Mesalazine initiates an anti-oncogenic β-catenin / MUCDHL negative feed-back loop in colon cancer cells by cell-specific mechanisms
Emilie BersuderChloé TercioloMathilde LechevrelElisabeth MartinCéline QuesnelleJean–Noël FreundJean‐Marie ReimundIsabelle Groß
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Abstract:
Chronic inflammation associated with intestinal architecture and barrier disruption puts patients with inflammatory bowel disease (IBD) at increased risk of developing colorectal cancer (CRC). Widely used to reduce flares of intestinal inflammation, 5-aminosalicylic acid derivatives (5-ASAs) such as mesalazine appear to also exert more direct mucosal healing and chemopreventive activities against CRC. The mechanisms underlying these activities are poorly understood and may involve the up-regulation of the cadherin-related gene MUCDHL (CDHR5). This atypical cadherin is emerging as a new actor of intestinal homeostasis and opposes colon tumorigenesis. Here, we showed that mesalazine increase mRNA levels of MUCDHL and of other genes involved in the intestinal barrier function in most intestinal cell lines. In addition, using gain / loss of function experiments (agonists, plasmid or siRNAs transfections), luciferase reporter genes and chromatin immunoprecipitation, we thoroughly investigated the molecular mechanisms triggered by mesalazine that lead to the up-regulation of MUCDHL expression. We found that basal transcription of MUCDHL in different CRC cell lines is regulated positively by CDX2 and negatively by β-catenin through a negative feed-back loop. However, mesalazine-stimulation of MUCDHL transcription is controlled by cell-specific mechanisms, involving either enhanced activation of CDX2 and PPAR-γ or repression of the β-catenin inhibitory effect. This work highlights the importance of the cellular and molecular context in the activity of mesalazine and suggests that its efficacy against CRC depends on the genetic alterations of transformed cells.Keywords:
Mesalazine
Proinflammatory cytokine
CDX2
BACKGROUND Curcumin is a polyphenol compound extracted from the root of the herb Curcuma longa, which is used in traditional Chinese medicine (TCM). Worldwide, colorectal carcinoma (CRC) is an increasing cause of morbidity and mortality. This study aimed to investigate the effects of increasing concentrations of curcumin on cell viability, proliferation, and apoptosis of SW620 human colonic adenocarcinoma cells cultured in vitro, and the signaling pathways involved. MATERIAL AND METHODS SW620 human colonic adenocarcinoma cells were cultured in curcumin at concentrations of 0, 4, 8, 16, and 32 μmol/l for 48 hours. Specific small interfering RNA (siRNA) was transfected into SW620 cells to silence the expression of caudal type homeobox-2 (CDX2). Cell viability was measured using the MTT assay. Flow cytometry evaluated cell apoptosis. Western blot and reverse transcriptase-polymerase chain reaction (RT-PCR) were used to assess the nuclear translocation of b-catenin and the activation of Wnt signaling. RESULTS Curcumin reduced cell viability and increased apoptosis of SW620 human colonic adenocarcinoma cells in a dose-dependent way, and increased the expression of CDX2 but decreased ß-catenin nuclear translocation and the expression of Wnt3a, c-Myc, survivin, and cyclin D1. CDX2 silencing significantly reduced the effects of curcumin on SW620 human colonic adenocarcinoma cells. The nuclear translocation of ß-catenin, and expression levels of Wnt3a, c-Myc, survivin, and cyclin D1 were significantly higher in CDX2-silenced SW620 cells. CONCLUSIONS Curcumin reduced cell viability and increased apoptosis in SW620 human colonic adenocarcinoma cells by restoring CDX2, which inhibited the Wnt/ß-catenin signaling pathway.
CDX2
Viability assay
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Cdx2 is an intestine-specific transcription factor known to regulate proliferation and differentiation. We have reported previously that Cdx2 limits the proliferation of human colon cancer cells by inhibiting the transcriptional activity of the β-catenin–T-cell factor (TCF) bipartite complex. Herein we further elucidate this mechanism. Studies with a classic Cdx2 target gene and a canonical Wnt/β-catenin/TCF reporter suggest that Cdx2 regulates these promoters by distinctly different processes. Specifically, inhibition of β-catenin/TCF activity by Cdx2 does not require Cdx2 transcriptional activity. Instead, Cdx2 binds β-catenin and disrupts its interaction with the DNA-binding TCF factors, thereby silencing β-catenin/TCF target gene expression. Using Cdx2 mutants, we map the Cdx2 domains required for the inhibition of β-catenin/TCF activity. We identify a subdomain in the N-terminus that is highly conserved and when mutated significantly reduces Cdx2 inhibition of β-catenin/TCF transcriptional activity. Mutation of this subdomain also abrogates Cdx2's anti-proliferative effects in colon cancer cells. In summary, we conclude that Cdx2 binds β-catenin and disrupts the β-catenin–TCF complex. Considering the pivotal role of β-catenin/TCF activity in driving proliferation of normal intestinal epithelial and colon cancer cells, our findings suggest a novel mechanism for Cdx2-mediated regulation of Wnt/β-catenin signaling and cell proliferation.
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Beta-catenin
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Objective: In order to learn more side-effects of Mesalazine,one case that Mesalazine indced fever in a patient with Crohn disease(CD) was investigated.Methods:Many clinical case-report about side-effects of Mesalazine were observed by index system.Results:Patient's temperature returned to normal after Mesalazine disused for two days.Conclusion:It's necessary to pay more attention on rare side-effects of Mesalazine,fever,which was reported less in clinic.
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Objective To evaluate the clinical efficacy of bifico combined with mesalazine in patients with mild to moderate ulcerative colitis(UC),and to explore its mechanism.Methods Sixty patients with mild to moderate active UC were randomized to combination group(n=30) and mesalazine group(n=30).The patients were treated by bifico and mesalazine in combination group and only by mesalazine in mesalazine group for 8 weeks.The changes of clinical symptoms and disease activity under endoscopy were evaluated before and after the treatment.The expression of NF-κB in colonic mucosa was also detected by immunohistochemical staining.Results The clinical symptoms and disease activity under endoscopy were improved more in combination group than in mesalazine group(P0.05).The expression of NF-κB significantly lower in combination group than that in mesalazine group(P0.05).Conclusion The combination of bifico and mesalazine is more effective than mesalazine alone in treatment of mild to moderate active UC.Bifico is an effective agent in the treatment of mild to moderate active UC probably by decreasing expression of NF-κB.
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Ulcerative proctitis (UP) is a prevalent condition associated with increased morbidity, and topical mesalazine (5-aminosalicylic acid [5-ASA]) is known to inhibit the inflammatory processes in UP. We successfully devised mesalazine suppositories, in which 250mg mesalazine was equally distributed and remained stable for at least 2 weeks. We evaluated the effect of using mesalazine suppositories twice a day (BID) on two UP patients. The results demonstrated that mesalazine suppositories were efficacious, well tolerated and safe for the long-term maintenance of UP remission.
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Aminosalicylic acid
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目的：炎症性腸疾患患者でmesalazine不耐症に対して脱感作療法を行い，mesalazineの服用が可能になることを試みた．方法：28例のmesalazine不耐症症例に対して脱感作療法を行った．脱感作はmesalazineを粉砕し，1mg/dayから増量していくHoldsworth1）の方法で行った．結果：脱感作療法を行った28例中，2例が脱落し，26例で評価した｡成功は22例【84.6％】，不成功は4例【15.4％】であった｡成功例のうちの17例【77.3％】はその後mesalazine のみで寛解を維持しており，他の治療が必要であったのは5例であった．結語：脱感作療法はmesalazine不耐症症例に対して有用な治療法であった．
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Background Ulcerative colitis (UC) is characterised by chronic mucosal inflammation primarily in the colon. Guidelines recommend mesalazine as first-line therapy for induction of maintenance in mild-to-moderate Ulcerative colitis. Patients' preferences, response to treatment, site and extent of inflammation and cost are important considerations when selecting mesalazine therapy. Aims/Methods This article reviews mesalazine's role in ulcerative colitis and explores the factors to consider when optimising mesalazine-based therapy. Findings Up to two-thirds of patients fail to respond to induction therapy within 8 weeks, thereby prompting a switch of formulations or escalation to oral corticosteroids. While there are no major variations in efficacy, different mesalazine formulations are not interchangeable because of differences in mode of drug delivery, site of drug release and excipients. Switching mesalazine products before escalating therapy may, therefore, spare patients from wider side effects and higher costs. Conclusions Optimising mesalazine-based therapy requires individualised treatment plans based on patient preferences, site and extent of inflammation, response to treatment and potential side effects. An algorithm exists to guide the selection of alternative mesalazine formulations when required.
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Maintenance therapy
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AIM: To analyze the association of the expression of β-catenin and CDX2 with invasion,metastasis,and prognosis of human gastric carcinoma.METHODS: Eighty patients with gastric carcinoma and 12 normals as control were examined for the expression of β-catenin and CDX2 by SP immunohistochemistry.RESULTS: β-catenin was present in all normal gastric mucomembranous epithelium,but CDX2 was not.β-catenin was decreased,deficient,or abnormaliy distributed in gastric carcinoma tissues.These two markers were associated with the differentiation,invasion,metastasis of gastric carcinoma(P0.01).The 5-year survival rate was highest in patients with co-expression of β-catenin and CDX2(P0.05).CONCLUSION: The expression of CDX2 or β-catenin may be associated with the genesis,invasion,and metastasis of gastric carcinoma.
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Gastric carcinoma
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To investigate the expressions of E-cadherin, β-catenin, transcription factor 4 (TCF4), which are related with Wnt/β-catenin signaling pathway, and Caudal-type Homeobox Protein 2 (CDX2) originated from intestine, in various gastric diseases and its influence on gastric carcinogenesis and differentiation. A total of 319 various gastric diseases samples from gastroscopy were detected in situ using immunohistochemistry, and data were analyzed with χ 2 test and Kendall’s tau-b rank correlation coefficient analysis. Along with the progression from superficial gastritis (SG) to atrophic gastritis (AG) to gastric cancer (GC), the expressions of E-cadherin and β-catenin appeared a decreasing tendency in total, while β-catenin emerged a decreasing tendency in the cell membrane and an increasing in the nucleus, and the highly positive expression rate of intranuclear transcription factor TCF4 appeared an increasing tendency. The transcription factor CDX2 had a higher expression in AG and GC than that in SG. The expression rates of the four proteins above in intestinal type adenocarcinoma were all higher than those in diffuse type carcinoma. There were positive correlations between E-cadherin and β-catenin expressed in cytoplasm, between β-catenin expressed in cell membrane and β-catenin in cytoplasm, between β-catenin expressed in cytoplasm and β-catenin in nucleus, between β-catenin and TCF4 in nucleus, between TCF4 and CDX2 in nucleus, respectively (P<0.05). And β-catenin and CDX2 had no relevance in nucleus (P>0.05). We found that the four proteins were involved in gastric carcinogenesis and the differentiation to intestinal type adenocarcinoma.
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TCF4
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