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  • p kip is a member of the cyclin dependent


    p27kip1 is a member of the cyclin-dependent kinase (CDK) inhibitor family that acts as a potent tumor suppressor in a variety of human cancers and negatively regulates the transition of cells from the G1 to S phase of the cell cycle, protects against inflammatory injury and promotes epithelial differentiation [21]. Moreover, various studies have shown that p27kip1 is involved in cell differentiation, proliferation, apoptosis, cell-cell adhesion, and growth inhibition [22], [23]. Recently, p27kip1 has been shown to be dysregulated in inflammatory bowel disease-associated neoplasia. Loss of p27kip1 protein expression has also been associated with aggressive behavior in IBD-associated neoplasia [21]. As reported, in some cancers, p27kip1 is mislocalized from its O-propargyl-puromycin inhibitory location in the nucleus to the cytoplasm, which changes its role from a tumor suppressor to a tumor promoter [24]. The exact molecular mechanisms responsible for the down-regulation and mislocalization of p27kip1 remain unknown. However, phosphorylation is highly correlated with the mislocalization of p27kip1 to the cytoplasm. Furthermore, CRM1 has been reported to induce the export of p27kip1 from the nucleus, thus promoting DNA damage and the re-entry of neurons into the cell cycle, leading to neuronal apoptosis via active caspase-3 [20]. However, the detailed mechanisms of the expression and localization of p27kip1 in CD are largely unknown.
    Materials and methods
    Discussion Crohn's disease is characterized by chronic recurrent inflammation with variable clinical symptoms that affect the gastrointestinal tract. Due to its serious morbidity, its link to colorectal cancer [32], and its difficulty to cure [33], [34], intensive studies have been dedicated to uncovering the pathophysiology of CD and to exploring effective therapeutic targets. Although the etiology of CD is still unknown, evidence has revealed that breakdown of epithelial barrier function is crucial in the pathogenesis of the disease [8], [9]. In the present study, we present new insight regarding the mechanisms of IEC apoptosis regulated by CRM1 in CD, which are at least partially dependent on activation of p27kip1. CRM1, which is a member of the karyopherin-β protein family, is the major mammalian export protein that facilitates the transport of large macromolecules, including RNA and proteins, from the nuclei to the cytoplasm [35]. Extensive studies have demonstrated that CRM1 is up-regulated in a broad range of cancers and, thus, may be a promising target for treating tumors [16], [17], [18]. Moreover, CRM1 has been reported to regulate neuronal apoptosis after traumatic brain injury (TBI) [20]. This study is the first to report increased expression of CRM1 in IECs in CD based on immunohistochemistry analysis of mucosal biopsies from patients with CD. CRM1 was both detected in the nuclei and cytoplasm of IECs of patients with CD. Using a murine model of TNBS-induced colitis that mimics CD, we found that CRM1 was significantly increased, which was accompanied by increased active caspase-3 and cleaved PARP, key executioners of cell apoptosis, in IECs of the colitis group [36], [37]. Furthermore, a high level of CRM1 was detected in IECs that also expressed E-cadherin, and enhanced CRM1 and active caspase-3 were observed and co-localized in colitis IECs according to double labeling, indicating the association of CRM1 with IEC apoptosis. To further confirm O-propargyl-puromycin this result, we constructed a TNF-α-induced apoptosis model in HT-29 cells in vitro. Cell apoptosis was observed with TNF-α-induced up-regulation of active caspase-3 and cleaved PARP. CRM1 was increased in TNF-α-induced HT-29 cells, which reached peak levels at 48h. Moreover, CRM1 knockdown by siRNA in TNF-α-stimulated HT-29 cells partially mitigated TNF-α-induced apoptosis. The down-regulation of the key regulators of cell apoptosis mentioned above, as observed by flow cytometry and CCK-8 cell viability assays, suggests that CRM1 may promote caspase-dependent IEC apoptosis in CD.