GSTT1 deletion is related to polycyclic aromatic hydrocarbons-induced DNA damage and lymphoma progression
- Authors
- Yang, F., Xiong, J., Jia, X.E., Gu, Z.H., Shi, J.Y., Zhao, Y., Li, J.M., Chen, S.J., Zhao, W.L.
- ID
- ZDB-PUB-140513-436
- Date
- 2014
- Source
- PLoS One 9: e89302 (Journal)
- Registered Authors
- Yang, Fan, Zhao, Yan
- Keywords
- none
- MeSH Terms
-
- Reverse Transcriptase Polymerase Chain Reaction
- Disease Progression
- Young Adult
- DNA Copy Number Variations/genetics
- Mice
- RNA, Messenger/genetics
- Animals
- In Situ Hybridization
- Lymphoma, T-Cell/drug therapy
- Lymphoma, T-Cell/etiology
- Lymphoma, T-Cell/pathology*
- Female
- DNA Damage/drug effects*
- DNA Damage/genetics
- Genotype
- Real-Time Polymerase Chain Reaction
- Genetic Predisposition to Disease
- Follow-Up Studies
- Mice, Inbred BALB C
- Apoptosis/drug effects
- Adult
- Immunoenzyme Techniques
- Polycyclic Aromatic Hydrocarbons/toxicity*
- Blotting, Western
- Adolescent
- Middle Aged
- Aged, 80 and over
- Humans
- Mice, Nude
- Prognosis
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Lymphoma, Large B-Cell, Diffuse/etiology
- Lymphoma, Large B-Cell, Diffuse/pathology*
- Male
- DNA Adducts
- Genome, Human
- Xenograft Model Antitumor Assays
- Cell Proliferation/drug effects
- Aged
- Zebrafish/genetics
- Zebrafish/growth & development
- Tumor Cells, Cultured
- Glutathione Transferase/genetics*
- Polymorphism, Genetic/genetics*
- Sequence Deletion/genetics*
- PubMed
- 24586676 Full text @ PLoS One
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.