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

被引:34
作者
Banerjee, Mayukh [1 ]
Cardoso, Ana Ferragut [1 ]
Al-Eryani, Laila [1 ,7 ]
Pan, Jianmin [2 ,6 ]
Kalbfleisch, Theodore S. [3 ,8 ]
Srivastava, Sudhir [4 ,5 ]
Rai, Shesh N. [2 ,4 ,6 ]
States, J. Christopher [1 ]
机构
[1] Univ Louisville, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA
[2] Univ Louisville, Biostat & Bioinformat Facil, James Graham Brown Canc Ctr, Louisville, KY USA
[3] Univ Louisville, Dept Biochem & Mol Genet, Louisville, KY USA
[4] Univ Louisville, Dept Bioinformat & Biostat, Louisville, KY USA
[5] ICAR Indian Agr Stat Res Inst, Ctr Agr Bioinformat, New Delhi 110012, India
[6] Univ Louisville, Biostat & Informat Facil, Ctr Integrat Environm Hlth Sci, Louisville, KY USA
[7] NCI, Knowledge Management & Special Projects Branch, Ctr Strateg Sci Initiat HNC1L, NIH, Bethesda, MD USA
[8] Univ Kentucky, Gluck Equine Res Ctr, Lexington, KY USA
关键词
Arsenic; Skin carcinogenesis; Differential gene expression; Pathway analysis; Passage matching; Endoplasmic reticulum stress; EPITHELIAL-MESENCHYMAL TRANSITION; UNFOLDED PROTEIN RESPONSE; NITRIC-OXIDE; NUCLEAR RECEPTORS; SEQ EXPERIMENTS; BREAST-CANCER; GENE; PROGRESSION; DISRUPTION; MECHANISMS;
D O I
10.1007/s00204-021-03084-2
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
Chronic arsenic exposure causes skin cancer, although the underlying molecular mechanisms are not well defined. Altered microRNA and mRNA expression likely play a pivotal role in carcinogenesis. Changes in genome-wide differential expression of miRNA and mRNA at 3 strategic time points upon chronic sodium arsenite (As3+) exposure were investigated in a well-validated HaCaT cell line model of arsenic-induced cutaneous squamous cell carcinoma (cSCC). Quadruplicate independent HaCaT cell cultures were exposed to 0 or 100 nM As3+ for up to 28-weeks (wk). Cell growth was monitored throughout the course of exposure and epithelial-mesenchymal transition (EMT) was examined employing immunoblot. Differentially expressed miRNA and mRNA profiles were generated at 7, 19, and 28-wk by RNA-seq, followed by identification of differentially expressed mRNA targets of differentially expressed miRNAs through expression pairing at each time point. Pathway analyses were performed for total differentially expressed mRNAs and for the miRNA targeted mRNAs at each time point. RNA-seq predictions were validated by immunoblot of selected target proteins. While the As3+-exposed cells grew slower initially, growth was equal to that of unexposed cells by 19-wk (transformation initiation), and exposed cells subsequently grew faster than passage-matched unexposed cells. As3+-exposed cells had undergone EMT at 28-wk. Pathway analyses demonstrate dysregulation of carcinogenesis-related pathways and networks in a complex coordinated manner at each time point. Immunoblot data largely corroborate RNA-seq predictions in the endoplasmic reticulum stress (ER stress) pathway. This study provides a detailed molecular picture of changes occurring during the arsenic-induced transformation of human keratinocytes.
引用
收藏
页码:2351 / 2365
页数:15
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