Abstract
In the present report, we demonstrate that sub-lethal stress induced by consecutive exposure to 0.25 µM arsenic (As3+) for six months can trigger reprogramming of the human bronchial epithelial cell (BEAS-2B) to form cancer stem cells (CSCs) without forced introduction of the stemness transcription factors. These CSCs formed from As3+-induced sub-lethal stress featured with an increased expression of the endogenous stemness genes, including Oct4, Sox2, Klf4, Myc, and others that are associated with the pluripotency and self-renewal of the CSCs. Flow cytometry analysis indicated that 90% of the CSC cells are CD61¯, whereas 100% of the parental cells are CD61+. These CD61¯ CSCs are highly tumorigenic and metastatic to the lung in xenotransplantation tests in NOD/SCID Il2rγ-/- mice. Additional tests also revealed that the CD61¯ CSCs showed a significant decrease in the expression of the genes important for DNA repair and oxidative phosphorylation. To determine the clinical relevance of the above findings, we stratified human lung cancers based on the level of CD61 protein and found that CD61low cancer correlates with poorer survival of the patients. Such a correlation was also observed in human breast cancer and ovarian cancer. Taken together, our findings suggest that in addition to the traditional approaches of enforced introduction of the exogenous stemness circuit transcription factors, sub-lethal stress induced by consecutive low dose As3+ is also able to convert non-stem cells to the CSCs.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Arsenic / toxicity*
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Breast Neoplasms / chemistry
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Breast Neoplasms / mortality
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Bronchi / cytology
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Cell Line
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Cell Transformation, Neoplastic / drug effects*
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / pathology
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Cellular Reprogramming / drug effects*
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DNA Repair / genetics
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Epithelium / drug effects
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Female
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Gene Expression / drug effects
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Gene Knockdown Techniques
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Genes, myc
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Humans
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Integrin beta3 / analysis*
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Integrin beta3 / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism
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Kruppel-Like Factor 4
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Kruppel-Like Transcription Factors / genetics
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Lung Neoplasms / chemistry*
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Lung Neoplasms / mortality
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Lung Neoplasms / secondary
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Inbred NOD
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Mice, SCID
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Neoplasms, Experimental / chemistry*
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Neoplasms, Experimental / pathology*
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Neoplastic Stem Cells / chemistry*
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Neoplastic Stem Cells / pathology*
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Octamer Transcription Factor-3 / genetics
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Ovarian Neoplasms / chemistry
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Ovarian Neoplasms / mortality
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Phenotype
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Phosphorylation / genetics
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Receptors, Interleukin-2 / genetics
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SOXB1 Transcription Factors / genetics
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Spheroids, Cellular
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Stress, Physiological
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Survival Rate
Substances
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ITGB3 protein, human
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Integrin beta3
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KLF4 protein, human
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Klf4 protein, mouse
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Kruppel-Like Factor 4
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Kruppel-Like Transcription Factors
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Octamer Transcription Factor-3
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POU5F1 protein, human
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Receptors, Interleukin-2
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SOX2 protein, human
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SOXB1 Transcription Factors
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JNK Mitogen-Activated Protein Kinases
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Arsenic