Association study of estrogen receptor alpha gene polymorphisms with spontaneous abortion: is this a possible reason for unexplained spontaneous abortion?

Estrogen plays a crucial role in fetal and placental development through estrogen receptors. Association of estrogen receptor alpha gene (ESR1) polymorphisms with spontaneous abortion has been shown in some studies. Our main goal was to study the potential association of spontaneous abortion with the ESR1 gene variations (PvuII and XbaI) in fetal tissue. Totally, 161 samples were recruited including 80 samples of formalin-fixed paraffin-embedded fetal tissue from spontaneous abortion and 81 samples of normal term placental tissue. The restriction fragment length polymorphism (RFLP) method was performed for genotyping the rs2234693 (A/G XbaI) and rs9340799 (T/C PvuII) single nucleotide polymorphisms located in intron 1 of ESR1. The results have been confirmed by DNA sequencing analysis. The different genotypes distribution was detected in two study groups. Haplotype analysis indicated that ppxx is protective genotype against spontaneous abortion (P = 0.01). In conclusion, the potential role of ESR1 genetic variation in spontaneous abortion might be valuable in high-risk subjects, and that needs to be confirmed with future studies.

Combination effect of PectaSol and Doxorubicin on viability, cell cycle arrest and apoptosis in DU-145 and LNCaP prostate cancer cell lines.

The effect of PectaSol on Dox (Doxorubicin) cytotoxicity in terms of apoptosis and cell cycle changes in PCa (prostate cancer) cell lines (DU-145 and LNCaP) has been investigated. Combination of PectaSol and Dox resulted in a viability of 29.4 and 32.6% (P<0.001) in DU-145 and LNCaP cells. The IC50 values decreased 1.5-fold and 1.3-fold in the DU-145 and LNCaP cells respectively. In the DU-145 cells, combination of PectaSol and Dox resulted in a reduction in p27 gene and protein expression (P<0.001). In LNCaP cells, this combination increased p53, p27 and Bcl-2 expression. Treatment with both drugs in DU-145 cells led to an increase in sub-G1 arrest (54.6% compared with 12.2% in Dox). In LNCaP cells, combination of the drugs led to an increased in G2/M arrest (61.7% compared with 53.6% in Dox). Based on these findings, progressive cytotoxicity effect of Dox and PectaSol together rapidly induce cell death in DU-145 through apoptosis and in LNCaP cells through cell cycle arrest (G2/M arrest).

Association of p53/p21 expression with cigarette smoking and prognosis in esophageal squamous cell carcinoma patients.

AIM: To investigate the expression of p53 and p21 and associations with possible risk factors, such as cigarette smoking, in esophageal squamous cell carcinoma (ESCC) in northeastern Iran, a region with a high incidence of ESCC. METHODS: The expression of p53 and p21 proteins was investigated immunohistochemically in tumor tissue from 80 ESCC patients and in 60 available paraffin-embedded blocks of adjacent normal specimens from the cases, along with normal esophageal tissue from 80 healthy subjects. RESULTS: Positive expression of p53 protein was detected in 56.2% (45/80) of ESCC cases, and in none of the normal esophageal tissue of the control group (P < 0.001). Furthermore, 73.8% (59/80) of ESCC cases and 43.8% (35/80) of controls had positive expression of p21 protein (P < 0.001). Cigarette smoking was significantly associated with p53 over-expression in ESCC cases (P = 0.010, OR = 3.64; 95% CI: 1.32-10.02). p21 over-expression was associated with poorer clinical outcome among the ESCC patients (P = 0.009). CONCLUSION: Over-expression of p53 in association with cigarette smoking may play a critical role in ESCC carcinogenesis among this high-risk population of northeastern Iran. Furthermore, p21 over-expression was found to be associated with poor prognosis, specifically in the operable ESCC patients.

Role of cytochrome P450 2C19 genetic polymorphisms in the therapeutic efficacy of omeprazole in Iranian patients with erosive reflux esophagitis.

BACKGROUND: There are different clinical responses to omeprazole treatment in Iranian patients with gastroesophageal reflux disease. Omeprazole is metabolized in the liver by the cytochrome p450 2c19 (CYP2C19) enzyme. Two common polymorphisms of the CYP2C19 gene affect CYP2C19 enzyme activity. We investigated the effect of CYP2C19 gene polymorphisms on the clinical response to treatment with omeprazole in Iranian patients with erosive reflux esophagitis. METHODS: Eighty-two Iranian patients with reflux esophagitis were enrolled in the study and underwent treatment with omeprazole at 40 mg daily for 4 weeks. A 2 mL sample of venous blood was obtained from each subject. CYP2C19 genetic polymorphisms were detected using the PCR-RFLP method. The patients were grouped into homo-extensive metabolizers and hetero-extensive metabolizers based on their CYP2C19 polymorphism. The grade of esophagitis was determined via endoscopy. The symptoms score was assessed at the beginning of treatment. RESULTS: Our results showed that the rate of complete clinical response to treatment with omeprazole was 95% in the hetero-extensive metabolizers group, which was higher than in the homo-extensive metabolizers group (P<0.001). CONCLUSION: CYP2C19 polymorphism influences the therapeutic efficacy of omeprazole in the treatment of Iranian patients with erosive reflux esophagitis. The clinical response and endoscopic healing of esophagitis are both affected by CYP2C19 genotype condition.

P21(waf1/cip1) gene polymorphisms and possible interaction with cigarette smoking in esophageal squamous cell carcinoma in northeastern Iran: a preliminary study.

BACKGROUND: The incidence of esophageal squamous cell carcinoma (ESCC) is very high in northeastern Iran. However, the genetic predisposing factors to ESCC in this region have not been clearly defined. The P21(waf1/cip1) gene is involved in the arrest of cellular growth, as induced by the p53 tumor suppressor gene. Two polymorphisms of p21 gene in codon 31 (p21 C98A, dbSNP rs1801270) and the 3'UTR (p21 C70T, dbSNP rs1059234) may affect protein expression and play a role in cancer susceptibility. The present study aimed to investigate the association of p21 polymorphisms in codon 31 and the 3'UTR, and cigarette smoking on the risk of ESCC in northeastern Iran. METHODS: A case-control study was carried out to detect the p21 polymorphism in the 3'UTR and codon 31 of samples from 126 ESCC cases and 100 controls from 2006 to 2007. There were no significant differences of age and sex between cases and controls. Genotyping of p21 polymorphisms were determined with the PCR-RFLP method. Conditional logistic regression was used to adjust for potential confounders. RESULTS: None of the p21 genotypes were significantly associated with risk of ESCC, even after adjusting for age and gender (P=0.52, OR=1.24; 95%CI: 0.63-2.42). However, the presence of these polymorphisms in combination with cigarette smoking had a synergistic interaction in ESCC carcinogenesis in northeastern Iran (P=0.02, OR=8.38; 95%CI: 1.03-67.93). CONCLUSION: Our data suggests that these two p21 polymorphisms, both alone and in combination, are not genetic susceptibility biomarkers for ESCC. However, their interaction with cigarette smoking may influence the susceptibility to ESCC development in northeastern Iran.

p16INK4a hypermethylation and p53, p16 and MDM2 protein expression in esophageal squamous cell carcinoma.

BACKGROUND: Tumor suppressor genes p53 and p16INK4a and the proto-oncogene MDM2 are considered to be essential G1 cell cycle regulatory genes whose loss of function is associated with ESCC carcinogenesis. We assessed the aberrant methylation of the p16 gene and its impact on p16INK4a protein expression and correlations with p53 and MDM2 protein expressions in patients with ESCC in the Golestan province of northeastern Iran in which ESCC has the highest incidence of cancer, well above the world average. METHODS: Cancerous tissues and the adjacent normal tissue obtained from 50 ESCC patients were assessed with Methylation-Specific-PCR to examine the methylation status of p16. The expression of p16, p53 and MDM2 proteins was detected by immunohistochemical staining. RESULTS: Abnormal expression of p16 and p53, but not MDM2, was significantly higher in the tumoral tissue. p53 was concomitantly accumulated in ESCC tumor along with MDM2 overexpression and p16 negative expression. Aberrant methylation of the p16INK4a gene was detected in 31/50 (62%) of esophageal tumor samples, while two of the adjacent normal mucosa were methylated (P < 0.001). p16INK4a aberrant methylation was significantly associated with decreased p16 protein expression (P = 0.033), as well as the overexpression of p53 (P = 0.020). CONCLUSIONS: p16 hypermethylation is the principal mechanism of p16 protein underexpression and plays an important role in ESCC development. It is associated with p53 protein overexpression and may influence the accumulation of abnormally expressed proteins in p53-MDM2 and p16-Rb pathways, suggesting a possible cross-talk of the involved pathways in ESCC development.

Prevalence of esophageal cancer risk factors among Turkmen and non-Turkmen ethnic groups in a high incidence area in Iran.

BACKGROUND: Golestan Province in north-eastern Iran has one of the highest incidence rates for esophageal squamous cell carcinoma (ESCC) worldwide. Earlier studies have reported higher incidence rates in the areas of Golestan which are mainly inhabited by individuals of the Turkmen ethnic group. However, it is not clear whether in those areas the incidence among Turkmens is higher in comparison to non-Turkmens. Some previous studies have suggested that environmental factors might play a more essential role in ESCC carcinogenesis in Golestan than a genetic background. If environmental factors instead of a genetic background are the major risk factors, therefore the prevalence of known environmental risk factors would not significantly differ among ESCC cases of different ethnic groups. To investigate the role of environmental factors versus genetic background by using the above concept, we have compared the prevalence of known risk factors for ESCC among Turkmen and non-Turkmen ESCC cases. METHODS: Study participants were histopathologically proven ESCC cases from Golestan Province. They were recruited in the study from December 2003 to June 2007. The prevalence of the most important known risk factors for ESCC in Turkmen and non-Turkmen ESCC cases was compared using Chi-squared and Fisher's exact tests. RESULTS: Of 300 ESCC cases recruited in the study, 171 (57.0%) and 129 (43.0%) cases were Turkmen and non-Turkmen, respectively. In the majority of the investigated risk factors which included tobacco, nass, and opium use, hot and extremely hot tea consumption, as well as decreased levels of education; there was no significant difference between Turkmen and non-Turkmen ESCC cases in the prevalence of exposure. CONCLUSION: Our findings support the suggestion that a substantial difference between Turkmens and non-Turkmens in terms of genetic susceptibility to ESCC is unlikely. Nevertheless, the moderate effect of genetic factors cannot be ruled out. Further studies to investigate potential environmental and genetic risk factors of ESCC in Golestan and the interaction between environmental and genetic factors are warranted.