Alternative splicing in arsenical skin carcinogenesis

砷皮肤癌发生中的选择性剪接

基本信息

批准号：
10215536
负责人：
J CHRISTOPHER STATES
金额：
$ 19.5万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-14 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10215536
关键词：
3&apos Untranslated Regions 5&apos Untranslated Regions Affect Alternative Splicing Area Arsenic Arsenicals Arsenites Attention Automobile Driving Biogenesis Biological Biological Process Cell Cycle Regulation Cell physiology Cells Chronic Chronic Disease Complex Country DNA Repair DNA damage checkpoint Data Disease Etiology Event Exposure to Gene Expression Gene Expression Regulation Genome Components Global Change Health Human Individual Lead Longitudinal Studies Malignant - descriptor Malignant Neoplasms Mass Spectrum Analysis Messenger RNA MicroRNAs Mitotic Modeling Oncogenic Organ Outcome Outcome Study Oxidative Stress PLK1 gene Paint Pathway Analysis Pathway interactions Phenotype Play Post-Transcriptional Regulation Process Production Protein Isoforms Proteins Proteome Proteomics RNA Splicing Regulation Research Reverse Transcriptase Polymerase Chain Reaction Role Sampling Shapes Signal Transduction Skin Skin Cancer Skin Carcinogenesis Squamous cell carcinoma System Testing Time Transcript arsenic-induced carcinogenesis base biological adaptation to stress carcinogenesis contaminated drinking water differential expression genome-wide keratinocyte programs proteomic signature public health relevance response sodium arsenite toxicant transcription factor transcriptome transcriptome sequencing transcriptomics tumorigenesis well water

项目摘要

Project Summary Chronic exposure to arsenic, most commonly through contaminated drinking water, plagues over 200 million individuals in over 70 countries including the USA. Arsenic is a multi-organ toxicant and chronic arsenic exposure causes several chronic diseases including cancer in multiple organs, skin cancer being the most common. While several mechanisms are postulated to be responsible for arsenic-induced carcinogenesis, a clear picture is yet to emerge. It is well known that chronic arsenic exposure radically changes the transcriptomic and proteomic signatures, but the underlying mechanism for such sweeping global changes are not yet clearly understood. Differential alternative splicing plays a role in carcinogenesis and may be at play in arsenic-induced carcinogenesis. We employed state-of-the-art RNA-Seq analysis in a well-established model of arsenic-induced skin cancer (HaCaT cells exposed continuously to 100 nM sodium arsenite for 32 weeks) in a longitudinal study to understand the global changes in splicing occurring during the transformation process. Our data indicate >600 differential alternative splicing events occurred at each of the time points studied (7, 19, 28 weeks of exposure). This differential splicing program, by dramatically changing the proteome, could be a key player in the arsenic-induced transformation of skin cells. The present proposal aims to examine the contribution of significant differential splicing events at each time point towards the process of carcinogenesis. We will specifically scrutinize if the significant splicing events predicted by our transcriptomic studies can be correlated with protein isoform expression profiles. Furthermore, we also aim to study if predicted significantly different spliced isoforms that take place in the 5' or 3' UTR of transcripts can be correlated to expression profile in the mature mRNA samples from exposed and unexposed cells. The outcomes from this study will further our understanding of how alternative splicing shapes the cellular events taking place before, during and after the time the HaCaT cells become malignant. In addition, our study will look to elaborate the mechanistic basis of how one change in an upstream regulatory alternative splicing factor can cause genome-wide synchronized alternative splicing changes by signal amplification through successive steps, leading to altered proteome and ultimately adverse health effects.

项目概要慢性接触砷（最常见的是通过受污染的饮用水）困扰着超过 2 亿人包括美国在内的 70 多个国家的个人。砷是一种多器官毒物，慢性砷中毒暴露会导致多种慢性疾病，包括多个器官的癌症，其中皮肤癌是最常见的常见的。虽然有几种机制被认为是砷诱发致癌的原因，但清晰的画面尚未出现。众所周知，长期接触砷会从根本上改变转录组和蛋白质组特征，但这种全面的全球变化的根本机制尚未明确了解。差异选择性剪接在致癌过程中发挥作用，可能位于砷诱发的致癌作用。我们采用了最先进的 RNA 测序分析砷诱导皮肤癌的成熟模型（HaCaT 细胞持续暴露于 100 nM 钠亚砷酸盐 32 周）进行纵向研究，以了解剪接过程中发生的全局变化转变过程。我们的数据表明，每个区域都发生了超过 600 个差异选择性剪接事件。研究的时间点（暴露 7、19、28 周）。这种差异拼接程序，通过极大地改变蛋白质组可能是砷诱导的皮肤细胞转化的关键参与者。目前的建议旨在检查每个时间点显着差异剪接事件对癌变过程。我们将特别审查我们预测的重大剪接事件是否转录组研究可以与蛋白质亚型表达谱相关。此外，我们还旨在研究是否可以预测转录本 5' 或 3' UTR 中发生的显着不同的剪接亚型与暴露和未暴露细胞的成熟 mRNA 样本中的表达谱相关。这这项研究的结果将进一步加深我们对选择性剪接如何影响细胞事件的理解发生在 HaCaT 细胞恶性之前、期间和之后。此外，我们的研究将希望详细阐述上游监管选择性剪接因子如何变化的机制基础可以通过连续的信号放大引起全基因组同步的选择性剪接变化步，导致蛋白质组改变并最终对健康产生不利影响。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

miRNA dysregulation is an emerging modulator of genomic instability.

DOI：
10.1016/j.semcancer.2021.05.004
发表时间：
2021-11
期刊：
Seminars in cancer biology
影响因子：
14.5
作者：
Ferragut Cardoso AP;Banerjee M;Nail AN;Lykoudi A;States JC
通讯作者：
States JC

Dynamic alteration in miRNA and mRNA expression profiles at different stages of chronic arsenic exposure-induced carcinogenesis in a human cell culture model of skin cancer.

DOI：
10.1007/s00204-021-03084-2
发表时间：
2021-07
期刊：
Archives of toxicology
影响因子：
6.1
作者：
Banerjee M;Ferragut Cardoso A;Al-Eryani L;Pan J;Kalbfleisch TS;Srivastava S;Rai SN;States JC
通讯作者：
States JC

Zinc supplementation prevents arsenic-induced dysregulation of ZRANB2 splice function.