Alternative splicing in arsenical skin carcinogenesis

砷皮肤癌发生中的选择性剪接

• 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
• 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' Untranslated Regions; 5' 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

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.

项目总结

项目成果

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.

• DOI: 10.1016/j.etap.2022.103921
• 发表时间: 2022-08
• 期刊: ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY
• 影响因子: 4.3
• 作者: Bastick, Jonathan C.;Banerjee, Mayukh;States, J. Christopher
• 通讯作者: States, J. Christopher