A Comprehensive Transcriptomic Analysis of Arsenic-Induced Bladder Carcinogenesis

Abstract

Arsenic (sodium arsenite: NaAsO2) is a potent carcinogen and a known risk factor for the onset of bladder carcinogenesis. The molecular mechanisms that govern arsenic-induced bladder carcinogenesis remain unclear. We used a physiological concentration of NaAsO2 (250 nM: 33 µg/L) for the malignant transformation of normal bladder epithelial cells (TRT-HU1), exposed for over 12 months. The increased proliferation and colony-forming abilities of arsenic-exposed cells were seen after arsenic exposure from 4 months onwards. Differential gene expression (DEG) analysis revealed that a total of 1558 and 1943 (padj < 0.05) genes were deregulated in 6-month and 12-month arsenic-exposed TRT-HU1 cells. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that cell proliferation and survival pathways, such as the MAPK, PI3K/AKT, and Hippo signaling pathways, were significantly altered. Pathway analysis revealed that the enrichment of stem cell activators such as ALDH1A1, HNF1b, MAL, NR1H4, and CDH1 (p < 0.001) was significantly induced during the transformation compared to respective vehicle controls. Further, these results were validated by qPCR analysis, which corroborated the transcriptomic analysis. Overall, the results suggested that stem cell activators may play a significant role in facilitating the arsenic-exposed cells to gain a survival advantage, enabling the healthy epithelial cells to reprogram into a cancer stem cell phenotype, leading to malignant transformation.

A small molecule inhibitor of Notch1 modulates stemness and suppresses breast cancer cell growth

“…Finally, the enriched product was sequenced using the Illumina HiSeq 2,000/2,500 platform, and paired ends were generated. The raw data was analyzed and differential expression analysis was performed using the previously described method (Shukla et al, 2022).…”

State of the Art of Genomic Technology in Toxicology: A Review

“…These findings could lead to more accurate descriptions of the role of As in molecular carcinogenesis. With respect to malignant cell transformation by As, Shukla et al [13] reported that stem cell activators may be crucial in enabling As-exposed cells to obtain a survival edge and reprogramming healthy epithelial cells into a cancer stem cell phenotype. Rehman et al [66] performed whole-genome gene-expression analysis in the blood of subjects exposed to arsenic (As) using microarrays.…”

Modification of lysine-260 2-hydroxyisobutyrylation destabilizes ALDH1A1 expression to regulate bladder cancer progression

“…RA then enters the nucleus and binds to retinoic acid receptors (RARs) or retinoid X receptors (RXRs) so as to induce the expression of its downstream target genes, which are especially focused on the cell differentiation and proliferation. 19 In the past studies, ALDH1A1 has been recognized as a diagnostic target in bladder cancer, 20 , 21 , 22 , 23 , 24 , 25 and ALDH1A1-induced drug resistance has been commonly reported in cancers. Moreover, specific ALDH1A1-targeted drugs developed by researchers have been used to treat cancers.…”