Dysregulation of mRNA expression by hsa-miR-186 overexpression in arsenic-induced skin carcinogenesis

Mayukh Banerjee; Angeliki Lykoudi; Jae Y Hwang; Jianmin Pan; Shesh N Rai; Juw W Park; J Christopher States

doi:10.1016/j.taap.2024.117209

Dysregulation of mRNA expression by hsa-miR-186 overexpression in arsenic-induced skin carcinogenesis

Toxicol Appl Pharmacol. 2024 Dec 22:495:117209. doi: 10.1016/j.taap.2024.117209. Online ahead of print.

Authors

Mayukh Banerjee¹, Angeliki Lykoudi², Jae Y Hwang³, Jianmin Pan⁴, Shesh N Rai⁴, Juw W Park³, J Christopher States⁵

Affiliations

¹ Department of Pharmacology and Toxicology, University of Louisville, 505 S. Hancock Street, Louisville, KY 40202, USA; Center for Integrative Environmental Health Sciences, University of Louisville, 505 S. Hancock Street, Louisville, KY 40202, USA.
² Department of Pharmacology and Toxicology, University of Louisville, 505 S. Hancock Street, Louisville, KY 40202, USA.
³ Center for Integrative Environmental Health Sciences, University of Louisville, 505 S. Hancock Street, Louisville, KY 40202, USA; Brown Cancer Center, University of Louisville, 505 S. Hancock Street, Louisville, KY 40202, USA; Department of Medicine, University of Louisville, 505 S. Hancock Street, Louisville, KY 40202, USA.
⁴ Center for Integrative Environmental Health Sciences, University of Louisville, 505 S. Hancock Street, Louisville, KY 40202, USA; Cancer Data Science Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Biostatistics and Informatics Shared Resources, University of Cincinnati Cancer Center, Cincinnati, OH, USA; Department of Biostatistics, Health Informatics and Data Sciences, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Department of Bioinformatics and Biostatistics, University of Louisville, 505 S. Hancock Street, Louisville, KY 40202, USA.
⁵ Department of Pharmacology and Toxicology, University of Louisville, 505 S. Hancock Street, Louisville, KY 40202, USA; Center for Integrative Environmental Health Sciences, University of Louisville, 505 S. Hancock Street, Louisville, KY 40202, USA. Electronic address: jcstates@louisville.edu.

PMID: 39719251
DOI: 10.1016/j.taap.2024.117209

Abstract

Dysregulated miRNA expression contributes to development of arsenic-induced cutaneous squamous cell carcinoma (cSCC). hsa-miR-186 (miR-186) is overexpressed in arsenical cSCC tissues as well as in preclinical cell line model of arsenical cSCC. Simultaneous miR-186 overexpression and chronic inorganic trivalent arsenite (iAs; 100 nM) exposure transformed human HaCaT cell line preferentially over miR-186 overexpression or iAs exposure alone. Both iAs and miR-186 regulate the expression of wide range of mRNA targets. However, how their interaction impacts the transcriptome-wide mRNA expression landscape ushering in cancer is unknown. We performed longitudinal RNA-seq analysis in passage-matched HaCaT cell clones (±miR-186 overexpression) with simultaneous chronic iAs exposure (0/100 nM) at 12 and 29 weeks. We determined the impact of each factor and their interaction towards differential gene expression and pathway dysregulation employing two different statistical approaches (t-statistic and 2-factor ANOVA). We show that a core set of pathways are dysregulated deterministically irrespective of the statistical approach chosen, possibly representing necessary changes for transformation. The data suggest that each clonal line could take a unique route to dysregulate this core set of pathways necessary for transformation, highlighting the possible role of stochasticity in cancer development. Evidence is presented to sift the strengths and weaknesses of each statistical methodology in providing biological understanding of events that play crucial roles in carcinogenesis in large datasets with multiple contributing variables.

Keywords: Arsenic; Carcinogenesis; Skin cancer; mRNA; miRNA.

Abstract

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