Abstract
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.