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      18β-glycyrrhetinic acid suppresses gastric cancer by activation of miR-149-3p-Wnt-1 signaling

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          Abstract

          18β-glycyrrhetinic acid (GRA) exerts anti-tumor effects on various types of cancer. In the present study, we found that GRA attenuated the severity of gastritis and suppressed gastric tumorigenesis in transgenic mice. We also discovered that miR-149-3p was downregulated in gastric cancer tissues and cell lines as compared to normal gastric tissues and epithelial cells, but was upregulated by GRA. miR-149-3p expression also correlated negatively with lymphnode metastasis. Our functional assays showed that miR-149-3p overexpression inhibited cell proliferation and cell cycle progression while inducing apoptosis, while inhibition of miR-149-3p had the opposite effects. In addition, we identified Wnt-1 as a direct target of miR-149-3p. These data suggest that GRA inhibits the initiation and progression of gastric tumors by ameliorating the inflammatory microenvironment through downregulation of COX-2 expression and by inhibiting Wnt-1 expression through the upregulation of tumor suppressor miR-149-3p. GRA may thus have the potential to serve as a useful therapeutic agent for the prevention and treatment of gastric cancer.

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          Roles of Wnt/β-catenin signaling in the gastric cancer stem cells proliferation and salinomycin treatment

          J Mao, S Y S Fan, W. Ma … (2014)
          The Wnt1 protein, a secreted ligand that activates Wnt signaling pathways, contributes to the self-renewal of cancer stem cells (CSCs) and thus may be a major determinant of tumor progression and chemoresistance. In a series of gastric cancer specimens, we found strong correlations among Wnt1 expression, CD44 expression, and the grade of gastric cancer. Stable overexpression of Wnt1 increased AGS gastric cancer cells' proliferation rate and spheroids formation, which expressed CSC surface markers Oct4 and CD44. Subcutaneous injection of nude mice with Wnt1-overexpressing AGS cells resulted in larger tumors than injection of control AGS cells. Salinomycin, an antitumor agent, significantly reduced the volume of tumor caused by Wnt1-overexpressing AGS cells in vivo. This is achieved by inhibiting the proliferation of CD44+Oct4+ CSC subpopulation, at least partly through the suppression of Wnt1 and β-catenin expression. Taken together, activation of Wnt1 signaling accelerates the proliferation of gastric CSCs, whereas salinomycin acts to inhibit gastric tumor growth by suppressing Wnt signaling in CSCs. These results suggest that Wnt signaling might have a critical role in the self-renewal of gastric CSCs, and salinomycin targeting Wnt signaling may have important clinical applications in gastric cancer therapy.
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            MiR-223 promotes the cisplatin resistance of human gastric cancer cells via regulating cell cycle by targeting FBXW7

            Xiaoying Zhou, Wujuan Jin, Hongyan Jia … (2015)
            Background Increasing evidence showed that miRNAs serve as modulators of human cancer, either as oncogene or tumor suppressors. Cisplatin resistance is the most common cause of chemotherapy failure in gastric cancer (GC). However, the roles of miRNAs in cisplatin resistance of GC remain largely unknown. The aim of the study was to identify a novel miRNA/gene pathway that regulates the sensitivity of GC cells to cisplatin. Methods In this study, we chose miR-223 by qRT-PCR analysis, the most significantly up-regulated miRNA in GC, to investigate its formation of DDP-resistant phenotype of GC cells and possible molecular mechanisms. Results We found that miR-223 was most significantly up-regulated miRNA in DDP-resistant GC cells compared with parental GC cells. Besides, its expression was also significantly up-regulated in GC tissues. FBXW7 was identified as the direct and functional target gene of miR-223. Overexpression of FBXW7 could mimic the effect of miR-223 down-regulation and silencing of FBXW7 could partially reverse the effect of miR-223 down-regulation on DDP resistance of DDP-resistant GC cells. Besides, miR-223 and FBXW7 could affect the G1/S transition of cell cycle by altering some certain cell cycle regulators. Furthermore, miR-223 was found to be significantly up-regulated in H. pylori infected tissues and cells, suggesting that H. pylori infection may lead to GC development and DDP resistance. Conclusions Our findings revealed the roles of miR-223/FBXW7 signaling in the DDP resistance of GC cells and targeting it will be a potential strategic approach for reversing the DDP resistance in human GC. Electronic supplementary material The online version of this article (doi:10.1186/s13046-015-0145-6) contains supplementary material, which is available to authorized users.
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              Carcinogenesis in mouse stomach by simultaneous activation of the Wnt signaling and prostaglandin E2 pathway.

              Masanobu Oshima, Hiroko Oshima, Makoto Taketo … (2006)
              Accumulating evidence indicates that prostaglandin E(2) (PGE(2)), a downstream product of cyclooxygenase 2 (COX-2), plays a key role in gastric tumorigenesis. The Wnt pathway is also suggested to play a causal role in gastric carcinogenesis. However, the molecular mechanism remains poorly understood of how the Wnt and PGE(2) pathways contribute to gastric tumorigenesis. To investigate the role of Wnt and PGE(2) in gastric cancer, we have generated transgenic mice that activate both pathways and examined their phenotypes. We constructed K19-Wnt1 transgenic mice expressing Wnt1 in the gastric mucosa using the keratin 19 promoter. We then crossed K19-Wnt1 mice with another transgenic line, K19-C2mE, to obtain K19-Wnt1/C2mE compound transgenic mice. The K19-C2mE mice express COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1) in the stomach, showing an increased gastric PGE(2) level. We examined the gastric phenotypes of both K19-Wnt1 and K19-Wnt1/C2mE mice. K19-Wnt1 mice had a significant suppression of epithelial differentiation and developed small preneoplastic lesions consisting of undifferentiated epithelial cells with macrophage accumulation. Importantly, additional expression of COX-2 and mPGES-1 converted the preneoplastic lesions in the K19-Wnt1 mice into dysplastic gastric tumors by 20 weeks of age. Notably, we found mucous cell metaplasia in the glandular stomach of the K19-Wnt1/C2mE mice as early as 5 weeks of age, before the dysplastic tumor development. Wnt signaling keeps the gastric progenitor cells undifferentiated. Simultaneous activation of both Wnt and PGE(2) pathways causes dysplastic gastric tumors through the metaplasia-carcinoma sequence.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncotarget
                Journal ID (iso-abbrev): Oncotarget
                Journal ID (publisher-id): Oncotarget
                Journal ID (publisher-id): ImpactJ
                Title: Oncotarget
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1949-2553
                Publication date Collection: 1 November 2016
                Publication date (Electronic): 4 October 2016
                Volume: 7
                Issue: 44
                Pages: 71960-71973
                Affiliations
                1 Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin 130021, China
                2 Department of Gastric and Colorectal Surgery, First Hospital of Jilin University, Changchun, Jilin 130021, China
                3 Department of Diagnostic Pathology I, School of Medicine, Fujita Health University, Toyoake, 470-1192, Japan
                4 Cancer Research Institute, Kanazawa University, Kanazawa, 920-1192, Japan
                Author notes
                Correspondence to: Jing Jiang, jiangjing19702000@ 123456jlu.edu.cn
                Article
                Publisher ID: 12443
                DOI: 10.18632/oncotarget.12443
                PMC ID: 5342136
                PubMed ID: 27713126
                SO-VID: 066aac7f-d478-41d7-8d2f-5c0e8f7a7e10
                Copyright © Copyright: © 2016 Cao et al.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 5 May 2016
                Date accepted : 24 September 2016
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: 18β-glycyrrhetinic acid,gastric cancer,cox-2,mir-149-3p,wnt-1
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: 18β-glycyrrhetinic acid, gastric cancer, cox-2, mir-149-3p, wnt-1

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