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
| Autor: | J. Christopher States, Jianmin Pan, Mayukh Banerjee, Laila Al-Eryani, Sudhir Srivastava, Theodore S. Kalbfleisch, Shesh N. Rai, Ana Paula Ferragut Cardoso |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Skin Neoplasms Pathway analysis Carcinogenesis Health Toxicology and Mutagenesis Cell Culture Techniques Toxicology medicine.disease_cause Arsenic 03 medical and health sciences 0302 clinical medicine microRNA medicine Humans Inorganic Compounds RNA Messenger Differential gene expression Messenger RNA Passage matching Chemistry Cell growth Endoplasmic reticulum General Medicine Cell biology Skin carcinogenesis MicroRNAs HaCaT 030104 developmental biology Cell culture 030220 oncology & carcinogenesis Endoplasmic reticulum stress Carcinoma Squamous Cell Unfolded protein response |
| Zdroj: | Archives of Toxicology |
| ISSN: | 1432-0738 0340-5761 |
| DOI: | 10.1007/s00204-021-03084-2 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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