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Park JM, Han YM, Hahm KB. Rejuvenation of Helicobacter pylori-Associated Atrophic Gastritis Through Concerted Actions of Placenta-Derived Mesenchymal Stem Cells Prevented Gastric Cancer. Front Pharmacol 2021; 12:675443. [PMID: 34483897 PMCID: PMC8416416 DOI: 10.3389/fphar.2021.675443] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 06/22/2021] [Indexed: 01/06/2023] Open
Abstract
Chronic Helicobacter pylori infection causes gastric cancer via the progression of precancerous chronic atrophic gastritis (CAG). Therefore, repairing gastric atrophy could be a useful strategy in preventing H. pylori-associated gastric carcinogenesis. Although eradication of the bacterial pathogen offers one solution to this association, this study was designed to evaluate an alternative approach using mesenchymal stem cells to treat CAG and prevent carcinogenesis. Here, we used human placenta-derived mesenchymal stem cells (PD-MSCs) and their conditioned medium (CM) to treat H. pylori-associated CAG in a mice/cell model to explore their therapeutic effects and elucidate their molecular mechanisms. We compared the changes in the fecal microbiomes in response to PD-MSC treatments, and chronic H. pylori-infected mice were given ten treatments with PD-MSCs before being sacrificed for end point assays at around 36 weeks of age. These animals presented with significant reductions in the mean body weights of the control group, which were eradicated following PD-MSC treatment (p < 0.01). Significant changes in various pathological parameters including inflammation, gastric atrophy, erosions/ulcers, and dysplastic changes were noted in the control group (p < 0.01), but these were all significantly reduced in the PD-MSC/CM-treated groups. Lgr5+, Ki-67, H+/K+-ATPase, and Musashi-1 expressions were all significantly increased in the treated animals, while inflammatory mediators, MMP, and apoptotic executors were significantly decreased in the PD-MSC group compared to the control group (p < 0.001). Our model showed that H. pylori-initiated, high-salt diet-promoted gastric atrophic gastritis resulted in significant changes in the fecal microbiome at the phylum/genus level and that PD-MSC/CM interventions facilitated a return to more normal microbial communities. In conclusion, administration of PD-MSCs or their conditioned medium may present a novel rejuvenating agent in preventing the progression of H. pylori-associated premalignant lesions.
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Affiliation(s)
- Jong Min Park
- College of Oriental Medicine, Daejeon University, Daejeon, Korea
| | - Young Min Han
- Western Seoul Center, Korea Basic Science Institute, Seoul, Korea
| | - Ki Baik Hahm
- Medpacto Research Institute, Medpacto, Seoul, Korea.,CHA Cancer Preventive Research Center, CHA Bio Complex, Seongnam, Korea
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El-Salhy M, Hausken T, Hatlebakk JG. Density of Musashi‑1‑positive stem cells in the stomach of patients with irritable bowel syndrome. Mol Med Rep 2020; 22:3135-3140. [PMID: 32945509 PMCID: PMC7453583 DOI: 10.3892/mmr.2020.11412] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 05/28/2020] [Indexed: 12/13/2022] Open
Abstract
Irritable bowel syndrome (IBS) affects ~12% of the global population. Although the etiology of IBS is not completely understood, several factors are known to serve a pivotal role in its pathophysiology, including genetic factors, diet, the intestinal microbiota, gastrointestinal endocrine cells and low‑grade inflammation. Musashi‑1 is expressed by stem cells and their early progeny, and is used as a stem cell marker. The low density of intestinal endocrine cells in patients with IBS is thought to be caused by decreased numbers of intestinal stem cells and their differentiation into enteroendocrine cells. The present study employed Musashi‑1 as a marker to detect stem cells in the stomach of 54 patients with IBS and 51 healthy subjects. The patients and controls underwent standard gastroscopy, and biopsy samples were taken from the corpus and antrum. Immunohistochemical staining of gastrin, somatostatin and Mushasi‑1 was carried out and semi‑quantified by computerized image analysis. The density (number of positive cells/mm2 epithelium) of gastrin‑positive cells in the controls and patients with IBS were 337.9±560 and 531.0±908 (median ± range; P<0.0001), respectively. For somatostatin‑positive cells, the density reached 364.4±526.0 in the healthy controls and 150.7±514.0 in patients with IBS (P<0.0001). The density of Musashi‑1‑positive cells was defined as the number of cells per gastric or pyloric gland neck. In the corpus, Musashi‑1‑positive cells density reached 3.0±7.0 in the corpus of the healthy controls and 3.8±7.7 in the patients with IBS. Moreover, the corresponding values in the antrum were 6.0±6.0 and 6.0±6.0, respectively. The Musashi‑1‑positive cell density did not differ significantly between the controls and patients with IBS in the corpus or antrum (P=0.4 and 0.3, respectively). These findings indicated that changes in the stomach endocrine cells observed in patients with IBS may not be explained by an abnormality in stem cells like those found in the small and large intestines of these patients.
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Affiliation(s)
- Magdy El-Salhy
- Section for Gastroenterology, Department of Medicine, Stord Hospital, 5416 Stord, Norway
| | - Trygve Hausken
- Department of Clinical Medicine, University of Bergen, 5020 Bergen; 3National Centre for Functional Gastrointestinal Disorders, 5021 Bergen, Norway
| | - Jan Gunnar Hatlebakk
- Department of Clinical Medicine, University of Bergen, 5020 Bergen; 3National Centre for Functional Gastrointestinal Disorders, 5021 Bergen, Norway
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Saad MN, Mabrouk MS, Eldeib AM, Shaker OG. Studying the effects of haplotype partitioning methods on the RA-associated genomic results from the North American Rheumatoid Arthritis Consortium (NARAC) dataset. J Adv Res 2019; 18:113-126. [PMID: 30891314 PMCID: PMC6403413 DOI: 10.1016/j.jare.2019.01.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 01/03/2019] [Accepted: 01/14/2019] [Indexed: 12/16/2022] Open
Abstract
Haplotype blocks methods plays a complementary role to the single-SNP approaches. CIT, FGT, SSLD, and single-SNP methods should be applied to discover the markers. Selection of the method used for the association has an impact on the biomarkers. SSLD method detected more significant SNPs than CIT, FGT, and single-SNP methods. The 383 SNPs discovered by all methods are significantly associated with RA. The human genome, which includes thousands of genes, represents a big data challenge. Rheumatoid arthritis (RA) is a complex autoimmune disease with a genetic basis. Many single-nucleotide polymorphism (SNP) association methods partition a genome into haplotype blocks. The aim of this genome wide association study (GWAS) was to select the most appropriate haplotype block partitioning method for the North American Rheumatoid Arthritis Consortium (NARAC) dataset. The methods used for the NARAC dataset were the individual SNP approach and the following haplotype block methods: the four-gamete test (FGT), confidence interval test (CIT), and solid spine of linkage disequilibrium (SSLD). The measured parameters that reflect the strength of the association between the biomarker and RA were the P-value after Bonferroni correction and other parameters used to compare the output of each haplotype block method. This work presents a comparison among the individual SNP approach and the three haplotype block methods to select the method that can detect all the significant SNPs when applied alone. The GWAS results from the NARAC dataset obtained with the different methods are presented. The individual SNP, CIT, FGT, and SSLD methods detected 541, 1516, 1551, and 1831 RA-associated SNPs respectively, and the individual SNP, FGT, CIT, and SSLD methods detected 65, 156, 159, and 450 significant SNPs respectively, that were not detected by the other methods. Three hundred eighty-three SNPs were discovered by the haplotype block methods and the individual SNP approach, while 1021 SNPs were discovered by all three haplotype block methods. The 383 SNPs detected by all the methods are promising candidates for studying RA susceptibility. A hybrid technique involving all four methods should be applied to detect the significant SNPs associated with RA in the NARAC dataset, but the SSLD method may be preferred because of its advantages when only one method was used.
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Affiliation(s)
- Mohamed N Saad
- Biomedical Engineering Department, Faculty of Engineering, Minia University, Minia, Egypt
| | - Mai S Mabrouk
- Biomedical Engineering Department, Faculty of Engineering, Misr University for Science and Technology, 6th of October City, Egypt
| | - Ayman M Eldeib
- Systems and Biomedical Engineering Department, Faculty of Engineering, Cairo University, Giza, Egypt
| | - Olfat G Shaker
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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Shou Z, Jin X, He X, Zhao Z, Chen Y, Ye M, Yao J. Overexpression of Musashi-1 protein is associated with progression and poor prognosis of gastric cancer. Oncol Lett 2017; 13:3556-3566. [PMID: 28521458 PMCID: PMC5431268 DOI: 10.3892/ol.2017.5879] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Accepted: 01/12/2017] [Indexed: 12/13/2022] Open
Abstract
Musashi-1, an evolutionally conserved RNA-binding protein, has been implicated in the promotion of pathological stem cell proliferation, including tumorigenesis. The objective of the present study was to evaluate the expression of Musashi-1 protein and its implications in the progression and prognosis of gastric cancer. The expression level of Musashi-1 protein in gastric cancer was determined by western blotting and immunohistochemistry, and compared with the clinicopathological parameters. The present study revealed that the expression level of Musashi-1 protein in gastric cancer was significantly upregulated and correlated with the tumor size, tumor-node-metastasis (TNM) stage, Lauren classification, depth of invasion, vessel invasion, lymph node metastasis and distant metastasis. The mean survival time for patients with low expression levels of Musashi-1 was significantly longer compared with patients with high expression levels of Musashi-1. For each TNM stage, the mean survival time for patients with a low Musashi-1 expression levels was also significantly longer compared with patients with a high Musashi-1 expression level. Notably, TNM stage II patients with a low Musashi-1 expression level demonstrated a longer mean survival time compared with TNM stage I patients with high Musashi-1 expression level (56.8 vs. 42.3 months; P=0.001), and TNM stage III patients with low Musashi-1 expression level exhibited a longer mean survival time compared with TNM stage II patients with a high Musashi-1 expression level (44.0 vs. 33.8 months; P=0.034). Multivariate Cox's regression test demonstrated that Musashi-1 protein expression level was an independent prognostic indicator for the survival rate of the patients with gastric cancer. The results of the present study highlighted an important role for Musashi-1 protein in the progression of gastric cancer. The detection of the Musashi-1 protein expression level alone or in combination with TNM staging may aid the prediction of the prognosis of patients with gastric cancer.
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Affiliation(s)
- Zhangxuan Shou
- Department of Pharmaceutical Sciences, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Xue Jin
- Department of Pharmaceutical Sciences, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Xujun He
- Key Laboratory of Gastroenterology of Zhejiang, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Zhongsheng Zhao
- Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Yuan Chen
- Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Meihua Ye
- Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Jiong Yao
- Department of Medical Records and Statistics, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
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Holla S, Prakhar P, Singh V, Karnam A, Mukherjee T, Mahadik K, Parikh P, Singh A, Rajmani RS, Ramachandra SG, Balaji KN. MUSASHI-Mediated Expression of JMJD3, a H3K27me3 Demethylase, Is Involved in Foamy Macrophage Generation during Mycobacterial Infection. PLoS Pathog 2016; 12:e1005814. [PMID: 27532872 PMCID: PMC4988650 DOI: 10.1371/journal.ppat.1005814] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 07/18/2016] [Indexed: 12/11/2022] Open
Abstract
Foamy macrophages (FM)s harbor lipid bodies that not only assist mycobacterial persistence within the granulomas but also are sites for intracellular signaling and inflammatory mediators which are essential for mycobacterial pathogenesis. However, molecular mechanisms that regulate intracellular lipid accumulation in FMs during mycobacterial infection are not clear. Here, we report for the first time that jumonji domain containing protein (JMJD)3, a demethylase of the repressive H3K27me3 mark, orchestrates the expression of M. tuberculosis H37Rv-, MDR-JAL2287-, H37Ra- and M. bovis BCG-induced genes essential for FM generation in a TLR2-dependent manner. Further, NOTCH1-responsive RNA-binding protein MUSASHI (MSI), targets a transcriptional repressor of JMJD3, Msx2-interacting nuclear target protein, to positively regulate infection-induced JMJD3 expression, FM generation and M2 phenotype. Investigations in in vivo murine models further substantiated these observations. Together, our study has attributed novel roles for JMJD3 and its regulators during mycobacterial infection that assist FM generation and fine-tune associated host immunity. Foamy macrophages (FMs) not only provide a suitable survival niche for the mycobacteria in the granuloma but also are reservoirs for several inflammatory mediators that regulate mycobacterial pathogenesis. Hence, understanding the mechanisms that regulate infection-induced FM generation assumes importance. In this investigation, we present empirical evidence to support the role of host epigenetic mechanisms in generating FMs and thus facilitating mycobacterial persistence in vivo. We show that the signaling pathways that mediate mycobacteria-induced expression of JMJD3, a demethylase of the facultative repression mark, regulate the genes assisting in FM generation. Importantly, the identified pathway could largely contribute to the evasive responses during mycobacterial infection and suppression of such pathways during infection could confer stronger immunity. Together, these regulators could be potential candidates for host-directed therapies against mycobacterial infection.
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Affiliation(s)
- Sahana Holla
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India
| | - Praveen Prakhar
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India
| | - Vikas Singh
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India
| | - Anupama Karnam
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India
| | - Tanushree Mukherjee
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India
| | - Kasturi Mahadik
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India
| | - Pankti Parikh
- Department of Microbiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, Karnataka, India
| | - Amit Singh
- Department of Microbiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, Karnataka, India
| | - R. S. Rajmani
- Department of Microbiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, Karnataka, India
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Yang YG, Sari IN, Zia MF, Lee SR, Song SJ, Kwon HY. Tetraspanins: Spanning from solid tumors to hematologic malignancies. Exp Hematol 2016; 44:322-8. [DOI: 10.1016/j.exphem.2016.02.006] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2016] [Revised: 02/11/2016] [Accepted: 02/13/2016] [Indexed: 02/06/2023]
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Sutherland JM, Siddall NA, Hime GR, McLaughlin EA. RNA binding proteins in spermatogenesis: an in depth focus on the Musashi family. Asian J Androl 2016; 17:529-36. [PMID: 25851660 PMCID: PMC4492041 DOI: 10.4103/1008-682x.151397] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Controlled gene regulation during gamete development is vital for maintaining reproductive potential. During the complex process of mammalian spermatogenesis, male germ cells experience extended periods of the inactive transcription despite heavy translational requirements for continued growth and differentiation. Hence, spermatogenesis is highly reliant on mechanisms of posttranscriptional regulation of gene expression, facilitated by RNA binding proteins (RBPs), which remain abundantly expressed throughout this process. One such group of proteins is the Musashi family, previously identified as critical regulators of testis germ cell development and meiosis in Drosophila, and also shown to be vital to sperm development and reproductive potential in the mouse. This review describes the role and function of RBPs within the scope of male germ cell development, focusing on our recent knowledge of the Musashi proteins in spermatogenesis. The functional mechanisms utilized by RBPs within the cell are outlined in depth, and the significance of sub-cellular localization and stage-specific expression in relation to the mode and impact of posttranscriptional regulation is also highlighted. We emphasize the historical role of the Musashi family of RBPs in stem cell function and cell fate determination, as originally characterized in Drosophila and Xenopus, and conclude with our current understanding of the differential roles and functions of the mammalian Musashi proteins, Musashi-1 and Musashi-2, with a primary focus on our findings in spermatogenesis. This review highlights both the essential contribution of RBPs to posttranscriptional regulation and the importance of the Musashi family as master regulators of male gamete development.
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Affiliation(s)
| | | | | | - Eileen A McLaughlin
- School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia
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Horisawa K, Imai T, Okano H, Yanagawa H. The Musashi family RNA-binding proteins in stem cells. Biomol Concepts 2015; 1:59-66. [PMID: 25961986 DOI: 10.1515/bmc.2010.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The Musashi family is an evolutionarily conserved group of RNA-binding proteins. In mammal, two members of the group, Msi1 and Msi2, have been identified to date. Msi1 is considered to play roles in maintaining the stem cell status (stemness) of neural stem/progenitor cells in adults and in the development of central nervous system through translational regulation of its target mRNAs, which encode regulators of signal transduction and the cell cycle. Recently, strong expression of Msi1 in various somatic stem/progenitor cells of adult tissues, such as eye, gut, stomach, breast, and hair follicle, has been reported. The protein is also expressed in various cancer cells, and ectopically emerging cells have been found in neural tissues of patients with diseases involving neural disorder, including epilepsy. Many novel target mRNAs and regulatory pathways of Msi1 have been reported in recent years. Here, we present a review of the functions and action mechanisms of Msi1 protein and discuss possible directions for further study.
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Kuang RG, Kuang Y, Luo QF, Zhou CJ, Ji R, Wang JW. Expression and significance of Musashi-1 in gastric cancer and precancerous lesions. World J Gastroenterol 2013; 19:6637-6644. [PMID: 24151393 PMCID: PMC3801380 DOI: 10.3748/wjg.v19.i39.6637] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Accepted: 09/29/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate expression of stem cell marker Musashi-1 (Msi-1) in relationship to tumorigenesis and progression of intestinal-type gastric cancer (GC).
METHODS: Endoscopic biopsy specimens and surgical specimens were obtained, including 54 cases of intestinal-type GC, 41 high-grade intraepithelial neoplasia, 57 low-grade intraepithelial neoplasia, 31 intestinal metaplasia, and 36 normal gastric mucosa. Specimens were fixed in 10% paraformaldehyde, conventionally dehydrated, embedded in paraffin, and sliced in 4-μm-thick serial sections. Two-step immunohistochemical staining was used to detect Msi-1 and proliferating cell nuclear antigen (PCNA) expression. Correlation analysis was conducted between Msi-1 and PCNA expression. The relationship between Msi-1 expression and clinicopathological parameters of GC was analyzed statistically.
RESULTS: There were significant differences in Msi-1 and PCNA expression in different pathological tissues (χ2 = 15.37, P < 0.01; χ2 = 115.36, P < 0.01). Msi-1 and PCNA-positive cells were restricted to the isthmus of normal gastric glands. Expression levels of Msi-1 and PCNA in intestinal metaplasia were significantly higher than in normal mucosa (U = 392.0, P < 0.05; U = 40.50, P < 0.01), whereas there was no significant difference compared to low or high-grade intraepithelial neoplasia. Msi-1 and PCNA expression in intestinal-type GC was higher than in high-grade intraepithelial neoplasia (U = 798.0, P < 0.05; U = 688.0, P < 0.01). There was a significantly positive correlation between Msi-1 and PCNA expression (rs = 0.20, P < 0.01). Msi-1 expression in GC tissues was correlated with their lymph node metastasis and tumor node metastasis stage (χ2 = 12.62, P < 0.01; χ2 = 11.24, P < 0.05), but not with depth of invasion and the presence of distant metastasis.
CONCLUSION: Msi-1-positive cells may play a key role in the early events of gastric carcinogenesis and may be involved in invasion and metastasis of GC.
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Sutherland JM, McLaughlin EA, Hime GR, Siddall NA. The Musashi family of RNA binding proteins: master regulators of multiple stem cell populations. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2013; 786:233-45. [PMID: 23696360 DOI: 10.1007/978-94-007-6621-1_13] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
In order to maintain their unlimited capacity to divide, stem cells require controlled temporal and spatial protein expression. The Musashi family of RNA-binding proteins have been shown to exhibit this necessary translational control through both repression and activation in order to regulate multiple stem cell populations. This chapter looks in depth at the initial discovery and characterisation of Musashi in the model organism Drosophila, and its subsequent emergence as a master regulator in a number of stem cell populations. Furthermore the unique roles for mammalian Musashi-1 and Musashi-2 in different stem cell types are correlated with the perceived diagnostic power of Musashi expression in specific stem cell derived oncologies. In particular the potential role for Musashi in the identification and treatment of human cancer is considered, with a focus on the role of Musashi-2 in leukaemia. Finally, the manipulation of Musashi expression is proposed as a potential avenue towards the targeted treatment of specific aggressive stem cell cancers.
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Affiliation(s)
- Jessie M Sutherland
- Priority Research Centre in Reproductive Science, School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW, 2308, Australia
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Zhang JH, Feng YG, Gao GP, Tao YY, Zhang XQ, Zhang HM, Jiao JX. Effects of CagA +Helicobacter pylori infection on expression of HIF-2α and ABCG2 in human gastric cancer cell line SGC7901 under normoxia and hypoxia conditions. Shijie Huaren Xiaohua Zazhi 2013; 21:293-299. [DOI: 10.11569/wcjd.v21.i4.293] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To observe the effect of CagA+Helicobacter pylori (H. pylori) on the expression of HIF-2α and ABCG2 in human gastric cancer cell line SGC7901 under normoxia and hypoxia conditions to investigate whether H. pylori infection and the tumor microenvironment have a synergistic effect in the initiation and development of gastric cancer.
METHODS: Gastric mucosal biopsy specimens collected by endoscopy were cultured under microaerophilic conditions and H. pylori isolates were identified. CagA+H. pylori strains were confirmed by PCR. Gastric cancer cell line SGC7901 was co-cultured with a CagA+H. pylori strain for 48 h under either normoxia or hypoxia condition (cells were divided into a normoxia control group, a hypoxia control group, a normoxia plus CagA+H. pylori group, and a hypoxia plus CagA+H. pylori group). Immunocytochemistry was used to detect the expression of HIF-2α and ABCG2 proteins, and RT-PCR was used to detect the expression of ABCG2 mRNA.
RESULTS: Immunocytochemistry results showed that HIF-2α and ABCG2 proteins were expressed at low levels under normoxia, while both hypoxia and CagA+H. pylori could significantly induce the expression of HIF-2α and ABCG2 proteins compared to the normoxia control group (all P < 0.01). Compared to the hypoxia control group and normoxia plus CagA+H. pylori group, the expression of HIF-2α and ABCG2 proteins was further elevated in the hypoxia plus CagA+H. pylori group (all P < 0.01). There was a positive correlation between the expression of HIF-2α and that of ABCG2 (r = 0.976, P < 0.05). Similar results were obtained for ABCG2 mRNA expression by RT-PCR.
CONCLUSION: CagA+H. pylori can stimulate the expression of HIF-2α and ABCG2 in gastric cancer cells under normoxia condition, and their expression can be further up-regulated under hypoxia condition. CagA+H. pylori and hypoxia have a synergistic effect on the expression of HIF-2α and ABCG2, suggesting that CagA+H. pylori and hypoxia may play an important role in inducing gastric cancer cell de-differentiation and chemotherapy resistance.
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Ding SZ, Zheng PY. Helicobacter pylori infection induced gastric cancer; advance in gastric stem cell research and the remaining challenges. Gut Pathog 2012; 4:18. [PMID: 23217022 PMCID: PMC3536631 DOI: 10.1186/1757-4749-4-18] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2012] [Accepted: 11/29/2012] [Indexed: 12/14/2022] Open
Abstract
Helicobacter pylori infection is the major cause of gastric cancer, which remains an important health care challenge. Recent investigation in gastric stem cell or progenitor cell biology has uncovered valuable information in understanding the gastric gland renewal and maintenance of homeostasis, they also provide clues for further defining the mechanisms by which gastric cancer may originate and progress. Lgr5, Villin-promoter, TFF2-mRNA and Mist have recently been identified as gastric stem/progenitor cell markers; their identification enriched our understanding on the gastric stem cell pathobiology during chronic inflammation and metaplasia. In addition, advance in gastric cancer stem cell markers such as CD44, CD90, CD133, Musashi-1 reveal novel information on tumor cell behavior and disease progression implicated for therapeutics. However, two critical questions remain to be of considerable challenges for future exploration; one is how H. pylori or chronic inflammation affects gastric stem cell or their progenitors, which give rise to mucus-, acid-, pepsinogen-, and hormone-secreting cell lineages. Another one is how bacterial infection or inflammation induces oncogenic transformation and propagates into tumors. Focus on the interactions of H. pylori with gastric stem/progenitor cells and their microenvironment will be instrumental to decipher the initiation and origin of gastric cancer. Future studies in these areas will be critical to uncover molecular mechanisms of chronic inflammation-mediated oncogenic transformation and provide options for cancer prevention and intervention. We review recent progress and discuss future research directions in these important research fields.
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Affiliation(s)
- Song-Ze Ding
- Department of Gastroenterology, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou, Henan, 450000, China.
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Nikpour P, Emadi-Baygi M, Mohhamad-Hashem F, Maracy MR, Haghjooy-Javanmard S. MSI1 overexpression in diffuse type of gastric cancer. Pathol Res Pract 2012; 209:10-3. [PMID: 23164718 DOI: 10.1016/j.prp.2012.09.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2012] [Revised: 09/13/2012] [Accepted: 09/20/2012] [Indexed: 11/25/2022]
Abstract
Being the third most frequent cause of cancer mortality in the world, gastric cancer is the major cause of cancer-related mortality in Iran. Musashi1 recognizes a motif in the 3'UTR of target mRNAs - involved in cell cycle regulation, proliferation and apoptosis - and represses the translation of the mRNAs. As tissue stem cells exist in many adult tissues other than the CNS, Musashi is considered to be associated with many malignancies. In the current study, we aimed to assess Musashi1 gene expression in human stomach cancer. In total, 30 paired gastric tumoral and adjacent non-tumoral tissue specimens were examined for gene expression by qReal-Time RT-PCR. Our results demonstrated that the expression of the gene did not significantly change between tumor/non-tumor tissues (p value: 16×10(-2)) and different grades (p value: 36×10(-2)). However, there was a statistical difference between the MSI1 gene expression in different tumor types, i.e., intestinal versus diffuse type (p value: 3×10(-2)). All together, further investigations should be done to elucidate the precise molecular mechanisms by which MSI1 contribute to the pathogenesis of gastric cancer.
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Affiliation(s)
- Parvaneh Nikpour
- Pediatric Inherited Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
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Wang T, Ong CW, Shi J, Srivastava S, Yan B, Cheng CL, Yong WP, Chan SL, Yeoh KG, Iacopetta B, Salto-Tellez M. Sequential expression of putative stem cell markers in gastric carcinogenesis. Br J Cancer 2011; 105:658-65. [PMID: 21829201 PMCID: PMC3188930 DOI: 10.1038/bjc.2011.287] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Gastric carcinogenesis has been well documented in the step-wise histopathological model, known as Correa pathway. Several biomarkers including CD44, Musashi-1 and CD133 have been reported as putative stem cell (PSC) markers. METHODS We investigated expression of PSC markers CD44, Musashi-1 and CD133 in relation to gastric carcinogenesis and prognosis and chemoresponse. Immunohistochemistry staining was performed in gastric cancer (GC) clinical specimens representing different steps of the Correa pathway. Gastric cancer samples taken before and after neoadjuvant chemotherapy with docetaxel, cisplatin and capecitabine (DCX) were also evaluated for PSC marker expression. RESULTS We showed that the expression of three PSC markers was significantly elevated in GC relative to normal gastric mucosa (P<0.001 for each marker). Precancerous lesions, including intestinal metaplasia and dysplasia, demonstrated increased expression of CD44 and Musashi-1. CD133 was predominantly expressed along the border between intramucosal carcinoma and connective tissue at later stages. High CD44 and CD133 expression showed prognostic value for worse patient survival (P=0.014 and P=0.019, respectively). A small number of tumours with high expression of CD44 and CD133 showed pathological response to DCX-based neoadjuvant chemotherapy. CONCLUSION CD44 and Musashi-1 are frequently expressed in both premalignant gastric lesions and invasive GC, whereas CD133 expression is restricted mainly to neoplastic tissues.
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Affiliation(s)
- T Wang
- Cancer Science Institute, National University Health System and Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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15
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Luo JY, Zhong Y, Cao JC, Cui HF. Efficacy of oral colon-specific delivery capsule of low-molecular-weight heparin on ulcerative colitis. Biomed Pharmacother 2010; 65:111-7. [PMID: 21227626 DOI: 10.1016/j.biopha.2010.12.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2010] [Accepted: 12/07/2010] [Indexed: 01/11/2023] Open
Abstract
Low-molecular-weight heparin has the potential for the treatment of ulcerative colitis, and targeted drug delivery to the colon is important for topical treatment of this disease, so low-molecular-weight heparin oral colon-specific delivery capsule was prepared, and the in vitro and in vivo drug release behavior was investigated. The macroscopical and histological scoring systems, wet colon mass index and myeloperoxidase activity were assessed to evaluate the efficacy of the capsule after administered orally to experimental colitis mice. Serum levels, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and a link factor of blood coagulation and inflammation factor Xa (FXa) were assayed by enzyme-linked immunosorbent assay. The expression of Musashi-1 (as an intestinal stem cell marker) in the colons was assessed by immunohistochemical analysis. The in vitro and in vivo drug release studies clearly indicated that the specific coated capsules were capable of protecting low-molecular-weight heparin from releasing in stomach and small intestine, while specifically delivering at colon. The oral colon-specific delivery capsule of low-molecular-weight heparin could attenuate macroscopic and histological features of colitis. The results showed that low-molecular-weight heparin oral colon-specific delivery capsule significantly decreased the serum levels of TNF-α, IL-6 as well as FXa, while increased the expression of Musashi-1 in colon compared with acetic acid-induced ulcerative colitis model group. The results showed that low-molecular-weight heparin oral colon-specific delivery capsule had the potential for treatment of inflammatory bowel disease.
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Affiliation(s)
- Jun-Yong Luo
- Institute of Biochemical and Biotechnological Drugs, Shandong University, Jinan 250012, China
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16
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Luo J, Cao J, Jiang X, Cui H. Effect of low molecular weight heparin rectal suppository on experimental ulcerative colitis in mice. Biomed Pharmacother 2010; 64:441-5. [PMID: 20359854 DOI: 10.1016/j.biopha.2010.01.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2009] [Accepted: 01/25/2010] [Indexed: 11/28/2022] Open
Abstract
The objective of this study was to investigate the effect and possible mechanism of rectally administered low molecular weight heparin (LMWH) on experimental ulcerative colitis. LMWH rectal suppository was prepared and its efficacy was studied by macroscopical and histological scoring systems as well as myeloperoxidase activity. Serum levels, including tumor necrosis factor-α (TNFα), interleukin-6 (IL-6) and a link factor of blood coagulation and inflammation factor Xa (FXa) were assayed by enzyme-linked immunosorbent assay. The expression of Musashi-1 (as an intestinal stem cell marker) in the colons was assessed by immunohistochemical analysis. The results showed that LMWH rectal suppository significantly decreased serum levels of TNF-α, IL-6 as well as FXa, while increased the expression of Musashi-1 in colon compared with acetic acid induced ulcerative colitis model group. All these preliminary results indicate LMWH rectal suppository is promising for treatment of ulcerative colitis.
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Affiliation(s)
- Junyong Luo
- Institute of Biochemical and Biotechnological Drugs, Shandong University, 44,Wenhua Xilu, Jinan 250012, China
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Abstract
Cellular and tissue regeneration in the gastrointestinal tract and liver depends on stem cells with properties of longevity, self-renewal and multipotency. Progress in stem cell research and the identification of potential esophageal, gastric, intestinal, colonic, hepatic and pancreatic stem cells provides hope for the use of stem cells in regenerative medicine and treatments for disease. Embryonic stem cells and induced pluripotent stem cells have the potential to give rise to any cell type in the human body, but their therapeutic application remains challenging. The use of adult or tissue-restricted stem cells is emerging as another possible approach for the treatment of gastrointestinal diseases. The same self-renewal properties that allow stem cells to remain immortal and generate any tissue can occasionally make their proliferation difficult to control and make them susceptible to malignant transformation. This Review provides an overview of the different types of stem cell, focusing on tissue-restricted adult stem cells in the fields of gastroenterology and hepatology and summarizing the potential benefits and risks of using stems cells to treat gastroenterological and liver disorders.
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Khoder G, Yamaoka Y, Fauchère JL, Burucoa C, Atanassov C. Proteomic Helicobacter pylori biomarkers discriminating between duodenal ulcer and gastric cancer. J Chromatogr B Analyt Technol Biomed Life Sci 2009; 877:1193-9. [PMID: 19328750 DOI: 10.1016/j.jchromb.2009.03.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2008] [Revised: 02/25/2009] [Accepted: 03/02/2009] [Indexed: 12/12/2022]
Abstract
Protein patterns of 129 Helicobacter pylori strains isolated from Korean and Colombian patients suffering from duodenal ulcer or gastric cancer were analyzed by the high-throughput methodology SELDI-TOF-MS. Eighteen statistically significant candidate biomarkers discriminating between the two clinical outcomes were selected by using the Mann-Whitney test. Three biomarker proteins were purified and identified as a neutrophil-activating protein NapA (HU HPAG1_0821), a RNA-binding protein (HPAG1_0813), and a DNA-binding histone-like protein HU, respectively (jhp0228). These novel biomarkers can be used for development of diagnostic assays predicting the evolution to gastric cancer in H. pylori-infected patients.
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Affiliation(s)
- Ghalia Khoder
- EA 4331 LITEC, Université de Poitiers, Poitiers, France
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Abstract
Chronic inflammation-induced carcinogenesis is a commonly accepted entity and is frequently seen within the gastrointestinal tract, although the underlying mechanisms remain unclear. Alterations in specific oncogenes and tumor suppressor genes are known to be responsible for malignant transformation. Nevertheless, the inflammatory microenvironment classically affects tumor promotion in its role as an altered stem cell niche and can also affect tumor initiation and tumor progression. The origin of the tumor cells is often attributed to stem cells, a unique subpopulation within tumors that possess the ability to initiate tumor growth and sustain self-renewal, as well as is largely responsible for their metastatic potential. Here, we review the link between inflammation and gastrointestinal carcinogenesis and the relationship between stem cells and cancer stem cells.
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Affiliation(s)
- Michael Quante
- Division of Digestive and Liver Diseases, Columbia University Medical Center, Irving Cancer Research Center, New York, New York
| | - Timothy Cragin Wang
- Division of Digestive and Liver Diseases, Columbia University Medical Center, Irving Cancer Research Center, New York, New York
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Tahara E. Abnormal growth factor/cytokine network in gastric cancer. CANCER MICROENVIRONMENT : OFFICIAL JOURNAL OF THE INTERNATIONAL CANCER MICROENVIRONMENT SOCIETY 2008; 1:85-91. [PMID: 19308687 PMCID: PMC2654359 DOI: 10.1007/s12307-008-0008-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/23/2007] [Accepted: 02/18/2008] [Indexed: 12/11/2022]
Abstract
Gastric cancer cells express a broad spectrum of the growth factor/cytokine receptor systems that organize the complex interaction between cancer cells and stromal cells in tumor microenvironment, which confers cell growth, apoptosis, morphogenesis, angiogenesis, progression and metastasis. However, these abnormal growth factor/cytokine networks differ in the two histological types of gastric cancer. Importantly, activation of nuclear factor-kB pathway by Helicobacter pylori infection may act as a key player for induction of growth factor/cytokine networks in gastritis and pathogenesis of gastric cancer. Better understanding of these events will no doubt provide new approaches for biomarkers of diagnosis and effective therapeutic targeting of gastric cancer.
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Affiliation(s)
- Eiichi Tahara
- Hiroshima University, Hiroshima Cancer Seminar Foundation, Naka-ku, Hiroshima, Japan.
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