The Hippo pathway regulates cell proliferation and apoptosis and it has been noted that loss of critical components of this pathway can lead to uncontrolled cell growth. Yap protein is an important component of this HIPPO pathway because YAP is the nuclear effector of the Hippo tumor suppressor pathway and it is crucial for the response to oxidative stress induced by cellular process and for different xenobiotics including arsenic (As). It has been proposed that YAP dysregulation can contribute to a malignant cellular phenotype acting as both a tumor suppressor and an oncogene.
The aim of the study was to assess and compare the expression of YAP in neoplastic and non-neoplastic breast tissue of women chronically exposed to As through drinking water.
YAP expression was assessed by immunohistochemistry in 120 breast biopsies from women with breast cancer and from women with other non-neoplastic breast pathologies. Arsenic concentration was quantified in urine and toenails.
The results disclosed a lower percentage of YAP expression in the nucleus and in the cytoplasm in cases when compared to the registered in controls. High As levels decreases mainly YAP expression at the nucleus. YAP high intensity staining decreases the risk for breast cancer.
The overall data suggest that YAP may acts as a tumor suppressor protein and that As is able to reduce the YAP translocation from the cytoplasm to the nucleus which can induce an environment favorable for inhibition of apoptosis and promoting cellular proliferation by increasing the genomic instability of cells.
Alteration of multidrug resistance-associated protein-1 (MRP1) expression has been associated with certain lung diseases, and this protein may be pivotal in protecting the lungs against endogenous or exogenous toxic compounds. The aim of this study was to evaluate and compare the expression of MRP1 in bronchoalveolar cells from subjects with and without lung cancer who had been chronically exposed to arsenic through drinking water. MRP1 expression was assessed in bronchoalveolar cells in a total of 102 participants. MRP1 expression was significantly decreased in those with arsenic urinary levels >50 μg/L when compared with the controls. In conclusion, chronic arsenic exposure negatively correlates with the expression of MRP1 in BAL cells in patients with lung cancer.
Disease manifestations or susceptibilities often differ among individuals exposed to the same concentrations of arsenic (As). These differences have been associated with several factors including arsenic metabolism, sex, age, genetic variants, nutritional status, smoking, and others. The present study evaluated the associations between four As metabolism-related gene polymorphisms/null genotypes with urinary As methylation profiles in girls and boys chronically exposed to As. In a total of 332 children aged 6-12 years, the frequency of AS3MT, GSTO1, GSTT1, and GSTM1 polymorphisms/null genotypes and As urinary metabolites were measured. The results revealed that total As and monomethyl metabolites of arsenic (MMA) levels were higher in boys than in girls. No differences in the frequency of the evaluated polymorphisms were found between girls and boys. In AS3MT-Met287Thr carriers, %MMA levels were higher and second methylation levels (defined as dimethylarsinic acid divided by MMA) were lower. In children with the GSTM1 null genotype, second methylation levels were higher. In boys, a positive association between the AS3MT-Met287Thr polymorphism with %MMA and between the GSTO1-Glu155del and Asv was found; whereas, a negative relationship was identified between AS3MT-Met287Thr and second methylation profiles. In girls, a positive association was found between the GSTO1-Ala140Asp polymorphism with second methylation levels. In conclusion, our data indicate that gender, high As exposure levels, and polymorphisms in the evaluated genes negatively influenced As metabolism.
Our data showed an inverse association between 1-OHP urinary levels and both sperm quality and the DNA integrity. Additionally, the heterozygote variants of CYP1A1-m1 and CYP1A1-m2 significantly increased the urinary excretion of 1-OHP, and the GSTM1 null variant was inversely associated with the comet parameters evaluated.
The identification of gene‐environment interactions related to breast cancer reveals the biological and molecular mechanisms underlying the disease and allows the distinction of women at high risk from women at lower risk, which could decrease the morbimortality of this neoplasm. The current study evaluated the association between polymorphisms rs1820453 and rs11225161 of the Yes‐associated protein (YAP) gene in women with breast cancer exposed to arsenic (As) through drinking water. In total, 182 women were assessed for the frequency of YAP rs1820453 and rs11225161 polymorphisms and As urinary levels. The results demonstrated a positive and significant association between breast cancer and smoking, type of drinking water, and levels of AsIII, AsV and inorganic As (iAs) but not the YAP gene polymorphisms evaluated. In conclusion, our data showed that the source of drinking water and AsV and iAs urinary levels increased the risk for breast cancer, but no interactions between YAP gene polymorphisms and As urinary levels were found.
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