scholarly journals G9a controls pluripotent-like identity and tumor-initiating function in human colorectal cancer

Oncogene ◽  
2020 ◽  
Author(s):  
Christopher J. Bergin ◽  
Aïcha Zouggar ◽  
Joshua R. Haebe ◽  
Angelique N. Masibag ◽  
François M. Desrochers ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Embryonic Stem ◽  
Transcriptome Profiling ◽  
Histone Methyltransferase ◽  
Cell Phenotype ◽  
Regulation Mechanism ◽  
Self Renewal ◽  
Undifferentiated State

AbstractColorectal tumors are hierarchically organized and governed by populations of self-renewing cancer stem cells, representing one of the deadliest types of cancers worldwide. Emergence of cancer stemness phenotype depends on epigenetic reprogramming, associated with profound transcriptional changes. As described for pluripotent reprogramming, epigenetic modifiers play a key role in cancer stem cells by establishing embryonic stem-like transcriptional programs, thus impacting the balance between self-renewal and differentiation. We identified overexpression of histone methyltransferase G9a as a risk factor for colorectal cancer, associated with shorter relapse-free survival. Moreover, using human transformed pluripotent cells as a surrogate model for cancer stem cells, we observed that G9a activity is essential for the maintenance of embryonic-like transcriptional signature promoting self-renewal, tumorigenicity, and undifferentiated state. Such a role was also applicable to colorectal cancer, where inhibitors of G9a histone methyltransferase function induced intestinal differentiation while restricting tumor-initiating activity in patient-derived colorectal tumor samples. Finally, by integrating transcriptome profiling with G9a/H3K9me2 loci co-occupancy, we identified the canonical Wnt pathway, epithelial-to-mesenchyme transition, and extracellular matrix organization as potential targets of such a chromatin regulation mechanism in colorectal cancer stem cells. Overall, our findings provide novel insights on the role of G9a as a driver of cancer stem cell phenotype, promoting self-renewal, tumorigenicity, and undifferentiated state.

scholarly journals RNAi mediated silencing of Nanog expression suppresses the growth of human colorectal cancer stem cells

2020 ◽  
Author(s):  
Chen Zhang ◽  
Yuanyuan Zhao ◽  
Yongjing Yang ◽  
Chunlian Zhong ◽  
Tianju Ji ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Small Interfering Rna ◽  
Embryonic Stem ◽  
Self Renewal ◽  
Nanog Expression ◽  
Hct 116 ◽  
Hct 116 Cells ◽  
Interfering Rna

Abstract Background: Colorectal cancer (CRC) is the third most common cancer in the world known for its poor recurrence-free prognosis. Previous studies have shown that it is closely linked with cancer stem cells (CSCs), which have self-renewal potential and the capacity to differentiate into diverse populations. Nanog is an important transcription factor that functions to maintain the self-renewal and proliferation of embryonic stem cells; however, many recent studies have shown that Nanog is also highly expressed in many cancer stem cells.Methods: To investigate whether Nanog plays a crucial role in maintaining the stemness of colorectal CSCs (CCSCs), RNA interference was used to downregulate Nanog expression in the CRC stem cell line, EpCAM+CD44+HCT-116. We examined the anti-tumor function of Nanog in vitro and in vivo, using small interfering RNA.Results: Our results revealed that the Nanog mRNA expression level in CCSCs was higher than that in HCT-116 cells. We found that the depletion of Nanog inhibited proliferation and promoted apoptosis in EpCAM+CD44+HCT-116 cells. In addition, the invasive ability of EpCAM+CD44+HCT-116 cells was markedly restricted when Nanog was silenced by small interfering RNA. Furthermore, we found that the silencing of Nanog decreased tumor size and weight and improved the survival rate of tumor-bearing mice.Conclusions: In conclusion, these findings collectively demonstrate that Nanog, which is highly expressed in CRC stem cells, is a key factor in the development of tumor growth, and it may serve as a potential marker of prognosis and a novel and effective therapeutic target for the treatment of CRC.

scholarly journals RNAi mediated silencing of Nanog expression suppresses the growth of human colorectal cancer stem cells

2020 ◽  
Author(s):  
Chen Zhang ◽  
Yuanyuan Zhao ◽  
Yongjing Yang ◽  
Chunlian Zhong ◽  
Tianju Ji ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Small Interfering Rna ◽  
Embryonic Stem ◽  
Self Renewal ◽  
Nanog Expression ◽  
Hct 116 ◽  
Hct 116 Cells ◽  
Interfering Rna

Abstract Background: Colorectal cancer (CRC) is the third most common cancer in the world known for its poor recurrence-free prognosis. Previous studies have shown that it is closely linked with cancer stem cells (CSCs), which have self-renewal potential and the capacity to differentiate into diverse populations. Nanog is an important transcription factor that functions to maintain the self-renewal and proliferation of embryonic stem cells; however, many recent studies have shown that Nanog is also highly expressed in many cancer stem cells. Methods: To investigate whether Nanog plays a crucial role in maintaining the stemness of colorectal CSCs (CCSCs), RNA interference was used to downregulate Nanog expression in the CRC stem cell line, EpCAM + CD44 + HCT-116. We examined the anti-tumor function of Nanog in vitro and in vivo, using small interfering RNA. Results: Our results revealed that the Nanog mRNA expression level in CCSCs was higher than that in HCT-116 cells. We found that the depletion of Nanog inhibited proliferation and promoted apoptosis in EpCAM + CD44 + HCT-116 cells. In addition, the invasive ability of EpCAM + CD44 + HCT-116 cells was markedly restricted when Nanog was silenced by small interfering RNA. Furthermore, we found that the silencing of Nanog decreased tumor size and weight and improved the survival rate of tumor-bearing mice. Conclusions: In conclusion, these findings collectively demonstrate that Nanog, which is highly expressed in CRC stem cells, is a key factor in the development of tumor growth, and it may serve as a potential marker of prognosis and a novel and effective therapeutic target for the treatment of CRC.

scholarly journals Dermatan-4-O-Sulfotransferase-1 Contributes to the Undifferentiated State of Mouse Embryonic Stem Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Chika Ogura ◽  
Shoko Nishihara
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Keratan Sulfate ◽  
Mouse Embryonic Stem Cells ◽  
Human Escs ◽  
Self Renewal ◽  
Human Neural Stem Cells ◽  
Undifferentiated State ◽  
Endodermal Differentiation

Mouse embryonic stem cells (mESCs) have the properties of self-renewal and pluripotency. Various signals and growth factors maintain their undifferentiated state and also regulate their differentiation. Glycosaminoglycans are present on the cell surface and in the cell matrix as proteoglycans. Previously, we and other groups reported that the glycosaminoglycan heparan sulfate contributes to both maintenance of undifferentiated state and regulation of mESC differentiation. It has been shown that chondroitin sulfate is needed for pluripotency and differentiation of mESCs, while keratan sulfate is a known marker of human ESCs or induced pluripotent stem cells. We also found that DS promotes neuronal differentiation from mESCs and human neural stem cells; however, the function of DS in the maintenance of mESCs has not yet been revealed. Here, we investigated the role of DS in mESCs by knockdown (KD) or overexpression (O/E) of the dermatan-4-O-sulfotransferase-1 (D4ST1) gene. We found that the activity of the ESC self-renewal marker alkaline phosphatase was reduced in D4ST1 KD mESCs, but, in contrast, increased in D4ST1 O/E mESCs. D4ST1 KD promoted endodermal differentiation, as indicated by an increase in Cdx2 expression. Conversely, Cdx2 expression was decreased by D4ST1 O/E. Wnt signaling, which is also involved in endodermal differentiation, was activated by D4ST1 KD and suppressed by D4ST1 O/E. Collectively, these results demonstrate that D4ST1 contributes to the undifferentiated state of mESCs. Our findings provide new insights into the function of DS in mESCs.

scholarly journals Lgr5+CD44+EpCAM+ Strictly Defines Cancer Stem Cells in Human Colorectal Cancer

2018 ◽  
Vol 46 (2) ◽  
pp. 860-872 ◽  
Author(s):  
Zhengwei Leng ◽  
Qinghua Xia ◽  
Jinhuang Chen ◽  
Yong Li ◽  
Jiqian Xu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Colony Formation ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Xenograft ◽  
Self Renewal ◽  
Mesenchymal Transition

Background/Aims: Although EpCAM+CD44+ cells exhibit more stem-like properties than did EpCAM-CD44- cells, the specificity of EpCAM combined with CD44 in defining CSCs needs further improvement. Lgr5 is used as a biomarker to isolate cancer stem cells (CSCs) in colorectal cancer. However, it remains unclear whether Lgr5, along with EpCAM and CD44, can further identify and define CSCs in colorectal cancer. Methods: Lgr5+CD44+EpCAM+, Lgr5+CD44+EpCAM-, Lgr5+CD44-EpCAM+, Lgr5-CD44+EpCAM+, and Lgr5-CD44-EpCAM-cells were separately isolated using fluorescence-activated cell sorting (FACS). Colony formation, self-renewal, differentiation, and tumorigenic properties of these cells were investigated through in vitro experiments and in vivo tumor xenograft models. The expression of stemness genes and CSC- and epithelial-mesenchymal transition (EMT)-related genes, such as KLF4, Oct4, Sox2, Nanog, CD133, CD44, CD166, ALDH1, Lgr5, E-cadherin, ZO-1, Vimentin, Snail, Slug, and Twist, was examined using real-time PCR. Results: Lgr5-positive subpopulations exhibited higher capacities for colony formation, self-renewal, differentiation, and tumorigenicity as well as higher expression of stemness genes and mesenchymal genes and lower expression of epithelial genes than did Lgr5-negative subpopulations. Conclusion: Our data revealed that tumorigenic cells were highly restricted to Lgr5-positive subpopulations. Most importantly, Lgr5+CD44+EpCAM+ cells exhibited more pronounced CSC-like traits than did any other subpopulation, indicating that Lgr5 combined with CD44 and EpCAM can further improve the stem-like traits of CSCs in colorectal cancer.

scholarly journals Oct4 Gene Expression in Primary Colorectal Cancer Promotes Liver Metastasis

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Shiki Fujino ◽  
Norikatsu Miyoshi
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Liver Metastasis ◽  
Embryonic Stem ◽  
Clinical Samples ◽  
Self Renewal ◽  
Oct4 Expression

Purpose. The Oct4 gene plays an important role in undifferentiated embryonic stem cells and regulates stem cell pluripotency. The aim of this study was to examine the relationship between Oct4 expression and liver metastasis of colorectal cancer (CRC) in clinical samples and investigate the role and abilities of Oct4-positive CRC cells. Methods. The study included 158 patients who underwent surgery for CRC between 2009 and 2011. The correlations between the Oct4 gene expression and the clinical parameters were assessed, and liver metastasis-free survival (LMFS) was evaluated in these patients. Oct4-EGFP-positive cells were established to examine their subpopulation and ability. The capacity to form liver metastasis in vivo was examined using CRC cell lines and primary cultured CRC cells. Results. LMFS was significantly poor in the Oct4 high-expression group compared with the low-expression group (P=0.008). Multivariate analyses showed that Oct4 expression (P=0.015) and TNM stage (P<0.001) were significantly correlated with LMFS. Oct4-EGFP-positive cells highly expressed stem cell-associated markers and had self-renewal and differentiation abilities. Oct4-high cells actively formed liver metastasis. Conclusion. The Oct4 expression was correlated with liver metastasis in CRC patients. Oct4 expression cells have self-renewal and differentiation abilities like those of cancer stem cells. Oct4 contributed to forming liver metastasis in CRC.

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