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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adolescent
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Adult
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Aged
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Aged, 80 and over
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Animals
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Apoptosis / drug effects
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Blotting, Western
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Cell Proliferation / drug effects
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DNA Adducts
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DNA Copy Number Variations / genetics
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DNA Damage / drug effects*
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DNA Damage / genetics
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Disease Progression
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Female
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Follow-Up Studies
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Genetic Predisposition to Disease
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Genome, Human
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Genotype
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Glutathione Transferase / genetics*
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Humans
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Immunoenzyme Techniques
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In Situ Hybridization
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Lymphoma, Large B-Cell, Diffuse / drug therapy
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Lymphoma, Large B-Cell, Diffuse / etiology
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Lymphoma, Large B-Cell, Diffuse / pathology*
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Lymphoma, T-Cell / drug therapy
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Lymphoma, T-Cell / etiology
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Lymphoma, T-Cell / pathology*
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Middle Aged
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Polycyclic Aromatic Hydrocarbons / toxicity*
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Polymorphism, Genetic / genetics*
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Prognosis
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Sequence Deletion / genetics*
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
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Young Adult
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Zebrafish / genetics
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Zebrafish / growth & development
Substances
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DNA Adducts
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Polycyclic Aromatic Hydrocarbons
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RNA, Messenger
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glutathione S-transferase T1
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Glutathione Transferase
Grants and funding
The work was supported, in part, by the National Natural Science Foundation of China (81325003, 81172254 and 81101793), the Shanghai Commission of Science and Technology (11JC1407300), the Program of Shanghai Subject Chief Scientists (13XD1402700), and the “Shu Guang” project supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.