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      Cancer stem cell‐like characteristics and telomerase activity of the nasopharyngeal carcinoma radioresistant cell line CNE‐2R

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          Abstract

          The radioresistance of nasopharyngeal carcinoma ( NPC) may be related to cancer stem cells ( CSCs), and the characteristics of CSCs may be maintained by telomerase activity. In this study, we explored the CSC‐like characteristics and telomerase activity of the NPC radioresistant cell line CNE‐2R. This work provides a foundation for future studies on stem cell‐targeted therapies by targeting the radioresistance of NPC. The expression of stem cell‐related genes/proteins and the hTERT gene/protein in CNE‐2R and its parent radiosensitive cell line CNE‐2 were detected using qPCR/Western Blot. Label‐retaining cells ( LRCs) were detected through immunocytochemistry, and telomerase activity was detected using a PCRELISA kit. CD133 expression was detected with flow cytometry. CNE‐2R‐ CD133+ and CNE‐2R‐ CD133− cells were separated with magnetic‐activated cell sorting. The proliferation and tumorigenesis capacities of CNE‐2R‐ CD133+, CNE‐2R‐ CD133−, and CNE‐2R cells were compared with a CCK‐8 assay, sphere formation assay, and an in vivo experiment. Our results showed that the expression of stem cell‐related genes and the hTERT gene in CNE‐2R cells was higher than those in CNE‐2 cells. Similarly, the expression of stem cell‐related proteins and the hTERT protein in CNE‐2R cells was markedly higher than those in CNE‐2 cells. The proportion of LRCs in CNE‐2R and CNE‐2 cells was (3.10 ± 0.63%) vs (0.40 ± 0.35%; <  0.001), respectively. Telomerase activity in CNE‐2R cells was remarkably higher than that in CNE‐2 cells. Flow cytometry suggested that the CD133 positive rates in CNE‐2R and CNE‐2 cells were (2.49 ± 0.56%) vs (0.76 ± 0.25%; =  0.008), respectively. Meanwhile, the proliferation capacity, tumorigenesis capacity, and telomerase activity of CNE‐2R‐ CD133+ cells were notably higher than those of CNE‐2R‐ CD133− and CNE‐2R cells. Collectively, CNE‐2R displayed CSC‐like characteristics; our results also showed that CNE‐2R cells, especially the sorted CSCs, had high telomerase activity levels.

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          Most cited references41

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          Wnt/beta-catenin signaling in cancer stemness and malignant behavior.

          Stem cells are defined by their intrinsic capacity to self-renew and differentiate. Cancer stem cells retain both these features but have lost homeostatic mechanisms which maintain normal cell numbers. The canonical Wnt/beta-catenin signaling pathway plays a central role in modulating the delicate balance between stemness and differentiation in several adult stem cell niches such as the hair follicles in the skin, the mammary gland, and the intestinal crypt. Accordingly, constitutive Wnt signaling activation, resulting from mutations in genes encoding its downstream components, underlies tumorigenesis in these tissues. In the majority of sporadic colorectal cancer cases, the rate-limiting event is either loss of APC function or oncogenic beta-catenin mutations. However, although the presence of these initiating mutations would predict nuclear beta-catenin accumulation throughout the tumor mass, heterogeneous intracellular distributions of this key Wnt signaling molecule are observed within primary tumors and their metastases. In particular, tumor cells located at the invasive front and those migrating into the adjacent stromal tissues show nuclear beta-catenin staining. Hence, different levels of Wnt signaling activity reflect tumor heterogeneity and are likely to account for distinct cellular activities such as proliferation and epithelial-mesenchymal transitions, which prompt tumor growth and malignant behavior, respectively. Several intrinsic (cell-autonomous and/or autocrine) and extrinsic (paracrine, derived from the tumor microenvironment) factors may explain this heterogeneity of Wnt/beta-catenin signaling activity within the tumor mass.
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            Module map of stem cell genes guides creation of epithelial cancer stem cells.

            Self-renewal is a hallmark of stem cells and cancer, but existence of a shared stemness program remains controversial. Here, we construct a gene module map to systematically relate transcriptional programs in embryonic stem cells (ESCs), adult tissue stem cells, and human cancers. This map reveals two predominant gene modules that distinguish ESCs and adult tissue stem cells. The ESC-like transcriptional program is activated in diverse human epithelial cancers and strongly predicts metastasis and death. c-Myc, but not other oncogenes, is sufficient to reactivate the ESC-like program in normal and cancer cells. In primary human keratinocytes transformed by Ras and I kappa B alpha, c-Myc increases the fraction of tumor-initiating cells by 150-fold, enabling tumor formation and serial propagation with as few as 500 cells. c-Myc-enhanced tumor initiation is cell-autonomous and independent of genomic instability. Thus, activation of an ESC-like transcriptional program in differentiated adult cells may induce pathologic self-renewal characteristic of cancer stem cells.
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              Protein composition of catalytically active human telomerase from immortal cells.

              Telomerase is a ribonucleoprotein enzyme complex that adds 5'-TTAGGG-3' repeats onto the ends of human chromosomes, providing a telomere maintenance mechanism for approximately 90% of human cancers. We have purified human telomerase approximately 10(8)-fold, with the final elution dependent on the enzyme's ability to catalyze nucleotide addition onto a DNA oligonucleotide of telomeric sequence, thereby providing specificity for catalytically active telomerase. Mass spectrometric sequencing of the protein components and molecular size determination indicated an enzyme composition of two molecules each of telomerase reverse transcriptase, telomerase RNA, and dyskerin.
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                Author and article information

                Contributors
                zhuxdonggxmu@126.com
                Journal
                Cancer Med
                Cancer Med
                10.1002/(ISSN)2045-7634
                CAM4
                Cancer Medicine
                John Wiley and Sons Inc. (Hoboken )
                2045-7634
                13 August 2018
                September 2018
                : 7
                : 9 ( doiID: 10.1002/cam4.2018.7.issue-9 )
                : 4755-4764
                Affiliations
                [ 1 ] Department of Radiation Oncology Affiliated Tumor Hospital of Guangxi Medical University Cancer Institute of Guangxi Zhuang Autonomous Region Nanning Guangxi China
                [ 2 ] Department of Radiation Oncology The Second Affiliated Hospital of Xi'an Jiaotong University Xi'an Shanxi China
                [ 3 ] Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University) Ministry of Education Nanning Guangxi China
                [ 4 ] Wuming Hospital of Guangxi Medical University Nanning Guangxi China
                Author notes
                [*] [* ] Correspondence: Xiao‐Dong Zhu, Department of Radiation Oncology, Affiliated Tumor Hospital of Guangxi Medical University, No. 71 He Di Road, Nanning 530021, Guangxi, China ( zhuxdonggxmu@ 123456126.com ).
                Author information
                http://orcid.org/0000-0002-7997-8268
                Article
                CAM41729
                10.1002/cam4.1729
                6144248
                30105829
                590f12d9-43aa-4863-a261-75877f77673b
                © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 May 2018
                : 20 July 2018
                : 23 July 2018
                Page count
                Figures: 5, Tables: 2, Pages: 10, Words: 6008
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81760544
                Funded by: Natural Science Foundation of Guangxi Province
                Award ID: 2016GXNSFAA380127
                Categories
                Original Research
                Cancer Biology
                Original Research
                Custom metadata
                2.0
                cam41729
                September 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.9 mode:remove_FC converted:19.09.2018

                Oncology & Radiotherapy
                cancer stem cells,nasopharyngeal carcinoma,radioresistance,telomerase activity

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