Arsenic promotes the COX2/PGE2–SOX2 axis to increase the malignant stemness properties of urothelial cells
Chronic arsenic exposure is associated with the development of urothelial carcinoma of the bladder (UCB). To elucidate the contribution of arsenic exposure to urothelial cancer stem cell (CSC) generation, we established an in vitro stepwise malignant model transformed by chronically exposing human u...
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| Published in | International journal of cancer Vol. 143; no. 1; pp. 113 - 126 |
|---|---|
| Main Authors | , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Wiley Subscription Services, Inc
01.07.2018
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0020-7136 1097-0215 1097-0215 |
| DOI | 10.1002/ijc.31290 |
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| Abstract | Chronic arsenic exposure is associated with the development of urothelial carcinoma of the bladder (UCB). To elucidate the contribution of arsenic exposure to urothelial cancer stem cell (CSC) generation, we established an in vitro stepwise malignant model transformed by chronically exposing human urothelial cells to arsenic. Using this model, we found that chronic arsenic exposure endows urothelial cells with malignant stemness properties including increased expression of stemness‐related factors such as SOX2, sphere formation, self‐renewal, invasion and chemoresistance. SOX2 was gradually and irreversibly overexpressed in line with acquired sphere‐forming and self‐renewal abilities. Following gene set enrichment analyses of arsenic‐exposed and arsenic‐unexposed cells, we found COX2 as an enriched gene for oncogenic signature. Mechanistically, arsenic‐induced COX2/PGE2 increases SOX2 expression that eventually promotes malignant stem cell generation and repopulation. In urine samples from 90 subjects exposed to arsenic and 91 control subjects, we found a significant linear correlation between SOX2 and COX2 expression and the potential of SOX2 and COX2 expression as urinary markers to detect subjects exposed to arsenic. Furthermore, the combination marker yielded a high sensitivity for UCB detection in a separate cohort. Finally, our in vitro model exhibits basal‐type molecular features and dual inhibition of EGFR and COX2 attenuated stem cell enrichment more efficiently than an EGFR inhibitor alone. In conclusion, the COX2/PGE2‐SOX2 axis promotes arsenic‐induced malignant stem cell transformation. In addition, our findings indicate the possible use of SOX2 and COX2 expression as urinary markers for the risk stratification and detection of UCB.
What's new?
Environmental exposures to arsenic are associated with the development of urothelial carcinoma of the bladder (UCB). However, the molecular mechanisms of arsenic‐induced UCB remain elusive. In this study, chronic exposure to arsenic was found to induce malignant stem cell transformation in human urothelial HUC1 cells. Arsenic‐induced transformation was associated with increased expression of stemness‐related factors, including self‐renewal and invasion, and with overactivation of the COX2/PGE2–SOX2 axis. SOX2 and COX2 expression were significantly elevated in urine samples from UCB patients and may have potential as urinary markers for UCB detection and for risk assessment of arsenic exposure. |
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| AbstractList | Chronic arsenic exposure is associated with the development of urothelial carcinoma of the bladder (UCB). To elucidate the contribution of arsenic exposure to urothelial cancer stem cell (CSC) generation, we established an in vitro stepwise malignant model transformed by chronically exposing human urothelial cells to arsenic. Using this model, we found that chronic arsenic exposure endows urothelial cells with malignant stemness properties including increased expression of stemness-related factors such as SOX2, sphere formation, self-renewal, invasion and chemoresistance. SOX2 was gradually and irreversibly overexpressed in line with acquired sphere-forming and self-renewal abilities. Following gene set enrichment analyses of arsenic-exposed and arsenic-unexposed cells, we found COX2 as an enriched gene for oncogenic signature. Mechanistically, arsenic-induced COX2/PGE2 increases SOX2 expression that eventually promotes malignant stem cell generation and repopulation. In urine samples from 90 subjects exposed to arsenic and 91 control subjects, we found a significant linear correlation between SOX2 and COX2 expression and the potential of SOX2 and COX2 expression as urinary markers to detect subjects exposed to arsenic. Furthermore, the combination marker yielded a high sensitivity for UCB detection in a separate cohort. Finally, our in vitro model exhibits basal-type molecular features and dual inhibition of EGFR and COX2 attenuated stem cell enrichment more efficiently than an EGFR inhibitor alone. In conclusion, the COX2/PGE2-SOX2 axis promotes arsenic-induced malignant stem cell transformation. In addition, our findings indicate the possible use of SOX2 and COX2 expression as urinary markers for the risk stratification and detection of UCB. Chronic arsenic exposure is associated with the development of urothelial carcinoma of the bladder (UCB). To elucidate the contribution of arsenic exposure to urothelial cancer stem cell (CSC) generation, we established an in vitro stepwise malignant model transformed by chronically exposing human urothelial cells to arsenic. Using this model, we found that chronic arsenic exposure endows urothelial cells with malignant stemness properties including increased expression of stemness-related factors such as SOX2, sphere formation, self-renewal, invasion, and chemo-resistance. SOX2 was gradually and irreversibly overexpressed in line with acquired sphere-forming and self-renewal abilities. Following gene set enrichment analyses of arsenic-exposed and arsenic-unexposed cells, we found COX2 as an enriched gene for oncogenic signature. Mechanistically, arsenic-induced COX2/PGE2 increases SOX2 expression that eventually promotes malignant stem cell generation and repopulation. In urine samples from 90 subjects exposed to arsenic and 91 control subjects, we found a significant linear correlation between SOX2 and COX2 expression and the potential of SOX2 and COX2 expression as urinary markers to detect subjects exposed to arsenic. Furthermore, the combination marker yielded a high sensitivity for UCB detection in a separate cohort. Finally, our in vitro model exhibits basal-type molecular features, and dual inhibition of EGFR and COX2 attenuated stem cell enrichment more efficiently than an EGFR inhibitor alone. In conclusion, the COX2/PGE2-SOX2 axis promotes arsenic-induced malignant stem cell transformation. In addition, our findings indicate the possible use of SOX2 and COX2 expression as urinary markers for the risk stratification and detection of UCB. Chronic arsenic exposure is associated with the development of urothelial carcinoma of the bladder (UCB). To elucidate the contribution of arsenic exposure to urothelial cancer stem cell (CSC) generation, we established an in vitro stepwise malignant model transformed by chronically exposing human urothelial cells to arsenic. Using this model, we found that chronic arsenic exposure endows urothelial cells with malignant stemness properties including increased expression of stemness‐related factors such as SOX2, sphere formation, self‐renewal, invasion and chemoresistance. SOX2 was gradually and irreversibly overexpressed in line with acquired sphere‐forming and self‐renewal abilities. Following gene set enrichment analyses of arsenic‐exposed and arsenic‐unexposed cells, we found COX2 as an enriched gene for oncogenic signature. Mechanistically, arsenic‐induced COX2/PGE2 increases SOX2 expression that eventually promotes malignant stem cell generation and repopulation. In urine samples from 90 subjects exposed to arsenic and 91 control subjects, we found a significant linear correlation between SOX2 and COX2 expression and the potential of SOX2 and COX2 expression as urinary markers to detect subjects exposed to arsenic. Furthermore, the combination marker yielded a high sensitivity for UCB detection in a separate cohort. Finally, our in vitro model exhibits basal‐type molecular features and dual inhibition of EGFR and COX2 attenuated stem cell enrichment more efficiently than an EGFR inhibitor alone. In conclusion, the COX2/PGE2‐SOX2 axis promotes arsenic‐induced malignant stem cell transformation. In addition, our findings indicate the possible use of SOX2 and COX2 expression as urinary markers for the risk stratification and detection of UCB. What's new? Environmental exposures to arsenic are associated with the development of urothelial carcinoma of the bladder (UCB). However, the molecular mechanisms of arsenic‐induced UCB remain elusive. In this study, chronic exposure to arsenic was found to induce malignant stem cell transformation in human urothelial HUC1 cells. Arsenic‐induced transformation was associated with increased expression of stemness‐related factors, including self‐renewal and invasion, and with overactivation of the COX2/PGE2–SOX2 axis. SOX2 and COX2 expression were significantly elevated in urine samples from UCB patients and may have potential as urinary markers for UCB detection and for risk assessment of arsenic exposure. Chronic arsenic exposure is associated with the development of urothelial carcinoma of the bladder (UCB). To elucidate the contribution of arsenic exposure to urothelial cancer stem cell (CSC) generation, we established an in vitro stepwise malignant model transformed by chronically exposing human urothelial cells to arsenic. Using this model, we found that chronic arsenic exposure endows urothelial cells with malignant stemness properties including increased expression of stemness‐related factors such as SOX2, sphere formation, self‐renewal, invasion and chemoresistance. SOX2 was gradually and irreversibly overexpressed in line with acquired sphere‐forming and self‐renewal abilities. Following gene set enrichment analyses of arsenic‐exposed and arsenic‐unexposed cells, we found COX2 as an enriched gene for oncogenic signature. Mechanistically, arsenic‐induced COX2/PGE2 increases SOX2 expression that eventually promotes malignant stem cell generation and repopulation. In urine samples from 90 subjects exposed to arsenic and 91 control subjects, we found a significant linear correlation between SOX2 and COX2 expression and the potential of SOX2 and COX2 expression as urinary markers to detect subjects exposed to arsenic. Furthermore, the combination marker yielded a high sensitivity for UCB detection in a separate cohort. Finally, our in vitro model exhibits basal‐type molecular features and dual inhibition of EGFR and COX2 attenuated stem cell enrichment more efficiently than an EGFR inhibitor alone. In conclusion, the COX2/PGE2‐SOX2 axis promotes arsenic‐induced malignant stem cell transformation. In addition, our findings indicate the possible use of SOX2 and COX2 expression as urinary markers for the risk stratification and detection of UCB. What's new? Environmental exposures to arsenic are associated with the development of urothelial carcinoma of the bladder (UCB). However, the molecular mechanisms of arsenic‐induced UCB remain elusive. In this study, chronic exposure to arsenic was found to induce malignant stem cell transformation in human urothelial HUC1 cells. Arsenic‐induced transformation was associated with increased expression of stemness‐related factors, including self‐renewal and invasion, and with overactivation of the COX2/PGE2–SOX2 axis. SOX2 and COX2 expression were significantly elevated in urine samples from UCB patients and may have potential as urinary markers for UCB detection and for risk assessment of arsenic exposure. Chronic arsenic exposure is associated with the development of urothelial carcinoma of the bladder (UCB). To elucidate the contribution of arsenic exposure to urothelial cancer stem cell (CSC) generation, we established an in vitro stepwise malignant model transformed by chronically exposing human urothelial cells to arsenic. Using this model, we found that chronic arsenic exposure endows urothelial cells with malignant stemness properties including increased expression of stemness-related factors such as SOX2, sphere formation, self-renewal, invasion and chemoresistance. SOX2 was gradually and irreversibly overexpressed in line with acquired sphere-forming and self-renewal abilities. Following gene set enrichment analyses of arsenic-exposed and arsenic-unexposed cells, we found COX2 as an enriched gene for oncogenic signature. Mechanistically, arsenic-induced COX2/PGE2 increases SOX2 expression that eventually promotes malignant stem cell generation and repopulation. In urine samples from 90 subjects exposed to arsenic and 91 control subjects, we found a significant linear correlation between SOX2 and COX2 expression and the potential of SOX2 and COX2 expression as urinary markers to detect subjects exposed to arsenic. Furthermore, the combination marker yielded a high sensitivity for UCB detection in a separate cohort. Finally, our in vitro model exhibits basal-type molecular features and dual inhibition of EGFR and COX2 attenuated stem cell enrichment more efficiently than an EGFR inhibitor alone. In conclusion, the COX2/PGE2-SOX2 axis promotes arsenic-induced malignant stem cell transformation. In addition, our findings indicate the possible use of SOX2 and COX2 expression as urinary markers for the risk stratification and detection of UCB.Chronic arsenic exposure is associated with the development of urothelial carcinoma of the bladder (UCB). To elucidate the contribution of arsenic exposure to urothelial cancer stem cell (CSC) generation, we established an in vitro stepwise malignant model transformed by chronically exposing human urothelial cells to arsenic. Using this model, we found that chronic arsenic exposure endows urothelial cells with malignant stemness properties including increased expression of stemness-related factors such as SOX2, sphere formation, self-renewal, invasion and chemoresistance. SOX2 was gradually and irreversibly overexpressed in line with acquired sphere-forming and self-renewal abilities. Following gene set enrichment analyses of arsenic-exposed and arsenic-unexposed cells, we found COX2 as an enriched gene for oncogenic signature. Mechanistically, arsenic-induced COX2/PGE2 increases SOX2 expression that eventually promotes malignant stem cell generation and repopulation. In urine samples from 90 subjects exposed to arsenic and 91 control subjects, we found a significant linear correlation between SOX2 and COX2 expression and the potential of SOX2 and COX2 expression as urinary markers to detect subjects exposed to arsenic. Furthermore, the combination marker yielded a high sensitivity for UCB detection in a separate cohort. Finally, our in vitro model exhibits basal-type molecular features and dual inhibition of EGFR and COX2 attenuated stem cell enrichment more efficiently than an EGFR inhibitor alone. In conclusion, the COX2/PGE2-SOX2 axis promotes arsenic-induced malignant stem cell transformation. In addition, our findings indicate the possible use of SOX2 and COX2 expression as urinary markers for the risk stratification and detection of UCB. |
| Author | Marchionni, Luigi Begum, Asma VandenBussche, Christopher J. Mao, Shifeng Hoque, Mohammad Obaidul Ooki, Akira Kates, Max |
| AuthorAffiliation | 3 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA 1 Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA 2 The Sidney Kimmel Comprehensive Cancer, Johns Hopkins University, Baltimore, Maryland 21231, USA 4 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231-2410, USA 6 Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA 5 Allegheny Health Network Cancer Institute, Pittsburgh, PA 15212, USA |
| AuthorAffiliation_xml | – name: 1 Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA – name: 5 Allegheny Health Network Cancer Institute, Pittsburgh, PA 15212, USA – name: 3 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA – name: 4 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231-2410, USA – name: 2 The Sidney Kimmel Comprehensive Cancer, Johns Hopkins University, Baltimore, Maryland 21231, USA – name: 6 Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA |
| Author_xml | – sequence: 1 givenname: Akira surname: Ooki fullname: Ooki, Akira organization: Johns Hopkins University School of Medicine – sequence: 2 givenname: Asma surname: Begum fullname: Begum, Asma organization: The Sidney Kimmel Comprehensive Cancer, Johns Hopkins University – sequence: 3 givenname: Luigi surname: Marchionni fullname: Marchionni, Luigi organization: Johns Hopkins University School of Medicine – sequence: 4 givenname: Christopher J. surname: VandenBussche fullname: VandenBussche, Christopher J. organization: Johns Hopkins University School of Medicine – sequence: 5 givenname: Shifeng surname: Mao fullname: Mao, Shifeng organization: Allegheny Health Network Cancer Institute – sequence: 6 givenname: Max surname: Kates fullname: Kates, Max organization: Johns Hopkins University School of Medicine – sequence: 7 givenname: Mohammad Obaidul orcidid: 0000-0001-6701-9978 surname: Hoque fullname: Hoque, Mohammad Obaidul email: mhoque1@jhmi.edu organization: Johns Hopkins University School of Medicine |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29396848$$D View this record in MEDLINE/PubMed |
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| Keywords | SOX2 COX2 cancer stem cell arsenic urothelial carcinoma of bladder |
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| SubjectTerms | Arsenic Arsenic - toxicity Biomarkers, Tumor - urine Bladder cancer Cancer cancer stem cell Cell Line, Tumor Cell Proliferation Cell self-renewal Cell Survival Cell Transformation, Neoplastic - chemically induced Cell Transformation, Neoplastic - genetics Cell Transformation, Neoplastic - metabolism Chemoresistance COX2 Cyclooxygenase 2 - genetics Cyclooxygenase 2 - metabolism Cyclooxygenase 2 - urine Cyclooxygenase-2 Dinoprostone - metabolism Epidermal growth factor receptors Gene Expression Profiling Gene Expression Regulation, Neoplastic Genetic transformation Humans Medical research Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - metabolism Oncology Prostaglandin E2 SOX2 SOXB1 Transcription Factors - genetics SOXB1 Transcription Factors - metabolism SOXB1 Transcription Factors - urine Stem cells Up-Regulation Urine Urothelial cancer Urothelial carcinoma urothelial carcinoma of bladder Urothelium - cytology Urothelium - drug effects Urothelium - metabolism |
| Title | Arsenic promotes the COX2/PGE2–SOX2 axis to increase the malignant stemness properties of urothelial cells |
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