Expression of p15 in a spectrum of spitzoid melanocytic neoplasms.

p15 在一系列 spitzoid 黑素细胞肿瘤中的表达。

• DOI: 10.1111/cup.13424
• 发表时间: 2019
• 期刊: Journal of cutaneous pathology
• 影响因子: 1.7
• 作者: Ma,SophiaA;O'Day,ConorP;Dentchev,Tzvete;Takeshita,Junko;Ridky,ToddW;Seykora,JohnT;Chu,EmilyY
• 通讯作者: Chu,EmilyY