Abstract
BackgroundIntracellular signaling through cyclic nucleotides, both cyclic AMP and cyclic GMP, is altered in colorectal cancer. Accordingly, it is hypothesized that an underlying mechanism for colorectal neoplasia involves altered function of phosphodiesterases (PDEs), which affects cyclic nucleotide degradation. Here we present an approach to evaluate the function of selected cyclic nucleotide-PDEs in colonic endoscopic biopsies from non-neoplastic appearing mucosa.MethodsBiopsies were obtained from patients with and without colorectal neoplasia. Activities of PDEs were characterized functionally by measurements of transepithelial ion transport and their expression and localization by employing real-time qPCR and immunohistochemistry.ResultsIn functional studies PDE subtype-4 displayed lower activity in colorectal neoplasia patients (p = 0.006). Furthermore, real-time qPCR analysis showed overexpression of subtype PDE4B (p = 0.002) and subtype PDE5A (p = 0.02) in colorectal neoplasia patients. Finally, immunohistochemistry for 7 PDE isozymes demonstrated the presence of all 7 isozymes, albeit with weak reactions, and with no differences in localization between colorectal neoplasia and control patients. Of note, quantification of PDE subtype immunostaining revealed a lower amount of PDE3A (p = 0.04) and a higher amount of PDE4B (p = 0.02) in samples from colorectal neoplasia patients.ConclusionIn conclusion, functional data indicated lower activity of PDE4 subtypes while expressional and abundance data indicated a higher expression of PDE4B in patients with colorectal neoplasia. We suggest that cyclic nucleotide-PDE4B is overexpressed as a malfunctioning protein in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia. If a predisposition of reduced PDE4B activity in colonic mucosa from colorectal neoplasia patients is substantiated further, this subtype could be a potential novel early diagnostic risk marker and may even be a target for future medical preventive treatment of colorectal cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2980-z) contains supplementary material, which is available to authorized users.
Highlights
Intracellular signaling through cyclic nucleotides, both cyclic Adenosine monophosphate (AMP) and cyclic Guanosine monophosphate (GMP), is altered in colorectal cancer
Functional characterization of PDE activity CTRL patients responded to rolipram (1 μM) with higher short circuit currents (SCC) increases compared to Colorectal neoplasia (CRN) patients (p = 0.006) (Figs. 1 and 2)
No significant change was observed in SCC when samples, after prestimulation with db-cyclic adenosine monophosphate (cAMP), were exposed to either cilostamide (1 μM), (p = 0.869) or sildenafil (1 μM), (p = 0.899)
Summary
Intracellular signaling through cyclic nucleotides, both cyclic AMP and cyclic GMP, is altered in colorectal cancer. It is hypothesized that an underlying mechanism for colorectal neoplasia involves altered function of phosphodiesterases (PDEs), which affects cyclic nucleotide degradation. We present an approach to evaluate the function of selected cyclic nucleotide-PDEs in colonic endoscopic biopsies from non-neoplastic appearing mucosa. Colorectal neoplasia (CRN) is correlated with the development of CRC [2]. With regards to CRC, non-steroidal anti-inflammatory drugs (NSAIDs) decrease mortality rate and inhibit de novo disease development. The exact mechanism by which NSAIDs exert their anticarcinogenic effect is not completely understood [3, 4]. Investigators attribute part of the anticancer activity of NSAIDs to their inhibition of the cyclooxygenase (COX) enzymes, leading to a decrease in activity of prostaglandins and cyclic adenosine monophosphate (cAMP) [5, 6]
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