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    • PDEs a group of metallophosphohydrolases hydrolyze the cycli

    2021-10-12

    PDEs, a group of metallophosphohydrolases, hydrolyze the 3′,5′-cyclic phosphate group on cyclic nucleotides to a 5′-monophosphate, thereby blocking cyclic AMP (cAMP) or cGMP signaling [8,9]. There are different types of PDE isozymes, with different substrate specificities. PDE5 (specific to cGMP) and PDE10 (specific to both cGMP and cAMP) are more associated with GUCY2C-mediated signaling than are other PDEs [9]. PDEs block GUCY2C-associated second messenger signaling by degrading cyclic GMP, while inhibition of PDEs activity prevents cGMP degradation and leads to amplification of GUCY2C-dependent cGMP signaling [10,11]. Accumulating evidence suggests that the paracrine hormone-mediated GUCY2C/cGMP/PDEs signaling pathway plays a key role in homeostasis of the intestinal crypt-villus axis, and its dysregulation is associated with intestinal tumorigenesis [5,6,[11], [12], [13], [14], [15], [16]].
    Role of the GUCY2C/cGMP/PDEs pathway in homeostasis of intestinal crypt-villus axis and colorectal tumorigenesis In the intestine, villi projecting into the lumen and flank-like crypts embedded in the mesenchyme are called the intestinal crypt-villus axis [17]. The luminal surface of the crypt-villus axis is covered with a single epithelial layer that provides a physical barrier between systemic and mucosal compartments. In the colon, tubular crypts in the mesenchyme possess proliferating zones that contain various types of cells, including stem cells. Intestinal stem CD 3254 can self-renew, and have the potential to give rise to all differentiated cell types (multipotency), including enterocytes, goblet cells, entero-endocrine cells, and paneth cells, in the bottom of the crypt [17]. The proliferation, migration, differentiation, and apoptosis of epithelial cells of the crypt-villus axis occur via a highly regulated process, and several signaling pathways are involved in maintenance of homeostasis [12,17]. Disruption of homeostasis in the crypt-villus axis leads to tumorigenesis in the colorectum [12,17]. The GUCY2C-paracrine hormone axis is considered a key regulator of homeostatic processes, including cell proliferation, migration, differentiation and apoptosis, as well as functions that are vital to the integrity of genome [5,6,[14], [15], [16]]. Suppression of GUCY2C is associated with altering genomic integrity (loss of APC heterozygosity and DNA damage) in colorectum that leads to tumorigenesis [15]. GUCY2C agonist suppressed proliferation and increased goblet cell density in non-neoplastic intestinal epithelium of APCMin/+ mice [9]. In GUCY2C knockout mice, there was increased cell proliferation, crypt hyperplasia, and migration (Table 1). Wilson et al. [18] reported that guanylin was found in colorectal mucosa specimens from healthy individuals (n = 30), but absent from patients with colorectal tumors (n = 54). Silencing of guanylin and uroguanylin, the endogenous hormones for GUCY2C, resulted in CRC tumorigenesis. GUCY2C/cGMP signaling maintains integrity and homeostasis of intestinal epithelial cells and preserves APC function, opposing neoplasia (Table 1) [19]. Disruption of the intestinal epithelial barrier resulted in inflammation and the generation of reactive oxygen species that cause DNA damage; the genotoxic effects led to intestinal tumorigenesis [20,21]. Silencing of GUCY2C is associated with intestinal epithelial barrier disruption and hyperpermeability, as well as elevated levels of oxidative DNA damage in circulating leukocytes. Conversely, protecting barrier integrity and restricting permeability was observed after activating GUCY2C with an agonist [20,21]. Obesity is one of the risk factors for CRC, which is associated with deficiency of the guanylin–GUCY2C signaling [[22], [23], [24], [25]]. Lin et al. [22] found that high-calorie diet-induced obesity is associated with deficiency of guanylin expression and blockade of GUCY2C-signaling in colon epithelial cells, leading to tumorigenesis. Mechanistic studies revealed that high-calorie diet-induced endoplasmic reticulum (ER) stress, which suppressed expression of guanylin during colon tumorigenesis [22,26]. Chemical chaperone taurodeoxycholic acid (oral dosage of 150 mg/kg body weight for 12 days), an FDA-approved drug for the treatment of cholestatic liver diseases, blocked ER stress and rescued expression of guanylin in colons of C57BL/6 mice fed with high-fat diet. PKR-like ER-localized eIF2α kinase (PERK) is involved in ER stress-induced unfolded protein response, and its inhibition allowed guanylin expression in intestinal epithelial cells [22,27]. Therefore, ER stress inhibitors and/or GUCY2C agonists, such as linaclotide, can be suggested as novel chemopreventive agents for obesity-induced CRC [[22], [23], [24], [25]].