Association between Arsenic Level, Gene Expression in Asian Population, and In Vitro Carcinogenic Bladder Tumor.
Association between Arsenic Level, Gene Expression in Asian Population, and In Vitro Carcinogenic Bladder Tumor.
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砷水平，亚洲种群中的基因表达与体外致癌性膀胱肿瘤之间的关联。
DOI：
10.1155/2022/3459855
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发表时间：
2022
影响因子：
--
通讯作者：
Singhal SK
中科院分区：
文献类型：
--
作者：
Singhal S;Ruprecht NA;Sens D;Tavakolian K;Gardner KL;Singhal SK
国际癌症研究机构将砷（As）归类为“对人类致癌”。尽管砷暴露会对健康产生影响，但目前还没有可用的分子特征可以预测何时暴露可能导致疾病的发展。为了了解砷暴露和疾病发展风险的分子过程，本研究使用来自人类暴露的基因表达来研究高砷暴露和疾病风险之间的功能关系。在本研究中，采用了三步分析：（1）从两个不同的砷暴露亚洲人群中获得的基因表达谱用于鉴定人类受试者中与砷暴露相关的差异表达基因，（2）在四种不同的骨髓瘤癌细胞系中由砷暴露诱导的基因表达谱用于确定砷暴露改变的共同基因和途径，以及（3）两项公开的人类膀胱癌研究的遗传谱被用于测试在步骤1和步骤2中鉴定的基因的共同关联的显著性，以开发和验证与砷暴露相关的原发性膀胱癌风险的预测模型。我们的分析表明，砷暴露于人类主要与有机体损伤和异常，免疫性疾病，炎症性疾病，胃肠道疾病，并增加各种癌症的发病率。此外，砷通过产生活性氧（ROS）和增加ROS的产生来发挥其毒性，导致细胞和组织损伤（氧化应激）的不平衡。氧化应激激活炎症途径，导致正常细胞特异性转化为肿瘤细胞;有显著证据表明，膀胱癌进展期间氧化/硝化应激发生了进展性变化。因此，我们研究了由于砷暴露在人类和膀胱癌的差异表达基因的关系，并建立了膀胱癌的风险预测模型。在这项研究中，整合素连接激酶（ILK）是两个砷暴露人群之间确定的最重要的途径之一，它在引发表皮细胞对氧化损伤的保护性反应中起着关键作用。另一方面，一些研究表明，三氧化二砷（ATO）是有用的抗癌治疗，虽然其矛盾的作用机制仍然没有很好地理解。ATO已显示出治疗多发性骨髓瘤的显著疗效;因此，了解ATO对骨髓瘤细胞发挥其抑制作用的潜在癌症生物学将是有帮助的。我们的研究发现MAPK是砷基因与ATO细胞系之间最活跃的网络之一，参与了氧化/亚硝化损伤的指示，并与膀胱癌的发生密切相关。该研究确定了一组独特的147个与砷暴露相关的基因，并与癌症的分子机制有关。基于147个基因的非常小的子集（NKIRAS 2、AKTIP和HLA-DQA 1），风险预测模型显示出对复发性膀胱肿瘤的最高预测能力，分别导致训练和验证数据的AUC为0.94（95%CI：0.744-0.995）和0.75（95%CI：0.343-0.933）。
The IARC classified arsenic (As) as “carcinogenic to humans.” Despite the health consequences of arsenic exposure, there is no molecular signature available yet that can predict when exposure may lead to the development of disease. To understand the molecular processes underlying arsenic exposure and the risk of disease development, this study investigated the functional relationship between high arsenic exposure and disease risk using gene expression derived from human exposure. In this study, a three step analysis was employed: (1) the gene expression profiles obtained from two diverse arsenic-exposed Asian populations were utilized to identify differentially expressed genes associated with arsenic exposure in human subjects, (2) the gene expression profiles induced by arsenic exposure in four different myeloma cancer cell lines were used to define common genes and pathways altered by arsenic exposure, and (3) the genetic profiles of two publicly available human bladder cancer studies were used to test the significance of the common association of genes, identified in step 1 and step 2, to develop and validate a predictive model of primary bladder cancer risk associated with arsenic exposure. Our analysis shows that arsenic exposure to humans is mainly associated with organismal injury and abnormalities, immunological disease, inflammatory disease, gastrointestinal disease, and increased rates of a wide variety of cancers. In addition, arsenic exerts its toxicity by generating reactive oxygen species (ROS) and increasing ROS production causing the imbalance that leads to cell and tissue damage (oxidative stress). Oxidative stress activates inflammatory pathways leading to transformation of a normal cell to tumor cell specifically; there is significant evidence of the advancing changes in oxidative/nitrative stress during the progression of bladder cancer. Therefore, we examined the relation of differentially expressed genes due to exposure of arsenic in human and bladder cancer and developed a bladder cancer risk prediction model. In this study, integrin-linked kinase (ILK) was one of the most significant pathways identified between both arsenic exposed population which plays a key role in eliciting a protective response to oxidative damage in epidermal cells. On the other hand, several studies showed that arsenic trioxide (ATO) is useful for anticancer therapy although the mechanisms underlying its paradoxical effects are still not well understood. ATO has shown remarkable efficacy for the treatment of multiple myeloma; therefore, it will be helpful to understand the underlying cancer biology by which ATO exerts its inhibitory effect on the myeloma cells. Our study found that MAPK is one of the most active network between arsenic gene and ATO cell line which is involved in indicative of oxidative/nitrosative damage and well associated with the development of bladder cancer. The study identified a unique set of 147 genes associated with arsenic exposure and linked to molecular mechanisms of cancer. The risk prediction model shows the highest prediction ability for recurrent bladder tumors based on a very small subset (NKIRAS2, AKTIP, and HLA-DQA1) of the 147 genes resulting in AUC of 0.94 (95% CI: 0.744-0.995) and 0.75 (95% CI: 0.343-0.933) on training and validation data, respectively.
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