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Park JS, Sung MJ, Na HJ. Drosophila model systems reveal intestinal stem cells as key players in aging. Ann N Y Acad Sci 2025. [PMID: 40276941 DOI: 10.1111/nyas.15351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2025]
Abstract
The intestines play important roles in responding immediately and dynamically to food intake, environmental stress, and metabolic dysfunction, and they are involved in various human diseases and aging. A key part of their function is governed by intestinal stem cells (ISCs); therefore, understanding ISCs is vital. Dysregulation of ISC activity, which is influenced by various cell signaling pathways and environmental signals, can lead to inflammatory responses, tissue damage, and increased cancer susceptibility. Aging exacerbates these dynamics and affects ISC function and tissue elasticity. Additionally, proliferation and differentiation profoundly affect ISC behavior and gut health, highlighting the complex interplay between environmental factors and gut homeostasis. Drosophila models help us understand the complex regulatory networks in the gut, providing valuable insights into disease mechanisms and therapeutic strategies targeting human intestinal diseases.
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Affiliation(s)
- Joung-Sun Park
- Institute of Nanobio Convergence, Pusan National University, Busan, Republic of Korea
- Department of Molecular Biology, Pusan National University, Busan, Republic of Korea
| | - Mi Jeong Sung
- Aging Research Group, Division of Food Functionality Research, Korea Food Research Institute, Wanju, Republic of Korea
| | - Hyun-Jin Na
- Aging Research Group, Division of Food Functionality Research, Korea Food Research Institute, Wanju, Republic of Korea
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FOLFOX Therapy Induces Feedback Upregulation of CD44v6 through YB-1 to Maintain Stemness in Colon Initiating Cells. Int J Mol Sci 2021; 22:ijms22020753. [PMID: 33451103 PMCID: PMC7828641 DOI: 10.3390/ijms22020753] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/04/2021] [Accepted: 01/09/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer initiating cells (CICs) drive tumor formation and drug-resistance, but how they develop drug-resistance characteristics is not well understood. In this study, we demonstrate that chemotherapeutic agent FOLFOX, commonly used for drug-resistant/metastatic colorectal cancer (CRC) treatment, induces overexpression of CD44v6, MDR1, and oncogenic transcription/translation factor Y-box-binding protein-1 (YB-1). Our study revealed that CD44v6, a receptor for hyaluronan, increased the YB-1 expression through PGE2/EP1-mTOR pathway. Deleting CD44v6, and YB-1 by the CRISPR/Cas9 system attenuates the in vitro and in vivo tumor growth of CICs from FOLFOX resistant cells. The results of DNA:CD44v6 immunoprecipitated complexes by ChIP (chromatin-immunoprecipitation) assay showed that CD44v6 maintained the stemness traits by promoting several antiapoptotic and stemness genes, including cyclin-D1,BCL2,FZD1,GINS-1, and MMP9. Further, computer-based analysis of the clones obtained from the DNA:CD44v6 complex revealed the presence of various consensus binding sites for core stemness-associated transcription factors “CTOS” (c-Myc, TWIST1, OCT4, and SOX2). Simultaneous expressions of CD44v6 and CTOS in CD44v6 knockout CICs reverted differentiated CD44v6-knockout CICs into CICs. Finally, this study for the first time describes a positive feedback loop that couples YB-1 induction and CD44 alternative splicing to sustain the MDR1 and CD44v6 expressions, and CD44v6 is required for the reversion of differentiated tumor cells into CICs.
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Yang F, Cui P, Lu Y, Zhang X. Requirement of the transcription factor YB-1 for maintaining the stemness of cancer stem cells and reverting differentiated cancer cells into cancer stem cells. Stem Cell Res Ther 2019; 10:233. [PMID: 31375149 PMCID: PMC6679460 DOI: 10.1186/s13287-019-1360-4] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 07/12/2019] [Accepted: 07/24/2019] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Cancer stem cells always express high levels of stemness-associated transcription factors to maintain their features. However, the regulatory mechanism of the stemness of cancer stem cells mediated by transcription factors has not been extensively explored. METHODS The YB-1 gene in cancer stem cells was knocked out by the CRISPR/Cas9 system. The YB-1 knockout cancer stem cells were transfected with a vector expressing YB-1 to rescue YB-1, and then the cell proliferation, cell cycle, apoptosis, and stemness, as well as tumorigenesis in nude mice, were assessed to examine the effect of YB-1 in cancer stem cells. The target genes of YB-1 were confirmed by CHIP-seq. The totipotency or pluripotency of differentiated cancer stem cells were detected by tumorsphere formation assay and quantitative real-time PCR. RESULTS The deletion of YB-1 gene inhibited the proliferation of breast cancer stem cells and melanoma stem cells, leading to cell cycle arrest and apoptosis, and induced irreversible differentiation of cancer stem cells. The tumorigenicity ability of YB-1-deleted cancer stem cells was significantly reduced in vitro and in vivo. The results of ChIP-seq showed that YB-1 maintained the stemness of cancer stem cells by promoting the expressions of stemness-associated genes (FZD-1, p21, GLP-1, GINS1, and Notch2). Furthermore, simultaneous expressions of YB-1 and the other four (SOX2, POU3F2, OCT-4, and OLIG1) or five (SOX2, SALL2, OCT-4, POU3F2, and Bmi-1) transcription factors in YB-1 knockout cancer stem cells restored the stemness of YB-1 knockout cancer stem cells. CONCLUSIONS Our study indicated that YB-1 was required for maintaining the stemness of cancer stem cells and reverting the differentiated tumor cells into cancer stem cells.
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Affiliation(s)
- Fan Yang
- College of Life Sciences and Laboratory for Marine Biology and Biotechnology of Qingdao National Laboratory for Marine Science and Technology, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Pei Cui
- College of Life Sciences and Laboratory for Marine Biology and Biotechnology of Qingdao National Laboratory for Marine Science and Technology, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Yu Lu
- College of Life Sciences and Laboratory for Marine Biology and Biotechnology of Qingdao National Laboratory for Marine Science and Technology, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Xiaobo Zhang
- College of Life Sciences and Laboratory for Marine Biology and Biotechnology of Qingdao National Laboratory for Marine Science and Technology, Zhejiang University, Hangzhou, 310058, People's Republic of China.
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Cheng XJ, Lin JC, Ding YF, Zhu L, Ye J, Tu SP. Survivin inhibitor YM155 suppresses gastric cancer xenograft growth in mice without affecting normal tissues. Oncotarget 2016; 7:7096-109. [PMID: 26771139 PMCID: PMC4872771 DOI: 10.18632/oncotarget.6898] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 12/31/2015] [Indexed: 01/06/2023] Open
Abstract
Survivin overexpression is associated with poor prognosis of human gastric cancer, and is a target for gastric cancer therapy. YM155 is originally identified as a specific inhibitor of survivin. In this study, we investigated the antitumor effect of YM155 on human gastric cancer. Our results showed that YM155 treatment significantly inhibited cell proliferation, reduced colony formation and induced apoptosis of gastric cancer cells in a dose-dependent manner. Accordingly, YM155 treatment significantly decreased survivin expression without affecting XIAP expression and increased the cleavage of apoptosis-associated proteins caspase 3, 7, 8, 9. YM155 significantly inhibited sphere formation of gastric cancer cells, suppressed expansion and growth of the formed spheres (cancer stem cell-like cells, CSCs) and downregulated the protein levels of β-catenin, c-Myc, Cyclin D1 and CD44 in gastric cancer cells. YM155 infusion at 5 mg/kg/day for 7 days markedly inhibited growth of gastric cancer xenograft in a nude mouse model. Immunohistochemistry staining and Western Blot showed that YM155 treatment inhibited expression of survivin and CD44, induced apoptosis and reduced CD44+ CSCs in xenograft tumor tissues in vivo. No obvious pathological changes were observed in organs (e.g. heart, liver, lung and kidney) in YM155-treated mice. Our results demonstrated that YM155 inhibits cell proliferation, induces cell apoptosis, reduces cancer stem cell expansion, and inhibits xenograft tumor growth in gastric cancer cells. Our results elucidate a new mechanism by which YM155 inhibits gastric cancer growth by inhibition of CSCs. YM155 may be a promising agent for gastric cancer treatment.
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Affiliation(s)
- Xiao Jiao Cheng
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jia Cheng Lin
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yan Fei Ding
- Department of Gastroenterology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Liming Zhu
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jing Ye
- Pôle Sino-Français de Recherches en Sciences du Vivant et Génomique, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Shui Ping Tu
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
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Influence of CD133+ expression on patients' survival and resistance of CD133+ cells to anti-tumor reagents in gastric cancer. Asian Pac J Trop Biomed 2015. [DOI: 10.1016/j.apjtb.2015.09.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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Liu GX, Xi HQ, Sun XY, Wei B. Role of periostin and its antagonist PNDA-3 in gastric cancer metastasis. World J Gastroenterol 2015; 21:2605-2613. [PMID: 25759527 PMCID: PMC4351209 DOI: 10.3748/wjg.v21.i9.2605] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2014] [Revised: 10/12/2014] [Accepted: 12/16/2014] [Indexed: 02/06/2023] Open
Abstract
The extracellular matrix component periostin is a secreted protein that functions as both a cell attachment protein and an autocrine or paracrine factor that signals through the cell adhesion molecule integrins αvβ3 and αvβ5. Periostin participates in normal physiological activities such as cardiac development, but is also involved in pathophysiological processes in vascular diseases, wound repair, bone formation, and tumor development. It is of increasing interest in tumor biology because it is frequently overexpressed in a variety of epithelial carcinomas and is functionally involved in multiple steps of metastasis progression. These include the maintenance of stemness, niche formation, EMT, the survival of tumor cells, and angiogenesis, all of which are indispensable for gastric cancer metastasis. Periostin has been reported to activate the PI-3K/AKT, Wnt, and FAK-mediated signaling pathways to promote metastasis. Therefore, periostin represents a potentially promising candidate for the inhibition of metastasis. In this review article, we summarize recent advances in knowledge concerning periostin, its antagonist PNDA-3, and their influence on such key processes in cancer metastasis as maintenance of stemness, niche formation, epithelial-to-mesenchymal transition, tumor cell survival, and angiogenesis. In particular, we focus our attention on the role of periostin in gastric cancer metastasis, speculate as to the usefulness of periostin as a therapeutic and diagnostic target for gastric cancer metastasis, and consider potential avenues for future research.
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Stem cells, colorectal cancer and cancer stem cell markers correlations. CURRENT HEALTH SCIENCES JOURNAL 2014; 40:153-61. [PMID: 25729599 PMCID: PMC4340434 DOI: 10.12865/chsj.40.03.01] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/21/2014] [Accepted: 06/10/2014] [Indexed: 02/07/2023]
Abstract
: The idea of stem cells as being progenitors of cancer was initially controversial, but later supported by research in the field of leukemia and solid tumors. Afterwards, it was established that genetic abnormalities can affect the stem and progenitor cells, leading to uncontrolled replication and deregulated differentiation. These alterations will cause the changeover to cancerous stem cells (CSC) having two main characteristics: tumor initiation and maintenance. This review will focus on the colorectal cancer stem cell (CR-CSCs) theory which provides a better understanding of different tumor processes: initiation, aggressive growth, recurrence, treatment resistance and metastasis. A search in PubMed/Medline was performed using the following keywords: colorectal cancer stem cells (CR-CSCs), colorectal neoplasms stem cells, colorectal cancer stem cell (CR-CSCs) markers, etc. Electronic searches were supplemented by hand searching reference lists, abstracts and proceedings from meetings. Isolation of CR-CSCs can be achieved by targeting and selecting subpopulation of tumor cells based on expression of one or multiple cell surface markers associated with cancer self-renewal, markers as: CD133, CD166, CD44, CD24, beta1 integrin-CD29, Lgr5, EpCAM (ESA), ALDH-1, Msi-1, DCAMLK1 or EphB receptors. The identification and localization of CR-CSCs through different markers will hopefully lead to a better stratification of prognosis and treatment response, as well as the development of new effective strategies for cancer management.
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Gu YY, Liu LP, Qin J, Zhang M, Chen Y, Wang D, Li Z, Tang JZ, Mo SL. Baicalein decreases side population proportion via inhibition of ABCG2 in multiple myeloma cell line RPMI 8226 in vitro. Fitoterapia 2014; 94:21-8. [PMID: 24468191 DOI: 10.1016/j.fitote.2014.01.019] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 01/14/2014] [Accepted: 01/17/2014] [Indexed: 01/08/2023]
Abstract
OBJECTIVE To investigate the effect of baicalein on side population in human multiple myeloma cell line RPMI 8226 and the underlying molecular mechanisms in vitro and in silico. METHODS MTT assay was applied to detect the anti-proliferation effect of baicalein. The detection of side population cells is based on the Hoechst 33342 exclusion assay technique and flow cytometric analysis. Western blotting assay was used to explore the expression of ABCG2 protein. Homology modeling and molecular docking were performed with Discovery Studio 2.1. RESULTS Baicalein decreased both cell viability with IC50=168.5 μM and the proportion of SP cells in a dose-dependent manner. Correspondingly, it significantly decreased the expression level of ABCG2 protein. Baicalein also shared similar binding sites and modes with fumitremorgin C to the protein. CONCLUSIONS Baicalein possessed novel anticancer properties, such as anti-proliferation and drug efflux inhibition in side population cells, which suggested its potential feature of targeting cancer stem cells of multiple myeloma.
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Affiliation(s)
- Yue-Yu Gu
- The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Li-Ping Liu
- The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Jian Qin
- The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Meng Zhang
- The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Yuling Chen
- Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia; Kiang Wu Hospital, Macau, China
| | - Dongmei Wang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Zhi Li
- The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Jing-Zhong Tang
- The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
| | - Sui-Lin Mo
- The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
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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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