A Comprehensive Transcriptomic Analysis of Arsenic-Induced Bladder Carcinogenesis.
A Comprehensive Transcriptomic Analysis of Arsenic-Induced Bladder Carcinogenesis.
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DOI：
10.3390/cells11152435
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发表时间：
2022-08-05
期刊：
影响因子：
6
通讯作者：
Damodaran, Chendil
中科院分区：
文献类型：
--
作者：
Shukla, Vaibhav;Chandrasekaran, Balaji;Tyagi, Ashish;Navin, Ajit Kumar;Saran, Uttara;Adam, Rosalyn M.;Damodaran, Chendil
砷（亚砷酸钠：NaAsO2）是一种强致癌物，是膀胱癌发病的已知危险因素。砷诱发膀胱癌的分子机制尚不清楚。我们使用生理浓度的NaAsO2 （250 nM: 33µg/L）对正常膀胱上皮细胞（TRT-HU1）进行恶性转化，暴露超过12个月。砷暴露后4个月，砷暴露细胞的增殖和集落形成能力增强。差异基因表达（DEG）分析显示，在6个月和12个月砷暴露的TRT-HU1细胞中，共有1558个和1943个基因（padj < 0.05）被解除调控。基因本体（GO）和京都基因与基因组百科全书（KEGG）分析显示，细胞增殖和存活途径，如MAPK、PI3K/AKT和Hippo信号通路，显著改变。通路分析显示，与各自的载体对照相比，在转化过程中，干细胞激活因子如ALDH1A1、HNF1b、MAL、NR1H4和CDH1的富集（p < 0.001）被显著诱导。此外，这些结果被qPCR分析证实，证实了转录组分析。总之，研究结果表明，干细胞激活剂可能在促进砷暴露细胞获得生存优势方面发挥重要作用，使健康上皮细胞重编程为癌症干细胞表型，从而导致恶性转化。
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.
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