Enhanced cell growth and tumorigenicity of rat glioma cells by stable expression of human CD133 through multiple molecular actions.
Abstract |
CD133 ( Prominin-1/AC133) is generally treated as a cell surface marker found on multipotent stem cells and tumor stem-like cells, and its biological function remains debated. Genetically modified rat glioma cell lines were generated by lentiviral gene delivery of human CD133 into rat C6 glioma cells (hCD133(+) -C6) or by infection of C6 cells with control lentivirus (mock-C6). Stable hCD133 expression promoted the self-renewal ability of C6-formed spheres with an increase in the expression of the stemness markers, Bmi-1 and SOX2. Akt phosphorylation, Notch-1 activation, and Notch-1 target gene expression (Hes-1, Hey1 and Hey2) were increased in hCD133(+) -C6 when compared to mock-C6. The inhibition of Akt phosphorylation, Notch-1 activation, and Hes-1 in hCD133(+) -C6 cells effectively suppressed their clonogenic ability, indicating that these factors are involved in expanding the growth of hCD133(+) -C6. An elevated expression of GTPase-activating protein 27 (Arhgap27) was detected in hCD133(+) -C6. A decline in the invasion of hCD133(+) -C6 by knockdown of Arhgap27 expression indicated the critical role of Arhgap27 in promoting cell migration of hCD133(+) -C6. In vivo study further showed that hCD133(+) -C6 formed aggressive tumors in vivo compared to mock-C6. Exposure of hCD133(+) -C6 to arsenic trioxide not only reduced Akt phosphorylation, Notch-1 activation and Hes-1 expression in vitro, but also inhibited their tumorigenicity in vivo. The results show that C6 glioma cells with stable hCD133 expression enhanced their stemness properties with increased Notch-1/Hes-1 signaling, Akt activation, and Arhgap27 action, which contribute to increased cell proliferation and migration of hCD133(+) -C6 in vitro, as well as progressive tumor formation in vivo.
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Authors | Kuan-Min Fang, Tzu-Chien Lin, Ti-Chun Chan, Shi-Zhang Ma, Bo-Cheng Tzou, Wen-Ruei Chang, Jun-Jen Liu, Shih-Hwa Chiou, Chung-Shi Yang, Shun-Fen Tzeng |
Journal | Glia
(Glia)
Vol. 61
Issue 9
Pg. 1402-17
(Sep 2013)
ISSN: 1098-1136 [Electronic] United States |
PMID | 23832679
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2013 Wiley Periodicals, Inc. |
Chemical References |
- AC133 Antigen
- ARHGAP27 protein, human
- Antigens, CD
- Antineoplastic Agents
- Arsenicals
- Basic Helix-Loop-Helix Transcription Factors
- Enzyme Inhibitors
- Formazans
- GTPase-Activating Proteins
- Glycoproteins
- Hes1 protein, rat
- Homeodomain Proteins
- Intercellular Signaling Peptides and Proteins
- Oxides
- PROM1 protein, human
- Peptides
- Prom1 protein, rat
- RNA, Messenger
- RNA, Small Interfering
- Receptor, Notch1
- Tetrazolium Salts
- Transcription Factor HES-1
- MTT formazan
- Oncogene Protein v-akt
- Arsenic Trioxide
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Topics |
- AC133 Antigen
- Animals
- Antigens, CD
(genetics, metabolism)
- Antineoplastic Agents
(pharmacology, therapeutic use)
- Arsenic Trioxide
- Arsenicals
(pharmacology)
- Basic Helix-Loop-Helix Transcription Factors
(genetics, metabolism)
- Brain Neoplasms
(drug therapy, metabolism, pathology)
- Cell Line, Tumor
- Cell Movement
(drug effects, genetics)
- Cell Proliferation
(drug effects)
- Cell Transformation, Neoplastic
(genetics, metabolism, pathology)
- Cerebral Cortex
(pathology)
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Enzyme Inhibitors
(pharmacology)
- Female
- Formazans
- GTPase-Activating Proteins
(genetics, metabolism)
- Gene Expression Regulation, Neoplastic
(drug effects, genetics)
- Glioma
(drug therapy, metabolism, pathology)
- Glycoproteins
(genetics, metabolism)
- Homeodomain Proteins
(genetics, metabolism)
- Humans
- Intercellular Signaling Peptides and Proteins
(pharmacology)
- Lentivirus
(genetics)
- Oncogene Protein v-akt
(genetics, metabolism)
- Oxides
(pharmacology)
- Peptides
(genetics, metabolism)
- RNA, Messenger
(metabolism)
- RNA, Small Interfering
(genetics, metabolism)
- Rats
- Rats, Sprague-Dawley
- Receptor, Notch1
(genetics, metabolism)
- Tetrazolium Salts
- Time Factors
- Transcription Factor HES-1
- Transfection
- Tumor Stem Cell Assay
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