Evaluation of Alpha 1-Antitrypsin for the Early Diagnosis of Colorectal Cancer

Previous proteomic studies have identified alpha 1-antitrypsin (A1AT) as a potential serum biomarker for colorectal cancer (CRC). In this case-control study, we evaluated plasma A1AT concentration and activity as a biomarker for the early diagnosis of colorectal cancer in a group of 113 sporadic CRC patients. We also analyzed A1AT gene promoter methylation, and genotypes in this group of CRC patients. The plasma A1AT and CEA concentrations were measured using the nephelometric and ELISA methods, respectively. A1AT activity was determined by Trypsin Inhibitor Capacity assay. The genomic DNA from blood samples were subjected to Z and S genotype analysis using PCR-RFLP method and the gene promoter methylation in tumors and their adjacent normal tissues was determined by methylation specific-PCR assay. The plasma levels of A1AT and CEA in patients (median, 2.3 g/L and 5.96 ng/ml, respectively) were significantly higher than those in healthy controls (medians, 1.43 g/L and 2.57 ng/ml, respectively) (p = 0.0001). The plasma A1AT activity and concentrations were positively correlated with the tumor stage and well-discriminated between early and advanced stages. The A1AT activity in plasma was the most useful marker for CRC diagnosis (median 4.8 mmol/min/ml in cases vs 1.91 mmol/min/ml in controls, p = 0.0001). No deficient Z or S alleles of A1AT was observed in patients’ genotype and the gene promoter tends to be more methylated in normal mucosa than in tumor tissues. We conclude that plasma A1AT activity has better sensitivity and specificity than CEA measurement for the early detection of CRC. Promoter demethylation might play a role in increasing plasma A1AT levels in CRC patients

Coevolution of activating and inhibitory receptors within mammalian carcinoembryonic antigen families

<p>Abstract</p> <p>Background</p> <p>Most rapidly evolving gene families are involved in immune responses and reproduction, two biological functions which have been assigned to the carcinoembryonic antigen (CEA) gene family. To gain insights into evolutionary forces shaping the CEA gene family we have analysed this gene family in 27 mammalian species including monotreme and marsupial lineages.</p> <p>Results</p> <p>Phylogenetic analysis provided convincing evidence that the primordial CEA gene family in mammals consisted of five genes, including the immune inhibitory receptor-encoding <it>CEACAM1 </it>(CEA-related cell adhesion molecule) ancestor. Our analysis of the substitution rates within the nucleotide sequence which codes for the ligand binding domain of CEACAM1 indicates that the selection for diversification is, perhaps, a consequence of the exploitation of CEACAM1 by a variety of viral and bacterial pathogens as their cellular receptor. Depending on the extent of the amplification of an ancestral <it>CEACAM1</it>, the number of <it>CEACAM1</it>-related genes varies considerably between mammalian species from less than five in lagomorphs to more than 100 in bats. In most analysed species, ITAM (immunoreceptor tyrosine-based activation motifs) or ITAM-like motif-containing proteins exist which contain Ig-V-like, ligand binding domains closely related to that of CEACAM1. Human CEACAM3 is one such protein which can function as a CEACAM1 decoy receptor in granulocytes by mediating the uptake and destruction of specific bacterial pathogens via its ITAM-like motif. The close relationship between <it>CEACAM1 </it>and its ITAM-encoding relatives appears to be maintained by gene conversion and reciprocal recombination. Surprisingly, secreted CEACAMs resembling immunomodulatory CEACAM1-related trophoblast-specific pregnancy-specific glycoproteins (PSGs) found in humans and rodents evolved only in a limited set of mammals. The appearance of <it>PSG</it>-like genes correlates with invasive trophoblast growth in these species.</p> <p>Conclusions</p> <p>These phylogenetic studies provide evidence that pathogen/host coevolution and a possible participation in fetal-maternal conflict processes led to a highly species-specific diversity of mammalian CEA gene families.</p

Evolutionary Descent of Prion Genes from the ZIP Family of Metal Ion Transporters

In the more than twenty years since its discovery, both the phylogenetic origin and cellular function of the prion protein (PrP) have remained enigmatic. Insights into a possible function of PrP may be obtained through the characterization of its molecular neighborhood in cells. Quantitative interactome data demonstrated the spatial proximity of two metal ion transporters of the ZIP family, ZIP6 and ZIP10, to mammalian prion proteins in vivo. A subsequent bioinformatic analysis revealed the unexpected presence of a PrP-like amino acid sequence within the N-terminal, extracellular domain of a distinct sub-branch of the ZIP protein family that includes ZIP5, ZIP6 and ZIP10. Additional structural threading and orthologous sequence alignment analyses argued that the prion gene family is phylogenetically derived from a ZIP-like ancestral molecule. The level of sequence homology and the presence of prion protein genes in most chordate species place the split from the ZIP-like ancestor gene at the base of the chordate lineage. This relationship explains structural and functional features found within mammalian prion proteins as elements of an ancient involvement in the transmembrane transport of divalent cations. The phylogenetic and spatial connection to ZIP proteins is expected to open new avenues of research to elucidate the biology of the prion protein in health and disease

Association of serum Copper and Zinc levels with colorectal cancer

Background: In recent years, measurement of the trace elements in human serum has been used for cancer diagnosis. The purpose of this study was to compare the serum concentrations of Cu, Zn and Cu /Zn ratio of colorectal cancer (CRC) patients with those of healthy subjects. Materials and Methods: This study was conducted on 130 patients with CRC (57 women and 73 men) and 128 health subjects (65 women and 63 men). Flame atomic absorption spectroscopy method was used to analyze the serum trace element concentrations. Results: The results showed that the serum Cu levels were significantly lower (P<0.01) in patients with CRC than the healthy controls, but no significant difference was observed between serum concentration of zinc in patients and healthy subjects. The concentrations of Zn in patients and healthy subjects were (68.38±44.76 vs. 142±37.61 ug/dl) and (84±53.51 vs. 140.37±63.43), respectively, in female and male subjects. Serum concentrations of Cu were (139±139.92 vs. 160.44±46.38 ug/dl) and (123.50±77.76 vs. 160.93±44.15 ug/dl), respectively, in female and male subjects. However, the Cu/Zn ratio increased significantly in both male (2.64±2.98 vs. 1.42± 0.88) and female (3.02±3.90 vs. 1.22±0.60) subjects. Conclusion: The serum copper levels and the Cu/Zn ratio may have an instrumental role in CRC development or can be used as a prognosis marker