Abstract
The interrelationship between genetic susceptibility and carcinogenic exposure is important in cancer development. Polymorphisms in detoxification enzymes of the glutathione-S-transferases (GST) family are associated with an increased incidence of lymphoma. Here we investigated the molecular connection of the genetic polymorphism of GSTT1 to the response of lymphocytes to polycyclic aromatic hydrocarbons (PAH). In neoplastic situation, GSTT1 deletions were more frequently observed in lymphoma patients (54.9%) than in normal controls (42.0%, P = 0.009), resulting in an increased risk for lymphoma in individuals with GSTT1-null genotype (Odds ratio = 1.698, 95% confidence interval = 1.145–2.518). GSTT1 gene and protein expression were accordingly decreased in GSTT1-deleting patients, consistent with activated profile of cell cycle regulation genes. Mimicking environmental exposure using long-term repeat culture with low-dose PAH metabolite Hydroquinone, malignant B- and T-lymphocytes presented increased DNA damage, pCHK1/MYC expression and cell proliferation, which were counteracted by ectopic expression of GSTT1. Moreover, GSTT1 expression retarded xenograft tumor formation of Hydroquinone-treated lymphoma cells in nude mice. In non-neoplastic situation, when zebrafish was exposed to PAH Benzo(a)pyrene, molecular silencing of gstt1 enhanced the proliferation of normal lymphocytes and upregulated myca expression. Collectively, these findings suggested that GSTT1 deletion is related to genetic predisposition to lymphoma, particularly interacting with environmental pollutants containing PAH.
Highlights
During the past decades, the incidence of lymphoma has been significantly increased, ranging it among the ten most frequent cancers [1]
Our study provided evidence that genetic polymorphisms in GSTT1-expressing lymphoma cells (GSTT1) gene, both in neoplastic and non-neoplastic situation, could modulate the response of the lymphocytes to the major component of environmental pollutants Polycyclic aromatic hydrocarbons (PAH) and might link to lymphoma development
This coincides with epidemiological studies from Western [4], African [5], and other Asian countries [6], the incidence of GSTT1 deletion varied among the geographical areas
Summary
The incidence of lymphoma has been significantly increased, ranging it among the ten most frequent cancers [1]. The etiologies of lymphoma remain largely undetermined. Epidemiological studies revealed that exposure to environmental pollutants is a susceptibility factor [2]. Polycyclic aromatic hydrocarbons (PAH) represent the main components of environmental pollutants that have genotoxic and carcinogenic properties. Genetic polymorphisms in detoxification enzymes are important determinants of individual variation in cancer risk. Glutathione Stransferases (GST) are the major detoxification enzymes in humans. As phase II biotransformation enzymes, GST catalyze the conjugation of reduced glutathione to electrophilic centres on a wide range of substrates, including activated exogenous molecules like PAH
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