Soluble-Mesothelin Related Peptide (SMRP) is a promising diagnostic biomarker for malignant pleural mesothelioma (MPM), but various confounders hamper its usefulness in surveillance programs. We previously showed that a single nucleotide polymorphism (SNP) within the 3'untranslated region (3'UTR) of mesothelin (MSLN) gene could affect the levels of SMRP. Here, we focused on SNPs located within MSLN promoter and found a strong association between serum SMRP and variant alleles of rs3764247, rs3764246 (that is in strong linkage disequilibrium with rs2235504), and rs2235503 in non-MPM subjects. The inclusion of the genotype information led to an increase in SMRP specificity from 79.9% to 85.5%. Although not statistically significant, the MPM population showed the same trend of association. In order to study the biological role of these SNPs, the promoter region of MSLN was cloned upstream a reporter gene and the four most common haplotypes were compared in a dual luciferase assay. Rs3764247 was shown to have a functional role itself. The other SNPs were shown to interact with each other in a more complex way. Altogether, these data support the idea that SMRP performance is affected by individual (i.e. genetic) variables and that MSLN expression is influenced by SNPs located within the promoter regulatory region.
Malignant pleural mesothelioma (MPM) is a cancer of the pleural cavity resistant to chemotherapy. The identification of novel therapeutic targets is needed to improve its poor prognosis. Following a review of literature and a screening of specimens we found that platelet-derived growth factor receptor beta (PDGFRB) is over-expressed, but not somatically mutated, in MPM tissues. We aimed to ascertain whether PDGFRB is a MPM-cancer driver gene. The approaches employed included the use of gene silencing and the administration of small molecules, such as crenolanib and imatinib (PDGFR inhibitors) on MPM cell lines (IstMes2, Mero-14, Mero-25). Met5A cells were used as non-malignant mesothelial cell line. PDGFRB-silencing caused a decrease in the proliferation rate, and a reduced colony formation capacity, as well as an increase of the share of cells in sub-G1 and in G2 phase, and increased apoptotic rate of MPM cell lines. Loss of migration ability was also observed. Similar, or even further enhanced, results were obtained with crenolanib. Imatinib showed the least effective activity on the phenotype. In conclusion, our study highlights PDGFRB as target with a clear role in MPM tumorigenesis and provided a rationale to explore further the efficacy of crenolanib in MPM patients, with promising results.
Differentiated thyroid carcinoma (DTC) results from complex interactions between genetic and environmental factors. Known etiological factors include exposure to ionizing radiations, previous thyroid diseases, and hormone factors. It has been speculated that dietary acrylamide (AA) formed in diverse foods following the Maillard's reaction could be a contributing factor for DTC in humans. Upon absorption, AA is biotransformed mainly by cytochrome P450 2E1 (CYP2E1) to glycidamide (GA). Considering that polymorphisms within CYP2E1 were found associated with endogenous levels of AA-Valine and GA-Valine hemoglobin adducts in humans, we raised the hypothesis that specific CYP2E1 genotypes could be associated with the risk of DTC. Analysis of four haplotype tagging SNPs (ht-SNPs) within the locus in a discovery case-control study (N = 350/350) indicated an association between rs2480258 and DTC risk. This ht-SNP resides within a linkage disequilibrium block spanning intron VIII and the 3'-untranslated region. Extended analysis in a large replication set (2429 controls and 767 cases) confirmed the association, with odds ratios for GA and AA genotypes of 1.24 (95 % confidence interval (CI) 1.03-1.48) and 1.56 (95 % CI, 1.06-2.30), respectively. Functionally, the minor allele was associated with low levels of CYP2E1 mRNA and protein expression as well as lower enzymatic activity in a series of 149 human liver samples. Our data support the hypothesis that inter-individual differences in CYP2E1 activity could modulate the risk of developing DTC suggesting that the exposure to specific xenobiotics, such as AA, could play a role in this process.
In a recent study, we demonstrated that the variant allele of rs2480258 within intron VIII of CYP2E1 is associated with reduced levels of mRNA, protein, and enzyme activity. CYP2E1 is the most important enzyme in the metabolism of acrylamide (AA) by operating its oxidation into glycidamide (GA). AA occurs in food, is neurotoxic and classified as a probable human carcinogen. The goal of the present study was to further assess the role of rs2480258 by measuring the rate of AA > GA biotransformation in vivo. In blood samples from a cohort of 120 volunteers, the internal doses of AA and GA were assessed by AA and GA adducts to hemoglobin (Hb) measured by mass spectrometry. The rate of biotransformation was assessed by calculating the GA-Hb/AA-Hb ratio. To maximize the statistical power, 60 TT was compared to 60 CC-homozygotes and the results showed that TT homozygotes had a statistically significant reduced rate of biotransformation. Present results reinforced the notion that T-allele of rs2480258 is a marker of low functional activity of CYP2E1. Moreover, we studied the role of polymorphisms (SNPs) within glutathione-S-transferases (GSTs) enzymes and epoxide hydrolase (EPHX), verifying previous findings that SNPs within GSTs and EPHX influence the metabolism rate.
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