Arsenic-Specific Stem Cell Selection During Malignant Transformation

Tokar, Erik J.; Qu, Wei; Liu, Jie; Liu, Wei; Webber, Mukta M.; Phang, James M.; Waalkes, Michael P.

doi:10.1093/jnci/djq093

Cited by 85 publications

(106 citation statements)

References 58 publications

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“…An additional possibility is that the increased ALDH1A1 expression might be related to an increased number of cancer stem cells in the iAs transformants but not in the Cd and MNU transformants as previously reported (Tokar et al , 2010; Tokar et al , 2011). This may also explain why ALDH1A1 was differentially expressed, being upregulated in the CAsE-PE but downregulated in the CTPE and B26..…”

Section: Discussionmentioning

confidence: 77%

Differential DNA methylation profile of key genes in malignant prostate epithelial cells transformed by inorganic arsenic or cadmium

Pelch

Tokar

Merrick

et al. 2015

Toxicology and Applied Pharmacology

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Previous work shows altered methylation patterns in inorganic arsenic (iAs)-or cadmium (Cd)-transformed epithelial cells. Here, the methylation status near the transcriptional start site was assessed in the normal human prostate epithelial cell line (RWPE-1) that was malignantly transformed by 10 μM Cd for 11 weeks (CTPE) or 5 μM iAs for 29 weeks (CAsE-PE), at which time cells showed multiple markers of acquired cancer phenotype. Next generation sequencing of the transcriptome of CAsE-PE cells identified multiple dysregulated genes. Of the most highly dysregulated genes, five genes that can be relevant to the carcinogenic process (S100P, HYAL1, NTM, NES, ALDH1A1) were chosen for in depth analysis of the DNA methylation profile. DNA was isolated, bisulfite converted, and combined bisulfite restriction analysis was used to identify differentially methylated CpG sites, which was confirmed with bisulfite sequencing. Four of the five genes showed differential methylation in transformants relative to control cells that was inversely related to altered gene expression. Increased expression of HYAL1 (>25-fold) and S100P (>40-fold) in transformants was correlated with hypomethylation near the transcription start site. Decreased expression of NES (>15-fold) and NTM (>1000-fold) in transformants was correlated with hypermethylation near the transcription start site. ALDH1A1 expression was differentially expressed in transformed cells but was not differentially methylated relative to control. In conclusion, altered gene expression observed in Cd and iAs transformed cells may result from altered DNA methylation status.

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Section: Discussionmentioning

confidence: 77%

Differential DNA methylation profile of key genes in malignant prostate epithelial cells transformed by inorganic arsenic or cadmium

Pelch

Tokar

Merrick

et al. 2015

Toxicology and Applied Pharmacology

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“…3 A, B). This prompted us to investigate innate resistance to arseniteinduced cytolethality since this was a trait associated with stemness in RWPE-1 cells as previously described [22]. After short-term (ie, 48 h) arsenite exposure (Fig.…”

Section: S-ship-gfp Promoter Reporter Tracks Subsets Of Rwpe-1 Cells mentioning

confidence: 99%

“…To test this hypothesis, we used as a model the nontumorigenic human prostate cell line RWPE-1 that was derived from normal human prostate epithelium immortalized by human papillomavirus 18 [20]. RWPE-1 cells and its derivatives contain stem, intermediate, and differentiated cell types and offer valuable models for studies of adult prostate stem cells [21,22].…”

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confidence: 99%

Enrichment of Human Stem-Like Prostate Cells with s-SHIP Promoter Activity Uncovers a Role in Stemness for the Long Noncoding RNA H19

Roy

Vennin

Brocqueville

et al. 2015

Stem Cells and Development

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Understanding normal and cancer stem cells should provide insights into the origin of prostate cancer and their mechanisms of resistance to current treatment strategies. In this study, we isolated and characterized stem-like cells present in the immortalized human prostate cell line, RWPE-1. We used a reporter system with green fluorescent protein (GFP) driven by the promoter of s-SHIP (for stem-SH2-domain-containing 5¢-inositol phosphatase) whose stem cell-specific expression has been previously shown. We observed that s-SHIP-GFPexpressing RWPE-1 cells showed stem cell characteristics such as increased expression of stem cell surface markers (CD44, CD166, TROP2) and pluripotency transcription factors (Oct4, Sox2), and enhanced sphereforming capacity and resistance to arsenite-induced cell death. Concomitant increased expression of the long noncoding RNA H19 was observed, which prompted us to investigate a putative role in stemness for this oncofetal gene. Targeted suppression of H19 with siRNA decreased Oct4 and Sox2 gene expression and colonyforming potential in RWPE-1 cells. Conversely, overexpression of H19 significantly increased gene expression of these two transcription factors and the sphere-forming capacity of RWPE-1 cells. Analysis of H19 expression in various prostate and mammary human cell lines revealed similarities with Sox2 expression, suggesting that a functional relationship may exist between H19 and Sox2. Collectively, we provide the first evidence that s-SHIP-GFP promoter reporter offers a unique marker for the enrichment of human stem-like cell populations and highlight a role in stemness for the long noncoding RNA H19.

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“…Furthermore, other recent studies showed that As 3+ is able to activate a signaling cascade from JNK and Stat3 to Akt-mediated EZH2 phosphorylation, which may be linked to the epigenetic reprogramming of the genome and the malignant transformation of cells [5]. Finally, As 3+ had been shown to be capable of converting normal stem cells into cancer stem cells (CSCs) in several experimental settings [6, 7]. …”

Section: Introductionmentioning

confidence: 99%

Arsenic-induced sub-lethal stress reprograms human bronchial epithelial cells to CD61¯ cancer stem cells

et al. 2013

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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.

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Arsenic-Specific Stem Cell Selection During Malignant Transformation

Cited by 85 publications

References 58 publications

Differential DNA methylation profile of key genes in malignant prostate epithelial cells transformed by inorganic arsenic or cadmium

Differential DNA methylation profile of key genes in malignant prostate epithelial cells transformed by inorganic arsenic or cadmium

Enrichment of Human Stem-Like Prostate Cells with s-SHIP Promoter Activity Uncovers a Role in Stemness for the Long Noncoding RNA H19

Arsenic-induced sub-lethal stress reprograms human bronchial epithelial cells to CD61¯ cancer stem cells

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