Dig Dis Sci DOI 10.1007/s10620-015-3800-z

ORIGINAL ARTICLE

CUEDC2 Protects Against Experimental Colitis and Suppresses Excessive Proliferation of Intestinal Mucosa Shaoxin Wang1 • Jiang Pu1 • Na Li2 • Chuanfeng Li3 • Chao Li1 • Lan Yu1 Xiaohui Wang1 • Shanfeng Fu1 • Lihong Cui1



Received: 18 May 2015 / Accepted: 4 July 2015 Ó Springer Science+Business Media New York 2015

Abstract Background CUEDC2, a CUE domain-containing protein, is highly expressed in many tumors, which also may be associated with inflammation. Aims In this study, we studied whether CUEDC2 plays a role in the progress of inflammatory bowel disease using CUEDC2 knockout (KO) mice and discussed the effects of CUEDC2 on cell proliferation in colonic mucosa. Methods CUEDC2 KO mice were administered with drinking dextran sodium sulfate (DSS) to establish colitis mice model. At different time points after DSS administration, body weight and stool consistency of mice were graded. Cytokines in colon tissue such as IL-6 were measured by RT-PCR. NF-jB and STAT3 signaling pathways in colon tissue were assessed by western blotting. Besides, cell proliferation of intestinal mucosa was analyzed by immunohistochemical staining. Results CUEDC2 alleviated the colonic inflammation, showing elevated body weight loss, worse diarrhea, and more severe colonic mucosal injury in CUEDC2 KO mice than WT mice. Moreover, pro-inflammatory cytokines such as

IL-6, TNFa, COX2, and MIP2 were significantly elevated. In CUEDC2 KO mice, the NF-jB and STAT3 signaling pathways were increasingly activated in different stages of progression of the colonic inflammation, and the percentage of proliferating cells as indicated by Ki67, CyclinD1, and BrdU in the inflammatory tissues was significantly increased. Conclusions Our findings demonstrate that CUEDC2 plays an important role in protection from colonic inflammation, primarily by inhibiting the NF-jB and STAT3 signaling pathways and preventing excessive proliferation of the inflammatory epithelial cell.

Shaoxin Wang and Jiang Pu are the Co-first authors.

Introduction

& Shaoxin Wang [email protected]

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders of the gastrointestinal tract, which are composed of ulcerative colitis and Crohn’s disease. The etiologies of the IBDs are unknown, but evidences have indicated that it may be related to infections, immune disorders, environmental factors, genetic susceptibility, and diet. Chronic relapse of inflammatory bowel disease directly accelerates the occurrence of colorectal cancer. Epidemiological studies demonstrate that the risk of colorectal cancer in IBD patients increases 0.5–1 % each year

Lihong Cui [email protected] 1

Department of Digestive, Navy General Hospital, Beijing 100048, China

2

Department of Laboratory, Navy General Hospital, Beijing 100048, China

3

Department of Digestive, The Third Hospital of Peking University, Beijing 100191, China

Keywords Inflammatory bowel disease  CUEDC2  Inflammation  Proliferation Abbreviations IBD Inflammatory bowel disease CUEDC2 CUE domain-containing 2 DSS Dextran sodium sulfate NF-jB Nuclear factor jB STAT3 Signal transducer and activator of transcription 3

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within 8–10 years after diagnosis [1]. During the active period of colitis, a large number of neutrophils and eosinophilic granulocytes infiltrate the mucosa and crypts, causing colonic mucosal crypt inflammation and a wide range of little ulcers. In this state of inflammation, a large number of immune cells are recruited and accumulated to release pro-inflammatory cytokines and chemokines including IL-10, IL-6, TNFa, EGF, MMP, VEGF, and arachidonic acid. These factors up-regulate angiogenesis and activate downstream signaling pathways such as NFjB, MAPK, and STAT3, altering the processes of DNA repair, apoptosis, and proliferation, thus promoting tissue repair and excessive proliferation. CUEDC2 is a novel protein containing the CUE structural domain, which is overexpressed in many cancers including renal cancer, ovarian cancer, and brain cancer. Several reports indicate that CUEDC2, IKK, and protein phosphatase 1 (PPI) coexist in a complex. When stimulated by the inflammatory cytokines such as tumor necrosis factor a (TNFa), PPI is recruited to the complex and IKK is dephosphorylated and inactivated, leading to inhibition of NF-jB activity [2]. These findings suggest that CUEDC2 is an IKK regulatory protein, which acts by recruiting PPI to inhibit the activation of the NF-jB signaling pathway, thus regulating the expression of a series of anti-apoptotic and pro-proliferative genes. Since it has been confirmed that CUEDC2 is involved in the cellular regulation of inflammatory reactions, we hypothesized that CUEDC2 plays an important role in inflammatory diseases such as colitis. In this study, we established a mouse model of chronic colitis by administering dextran sodium sulfate (DSS), which developed colonic inflammatory process. We found that CUEDC2 was an important regulatory gene in colon tissue and played a role in the inflammatory process. Expression of CUEDC2 reduced colonic inflammatory reactions, decreased the expression of pro-inflammatory cytokines, significantly inhibited the activation of signaling pathways such as NF-jB and STAT3, and prevented excessive proliferation of the inflammatory mucous epithelial cell.

Methods Animal Studies Male C57BL/6J, wild-type (WT), and CUEDC2 KO mice, 8–10 weeks old, with weights between 24 and 26 g were selected and raised in the SPF level sterile environment in the Animal Center of the Academy of Military Medical Sciences. All animal experiments were performed with the approval of the Institutional Animal Care and Use Committee of the National Center of Biomedical Analysis.

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CUEDC2 KO mice and WT littermates control were generated by germline transmission [3]. In the CUEDC2 gene of KO mice, LoxP-flanked sequences of EcoR V vector was deleted and exons 2–9 was removed. It took more than fifteen times that the KO mice backcrossed to C57BL/6J before usage in these experiments. In all DSS colitis experiments, the WT and KO mice bred and co-housed with each other in the same sterile environment. Water with 2.5 % dextran sodium sulfate (DSS, MW: 36,000–50,000) was given to WT and CUEDC2 KO mice for 6 days and then replaced with normal drinking water for 4 days. The body weights, stool consistency, and hematochezia of the mice were recorded and scored each day [4]. The stool consistency score (the sum of the consistency score and the hematochezia score) was analyzed. Tissue Analysis At the end of the protocol, the mice were killed, and the full length of the colon was removed. After the intestinal contents were cleaned, the colonic tissues were rolled as rings by the Swiss-roll method and fixed in 10 % formalin for Hematoxylin&Eosin (H&E) staining and immunohistochemistry. Histopathological evaluation was performed by colitis severity score: the sum of scores for ulceration [5] and inflammation score [6]. The immunohistochemical markers were antigens related to proliferation such as Ki67 (Sigma, RMA-0542), CyclinD1 (Epitomics, 2261) and BrdU (Sigma, B5002). For the detection of the proliferation marker BrdU, BrdU (100 mg/kg) was administered by intraperitoneal injection 4 h before the mice were killed, followed by routine immunohistochemistry assay. Three randomly selected fields from each histological sample were analyzed (using the Mike Audi CMIAS-II multifunctional pathology image analysis system) to determine the percentage of the markerpositive cells. Real-Time Quantitative PCR Tissue 5 mm from the end of the colon of the colitis model mice was split using Trizol, and tissue DNA was extracted. The reverse transcriptase kit (TaKaRa, DRR036A) and PCR reagent kit (TaKaRa, DRR081A) were used for the reverse transcription and PCRs, respectively, following the manufacturer’s instructions. The expression levels of inflammatory and proliferative markers, such as tumor necrosis factor (TNFa), interleukin-6 (IL-6), cyclooxygenase 2 (COX2), macrophage inflammatory protein-2 (MIP2), monocyte chemoattractant protein-1 (MCP1), cyclinD1, vascular cell adhesion molecule 1 (VCAM1), and B cell lymphoma 2 (BCL2), were measured by RT-PCR method. Gene expression analysis was performed using CFX Bio-Rad software.

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Western Blotting Colonic tissues, including the normal and inflammatory colon (7 and 10 days after DSS exposure) from the WT and CUEDC2 KO mice were split with RIPA for the western blotting assay. Proteins were separated via SDS-PAGE, with b-actin and a-tubulin as the internal reference in the immunoblotting. Primary antibodies used in the experiment included rabbit monoclonal antibody to p-STAT3 (Tyr705) (Epitomics company), rabbit polyclonal antibody to STAT3 (Santa Cruz Biotechnology), rabbit monoclonal antibody to p-IKKa/b (S176/180) (Cell signaling, 16A6), mouse monoclonal antibody to IKKa (Cell signaling, #2682), rabbit monoclonal antibody to p–p65 (S536) (93H1) (Cell signaling, #3033), rabbit monoclonal antibody to p65 (C22B4) (Cell signaling, #4764), mouse monoclonal antibody to a-tubulin (sigma, T5168), and mouse monoclonal antibody to b-actin (Abcam, ab6276). The rabbit polyclonal antibody to CUEDC2 was prepared in our laboratory. Statistical Analysis All results were collected from at least three independent experiments. Data were expressed as mean ± SEM. SPSS 13.0 was used for the Student’s t test analysis, with P \ 0.05 (**P \ 0.01) indicating statistical significance.

Results Severe Inflammation of the Colon in the CUEDC2 KO Mice In the DSS-induced colitis model mice, inflammatory lesions of the colon can result in body weight loss, bowel movements increase, and stool blood. This study found that, along with the progress of colitis, CUEDC2 KO mice lost more weight than the WT mice (Fig. 1a). The stool consistency and the hematochezia degree of CUEDC2 KO mice were significantly worse than that of WT mice (Fig. 1b). Compared with WT mice, the histopathology H&E staining analysis revealed that more and broader spreading colonic ulcers could be observed in CUEDC2 KO mice, with inflammatory cells infiltrating deeper into the mucosal laminae propria. Accordingly, the colitis severity score of CUEDC2 KO mice was significantly higher than that of WT mice (Fig. 1c, d). These above results confirmed that the degree of the colonic inflammation in the CUEDC2 KO mice was much more severe than that of WT mice.

CUEDC2 Knockout Promoted the Expression of Pro-inflammatory Cytokines in Mice In this experiment, it has been found that CUEDC2 can in part affect the colonic inflammation in mice under DSS stimulation. The histopathology H&E staining analysis revealed that ulcers were closer to the end of the colon (Fig. 1c). Therefore, the end of the colon from WT and CUEDC2 KO mice was collected on 10 days after the initiation of the experiment, which is the recovery period of colitis (Fig. 1a). The mRNA expression of the pro-inflammatory cytokines (IL-6, TNFa, MIP2, and COX2) in the inflammatory tissue in CUEDC2 KO mice was significantly higher than those in WT mice by RTPCR (Fig. 2a–d), in line with the histopathological observations (Fig. 1). This result indicated that in the inflammation process, the continually rising pro-inflammatory cytokines were another major reason for the much more severe inflammation in the colon tissue of CUEDC2 KO mice. CUEDC2 Regulated Inflammation Through NF-jB and STAT3 Signaling Pathways Since the signaling pathways of NF-jB and STAT3 are associated with inflammation, proliferation, immunity, and other biological processes, we performed Western blotting assay to test CUEDC2 regulation of the NF-jB and STAT3 signaling pathways, using the distal colon from the mice killed 0, 7, and 10 days after starting DSS administration. These results showed that the phosphorylation of IKKa/b in the colitis tissues of WT and CUEDC2 KO mice was significantly increased compared with the tissues before DSS induction. However, 10 days after experiment, the phosphorylation of IKKa/b in the colon tissues of WT mice was obviously decreased with recovery, but it was continually activated in CUEDC2 KO mice. Consistent with the phosphorylation of IKKa/b, p65 also presented the continual activation in CUEDC2 KO colon during the inflammation procession (Fig. 3a). Meanwhile, we also found that the phosphorylation of STAT3 was continuously increased 10 days after DSS administration in the inflammatory colon of CUEDC2 KO mice (Fig. 3b). Furthermore, the mRNA expression of target genes in the NF-jB and STAT3 signaling pathways in CUEDC2 KO mice was higher than those of WT mice, such as MCP1, VCAM1, CyclinD1, and BCL2 (Fig. 3c, d). These results suggest that CUEDC2 knockout can lead to sustained phosphorylation of NF-jB and STAT3 signaling pathways in the DSS-induced colitis. Interestingly, without DSS treatment, the phosphorylated STAT3 levels in the colonic tissue of CUEDC2 KO mice were slightly higher compared with that of WT mice, indicating that CUEDC2 loss induces the activation of STAT3 and results in higher susceptibility toward DSS-induced colitis.

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Dig Dis Sci Fig. 1 CUEDC2 KO mice are more susceptible to DSSinduced colitis. CUEDC2 KO and WT (littermate control) C57BL/6J mice were administered 2.5 % DSS in drinking water for 6 days and were returned to water until the end of the experiment. a Body weight, b stool consistency plus rectal bleeding score were scored daily. c Representative images of H&E-stained colon tissue, arrow heads indicate borders of ulcers. Left scale bar represents 500 lm, and right scale bar represents 100 lm; d colon severity score showing ulcer scope and inflammatory infiltration. Data represent mean ± SEM. n = 8/group; *P \ 0.05, **P \ 0.01 paired Student’s t test

CUEDC2 Inhibited the Proliferation of the Epithelial Cells in Colitis As shown the anterior experiment, CUEDC2 knockout in the DSS-induced colitis can regulate the NF-jB/STAT3 phosphorylation activity, aggravate the inflammation of the colon, and significantly activate anti-apoptotic target genes (such as BCL2). Therefore, we performed immunohistochemical assays for the proliferation-related antigens Ki67, Cyclin D1 and BrdU incorporation test. These results showed that the percentage of proliferation-related markerpositive cells in CUEDC2 KO mice was higher than that in WT mice during the recovery period of colitis (Fig. 4a–d). These findings clarified that in the experimental colitis, CUEDC2 knockout can aggravate the inflammatory process and cause excessive cell proliferation.

Discussion In the inflammatory responses of colon, damage to the function of mucous membrane barrier, including mucosal damage, inflammatory responses, and epithelial cell repair,

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is considered to be the most important pathophysiological bases of IBD. Damage to the mucosal layer increases the permeability of the layer and promotes an intestinal flora shift. A large number of intestinal microbes can enter into the intestinal submucosa from the lumen, resulting in repeated inflammatory responses and mucosal lesions. The DSS-induced colitis mouse model has greatly informed the pathophysiology of IBD and has been widely used in studies of the regulatory networks and molecular mechanisms of inflammation in the colon. In this experiment, the DSSinduced colitis mouse model was used. In addition, susceptibility to DSS colitis is affected by the genetic background of the mice. So, in our study we chose the littermate WT and CUEDC2 KO mice, avoiding the influence of other genetic factors. Although there was a report that CUEDC2 plays a role in protecting against colitis and maintaining intestinal length [3], our study demonstrated that colitis in CUEDC2 KO mice was much more severe than WT mice, showing the formation of larger and deeper ulcers, not limited to more ulcers as well as the worse diarrhea and bloody stool. The destruction of the function of the mucosal barrier in CUEDC2 KO mice was worsened, which in turn aggravated the inflammatory responses of colon. Therefore,

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Fig. 2 Enhanced pro-inflammatory cytokine levels in colon tissue of CUEDC2 KO mice. Distal section of colon tissue collected from DSS-treated mice at 10 days after DSS exposure was analyzed by RTPCR for the expression of a IL-6, b TNFa, c COX2, d MIP2 mRNA. Cytokine expression was normalized to GAPDH. Data represent three independent experiments, mean ± SEM. n = 6/group; *P \ 0.05, **P \ 0.01

the damage to colonic mucosal integrity and the barrier function is one of the important causes of the aggravation of inflammation in the colon. Besides the injure of mucosal barrier, colitis also manifests the movement of bacteria from the intestinal lumen into the mucous membrane, activation of innate immune responses, and the release of pro-inflammatory cytokines. Despite the fact that the exact pathogenic mechanisms of these small peptides are not clearly understood, it is physiologically important to keep the balance of proinflammatory and anti-inflammatory factors in the intestinal mucosa [7, 8]. Physiological intestinal inflammation is believed to be beneficial. However, the pathogenic immune response is mediated by a variety of inflammatory cytokines. Excessive generation of the pro-inflammatory mediators exacerbates these responses. As shown in the results (Fig. 2), the expression levels of the pro-inflammatory cytokines in the colon tissues of CUEDC2 KO mice were still high in the recovery period following the acute inflammation reaction. The overexpression of pro-inflammatory factors, such as TNFa, IL-6, IL-1, IL-12, and IL-23, and the insufficient expression of anti-inflammatory factors, such as IL-4, IL-10, IL-19, and IL-22, can cause disorder of the internal intestinal homeostasis and are also important steps in the pathogenesis of IBD [9]. In the

Fig. 3 CUEDC2 regulates inflammatory response through NF-jB and STAT3 signaling pathways. Distal section of colon tissue was collected from DSS-treated mice at 0, 7, and 10 days after administering DSS, respectively. a The distal colons were examined for phosphorylation of IKKa/b and p65 by western blot analysis. Each lane corresponds individual mouse. b Colon tissue collected at 0 and

10 days after DSS administration was processed for western blot analysis for p-STAT3. c, d Real-time PCR analysis for mRNA expression of MCP1, VCAM1, CyclinD1, and BCL2 in the tenth day distal colon of WT and CUEDC2 KO mice. Data represent three independent experiments, mean ± SEM. n = 6/group; *P \ 0.05, **P \ 0.01

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Dig Dis Sci Fig. 4 CUEDC2 regulates cell proliferation in intestinal epithelial cell. a, c Colons of colitis mice were stained with anti-Ki67 and anti-cyclinD1 antibody. Scale bar 200 lm. b, d Percentages of Ki67-positive and cyclinD1-positive cells within colitis tissues were analyzed. e BrdU incorporation (100 mg/kg, i.p. 4 h before killing) in colonic crypts of WT and CUEDC2 KO mice. Proliferative epithelial cells were stained with anti-BrdU antibody. Scale bar 100 lm. f Percentages of BrdU-positive cells were analyzed. Results are mean ± SEM; n = 6/group; *P \ 0.05, **P \ 0.01

colitis, COX2 is highly expressed, and it is positively related to the endoscopic classification and the histological grading of colitis [10, 11]. MIP2 and MCP1 are two immune response chemokines. In acute reactions, these proteins can induce chemotaxis of monocytes, macrophages, and neutrophils to the sites of inflammatory lesions [12, 13], which is additionally involved in the acute inflammatory process [14, 15]. Cytokines IL-6 and TNFa are the most common stimulating factors affecting the NF-jB and STAT3 pathways. When the cells are stimulated by these cytokines, these pathways can be quickly activated, playing roles in cell proliferation, differentiation, survival, and inflammation through the expression of a variety of target genes [16]. There have been reports that NF-jB pathways are related to inflammatory disorders, such as otitis media, colitis, or dermatitis. These pathways play a role in energy metabolism, tissue damage, and inflammatory reactions [17–19]. On the other hand, when the cells are continuously exposed

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to stimulating factors, STAT3 can become continuously phosphorylated, promoting cell transformation or inhibiting apoptosis, and it can also participate in various pathophysiological processes, including cancer [20]. In this experiment, we found that the CUEDC2 inhibited the NFjB and STAT3 phosphorylation and reduced the colon inflammation. These findings indicated that during the progression of colonic inflammation, the continually active NF-jB and STAT3 signaling pathway in CUEDC2 KO mice was the another regulatory mechanism underlying the aggravation of the colonic inflammation. Not only this, the percentage of Ki67- and BrdU-positive cells in WT mice was significantly lower than that in CUEDC2 KO mice, which indicate CUEDC2 suppresses the excessive proliferation of the intestinal epithelial cells, even the formation of malignant tumors. At present, there are more and more evidences indicating that chronic inflammation is associated with the risk of cancer. The internal factors (genetic background) or

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external factors (inflammation) are joined by means of transcription factors, soluble mediators (chemical factors, cytokines), and tumor-related factors (such as tumor-associated macrophages) to regulate the inflammatory reactions and promote tumor formation. Sustained inflammatory reactions may also promote genomic instability. Therefore, since CUEDC2 inhibits inflammatory reactions in the colon, suppresses the activation of NF-jB and STAT3 pathways as well as the following expression of downstream anti-apoptotic genes, these mechanisms can explain the finding that CUEDC2 can inhibit the formation of colitis-associated cancer (CAC) [3]. These results suggest that CUEDC2 has the potential to become the clinical marker for the evaluation of colitis and CAC, however, which also need to be confirmed in clinical samples. Acknowledgments The authors thank Mr. Li Tao, Mr. Jin Baofeng, and Ms. Chen Yuan for technical assistance. This work was supported by Navy General Hospital, Beijing, China. Compliance with Ethical Standards Conflict of interest

None.

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CUEDC2 Protects Against Experimental Colitis and Suppresses Excessive Proliferation of Intestinal Mucosa.

CUEDC2, a CUE domain-containing protein, is highly expressed in many tumors, which also may be associated with inflammation...
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