ABSTRACT
BACKGROUND: The glutathione S-transferases (GSTs) are a superfamily of phase II detoxifying enzymes that inactivates a wide variety of potential carcinogens through glutathione conjugation. Polymorphic changes in the GST genes have been reported to be associated with increased susceptibility to cancer development and anticancer drug resistance. In this study, we investigated the association between genetic variants in GSTM1 and GSTP1 and patients' clinicopathological parameters. The prognostic values of such associations were evaluated among bladder cancer patients. METHODS: Genotyping of GSTM1 and GSTP1 in bladder cancer patients was assessed using polymerase chain reaction followed by DNA sequencing. Overall survival was estimated using the Kaplan-Meier method and multiple logistic regression and correlation analysis were performed. RESULTS: The GSTM1 null genotype was significantly associated with poor overall survival compared with the wild-type GSTM1 genotype. There was a trend towards better overall survival in patients with wild-type GSTP1 allele (AA) compared with GSTP1 (AG/GG) genotype. Interestingly, Kaplan-meier survival curve for GSTM1 null patients adjusted for sub-cohort with amplified HER2 gene showed poor survival compared with the GSTM1 null/ non-amplified HER2 gene. Also the same population when adjusted with HER2 protein expression, data showed poor survival for patients harboring GSTM1 null/high HER2 protein expression compared with low protein expression. CONCLUSION: This study focuses on the impact of GSTM1 null genotype on bladder cancer patients' outcome. Further investigations are required to delineate the underlying mechanisms of combined GSTM-/- and HER2 status in bladder cancer.
Subject(s)
Genetic Predisposition to Disease/genetics , Genetic Variation , Glutathione S-Transferase pi/genetics , Glutathione Transferase/genetics , Urinary Bladder Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Female , Genetic Association Studies , Genotype , Humans , Male , Middle Aged , Mutation , Prognosis , Receptor, ErbB-2/metabolism , Saudi Arabia , Survival Analysis , Urinary Bladder Neoplasms/mortality , Urinary Bladder Neoplasms/pathologyABSTRACT
Bladder cancer (BC) is a deadly disease characterized by high recurrence rates and frequent progression to an aggressive phenotype. Dysregulation of various signaling pathways have been implicated in BC tumorigenesis, however, the clinical relevance of sonic hedgehog pathway (Shh) remains under investigated. The aim of the current study was to analyze the prognostic value of Shh expression in patients with bladder carcinoma. Immunohistochemical expression of Shh was performed using tissue microarray with 128 specimens from bladder cancer patients. Kaplan-meier survival was analysed and correlation between Shh protein expression and patients' clinicopathological parameters wasexamined using Fisher's exact test. The immuno-staining results revealed that Shh protein exhibits cytoplasmic localization and is expressed in 49% of the analyzed bladder cancer cohort. Our data indicated that high Shh expression significantly correlated with increased lymph node metastasis (p = 0.02), however no association was reported between Shh expression and other clinicopatholigical parameters. High expression of sonic hedgehog was associated with lymph node invasion which may indicate that Shh might play an important role in progression and metastasis of bladder cancer.
Subject(s)
Biomarkers, Tumor/metabolism , Hedgehog Proteins/metabolism , Muscle Neoplasms/secondary , Neoplasm Recurrence, Local/pathology , Urinary Bladder Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Humans , Lymphatic Metastasis , Male , Middle Aged , Muscle Neoplasms/metabolism , Muscle Neoplasms/surgery , Neoplasm Invasiveness , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/surgery , Prognosis , Survival Rate , Urinary Bladder Neoplasms/metabolism , Urinary Bladder Neoplasms/surgeryABSTRACT
OBJECTIVES: This study aimed to evaluate the comparative protective antioxidant effect of 5-aminosalicylic acid (5-ASA) and vitamin-E against acrylamide (ACR)-induced testicular toxicity in rats. METHODS: This study was performed at King Fahad Medical Research Centre, Jeddah, KSA. A total of 49 adult Wistar rats (250 ± 20 gm) that were 60 days old were divided into seven groups (control, ACR alone, ACR + 5-ASA, ACR + Vitamin-E, ACR + 5-ASA + Vitamin-E, Vitamin-E alone, 5-ASA alone). Acrylamide [45 mg/kg (bw)/day] and vitamin-E [200 mg/kg (bw)/day] were gavaged orally, and 5-ASA [25 mg/kg (bw)/day] were injected intra-peritoneally for five consecutive days after one day of observation. Rats were sacrificed by cervical dislocation. Histopathology of the testis, enzyme linked immunosorbent assay (ELISA) of testosterone, the lactate dehydrogenase (LDH) assay and a caudal sperm count were performed. RESULTS: Rats treated with ACR showed signs of aggression and rough coats, with reduced food and water intake. ACR treated rats showed histopathological changes in the form of a sloughed seminiferous epithelium in the tubular lumen with no multinucleated giant cells. Shrinkage of seminiferous tubules with widening of the interstitial space was also observed with atrophy and the shedding of normal mucosa. Our results indicated that maximum protection was conveyed by the combined antioxidant effect of vitamin-E and 5-ASA on testicular histopathology. CONCLUSION: We conclude that acrylamide-induced degeneration of seminiferous tubules can be partially reversed by the administration of 5-ASA and vitamin-E and suggests restricting exposure to ACR.
