Dataset Information

CD26-Related Serum Biomarkers: sCD26 Protein, DPP4 Activity, and Anti-CD26 Isotype Levels in a Colorectal Cancer-Screening Context.

ABSTRACT: Current screening trials are showing reduction in colorectal cancer incidence and mortality. However, participation rates are often low, and blood-based tests could complement existing screening strategies. CD26 protein (sCD26) and its dipeptidyl peptidase IV (DPP4) enzymatic activity in circulation have been proposed as biomarkers for colorectal cancer and other diseases. However, changes in sCD26 and DPP4 levels show complex degrees of correlation, and their physiological or pathophysiological role is unclear. The aim of this study was to analyse if anti-CD26 autoantibodies are related to sCD26 and DPP4 and to determine their relevance in a context of colorectal cancer screening for complementing the value of sCD26 and DPP4 as biomarkers. These biomarkers were measured in a large prospective cohort (n = 497, except the anti-CD26 antibodies, evaluated in 125 samples) that included a subgroup of individuals that were positive for the faecal immunological occult blood test (FIT) (n = 86) and underwent a colonoscopy (n = 47). We confirmed for the first time higher DPP4 activity in men compared to women (Student's t test, p = 0.002), though this difference between sexes was not seen for serum sCD26 protein. These biomarkers correlated (R = 0.246, p = 0.003) only in women. Correlations were found between anti-CD26 isotypes but not with DPP4 activity or sCD26 concentration, except for a negative correlation only in men between anti-CD26 IgA isotype and sCD26 (R = -0.232, p = 0.044), and an almost significant negative correlation between anti-CD26 IgG and sCD26 limited to FIT-positive men. Interestingly, patients with advanced adenomas displayed the most elevated mean levels of anti-CD26 IgA, IgM, and particularly IgG (Mann-Whitney U test, p = 0.030) in comparison with the other FIT positives without adenomas, and these levels did not correlate with sCD26 or its DPP4 activity. Our preliminary results suggest that the combination of these measures using sex as confounder could perhaps be used as biomarkers for colorectal disease. It also suggests that events affecting the gut influence the levels of anti-CD26 antibodies, which show little or no effect in antigen clearance. These findings should be confirmed in a larger cohort of individuals with colonoscopy. The physiological origin of the sex differences observed should be further addressed.

SUBMITTER: De Chiara L

PROVIDER: S-EPMC6995486 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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CD26-Related Serum Biomarkers: sCD26 Protein, DPP4 Activity, and Anti-CD26 Isotype Levels in a Colorectal Cancer-Screening Context.

De Chiara Loretta L Páez de la Cadena María M Rodríguez-Berrocal Javier J Alvarez-Pardiñas Mª Carmen MC Pardiñas-Añón Mª Carmen MC Varela-Calviño Rubén R Cordero Oscar J OJ

Disease markers 20200121

Current screening trials are showing reduction in colorectal cancer incidence and mortality. However, participation rates are often low, and blood-based tests could complement existing screening strategies. CD26 protein (sCD26) and its dipeptidyl peptidase IV (DPP4) enzymatic activity in circulation have been proposed as biomarkers for colorectal cancer and other diseases. However, changes in sCD26 and DPP4 levels show complex degrees of correlation, and their physiological or pathophysiological ...[more]

PMID: 32051696

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Project description:Introduction: CD26/dipeptidyl peptidase IV (DPP4) is a cell-surface glycoprotein present on most epithelial cells that modulates the local response to external signals. We have previously shown that the dietary flavone apigenin (4',5,7-trihydroxyflavone) upregulates cell-surface CD26/DPP4 on human colorectal carcinoma (CRC) cells and regulates its activities. We observed a unique synergistic interaction with the CRC chemotherapeutic agent irinotecan, which through its metabolite SN38 elevates CD26 at doses that are sub-cytotoxic. As SN38 interacts with topoisomerase 1 (Topo1) we evaluated whether apigenin influences Topo1 activity. Methods: We used a radioimmunoassay to selectively measure CD26 at the cell surface of HT-29 cells following various treatments. Topoisomerase 1 mRNA expression was measured by q-RT-PCR and protein abundance by western blot analysis. Direct inhibition of topoisomerase activity was measured using an assay of DNA supercoil relaxation with recombinant human Topo1. The role of Topo1 in the effect of apigenin was shown both pharmacologically and by siRNA silencing of Topo1. Molecular docking analysis was done with SBD computational software using the CDOCKER algorithm. Results: The interplay between apigenin and irinotecan was not observed when apigenin was combined with other chemotherapeutic drugs including the topoisomerase 2 inhibitors doxorubicin or etoposide. There was no enhancement of irinotecan action if apigenin was replaced with its hydroxylated metabolite luteolin (3',4',5,7-tetrahydroxyflavone) or emodin (6-methyl-1,3,8-trihydroxyanthraquinone), which is an inhibitor of the principal kinase target of apigenin, casein kinase 2 (CK2). Apigenin did not alter Topo1 mRNA expression, but siRNA knockdown of functional Topo1 eliminated the effect of apigenin and itself increased CD26 levels. Apigenin inhibited Topo1 activity in intact HT-29 cells and showed comparable inhibition of purified recombinant human Topo1 enzyme activity to that of SN-38, the active metabolite of irinotecan. Apigenin fits into the complex of Topo1 with DNA to directly inhibit Topo1 enzyme activity. Discussion: We conclude that apigenin has a unique fit into the Topo1-DNA functional complex that leads to direct inhibition of Topo1 activity, and suggest that this is the basis for the exceptional interaction with the CRC drug irinotecan. A combined action of these two agents may therefore exert a role to limit local signals that facilitate tumour progression.

Project description:BACKGROUND:Our study examined the use of decision-making styles, as identified by Scott and Bruce (1995) (i.e. differentiating between a rational, intuitive, dependent, avoidant and spontaneous decision-making style), within the context of colorectal cancer (CRC) screening participation. In the field of cancer screening, informed decision-making is considered important, which follows the Rational Decision model. Subsequently, gaining more insight into decision-making styles being used in real life, could improve support to people when making their screening decision. In addition, we examined whether the decision-making style that people used was associated with their experienced decisional conflict. METHODS:An online survey was carried out among a sample of first-time CRC screening invitees (1282 respondents, response rate 49%). We assessed people's decision-making styles, CRC screening participation, education level, self-reported health literacy, and decisional conflict, and examined the possible associations between them. RESULTS:In our study, people who had to decide about CRC screening scored high on using both a rational and intuitive decision-making style. Respondents scoring higher on using a spontaneous or dependent decision-making style were more likely to have participated in CRC screening, while respondents scoring higher on using an avoidant decision-making style were more likely not to have participated in CRC screening. However, differences were small. Generally, people in our study experienced low decisional conflict. CONCLUSION:Our eligible CRC screening population scored high on using both a rational and intuitive decision-making style. To optimise support to people, public education materials could be appealing more to the intuitive processes at hand. That being said, the current education materials aimed at informed/rational decision-making do not necessarily seem to create a problem, as people generally experienced low decisional conflict. Possible concerns regarding the use of a spontaneous, dependent or avoidant decision-making style could be that these styles might be contributing to less informed decisions. However, it is relevant to consider that the found differences are small and that any possible concern applies to a relatively small group of people.

Dataset Information

CD26-Related Serum Biomarkers: sCD26 Protein, DPP4 Activity, and Anti-CD26 Isotype Levels in a Colorectal Cancer-Screening Context.

Publications

CD26-Related Serum Biomarkers: sCD26 Protein, DPP4 Activity, and Anti-CD26 Isotype Levels in a Colorectal Cancer-Screening Context.

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