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Cancer stem-like cell characteristics induced by EB virus-encoded LMP1 contribute to radioresistance in nasopharyngeal carcinoma by suppressing the p53-mediated apoptosis pathway

Abstract Emerging evidence confirms that cancer stem cells (CSCs) are responsible for the chemoradioresistance of malignancies. EBV-encoded latent membrane protein 1 (LMP1) is associated with tumor relapse and poor prognosis of nasopharyngeal carcinoma (NPC). However, whether LMP1 induces the develo... Full description

Journal Title: Cancer letters 2013, Vol.344 (2), p.260-271
Main Author: Yang, Chang-Fu
Other Authors: Peng, Li-Xia , Huang, Tie-Jun , Yang, Guang-Da , Chu, Qiao-Qiao , Liang, Ying-Ying , Cao, Xue , Xie, Ping , Zheng, Li-Sheng , Huang, Hong-Bing , Cai, Mao-De , Huang, Jia-Ling , Liu, Ran-Yi , Zhu, Zhen-Yu , Qian, Chao-Nan , Huang, Bi-Jun
Format: Electronic Article Electronic Article
Language: English
Subjects:
DNA
Quelle: Alma/SFX Local Collection
Publisher: Ireland: Elsevier Ireland Ltd
ID: ISSN: 0304-3835
Link: https://www.ncbi.nlm.nih.gov/pubmed/24262659
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title: Cancer stem-like cell characteristics induced by EB virus-encoded LMP1 contribute to radioresistance in nasopharyngeal carcinoma by suppressing the p53-mediated apoptosis pathway
format: Article
creator:
  • Yang, Chang-Fu
  • Peng, Li-Xia
  • Huang, Tie-Jun
  • Yang, Guang-Da
  • Chu, Qiao-Qiao
  • Liang, Ying-Ying
  • Cao, Xue
  • Xie, Ping
  • Zheng, Li-Sheng
  • Huang, Hong-Bing
  • Cai, Mao-De
  • Huang, Jia-Ling
  • Liu, Ran-Yi
  • Zhu, Zhen-Yu
  • Qian, Chao-Nan
  • Huang, Bi-Jun
subjects:
  • Analysis
  • Animals
  • Apoptosis
  • Apoptosis - physiology
  • Apoptosis - radiation effects
  • Breast cancer
  • Cancer
  • Cancer stem cells (CSCs)
  • Cancer therapies
  • Carcinoma
  • Deoxyribonucleic acid
  • DNA
  • DNA damage
  • Epstein–Barr virus (EBV)
  • Genetic research
  • Grants
  • Hematology, Oncology and Palliative Medicine
  • Herpes viruses
  • Herpesvirus 4, Human - metabolism
  • Humans
  • Infrared Rays
  • Latent membrane protein 1 (LMP1)
  • Metastasis
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mutation
  • Nasopharyngeal Carcinoma
  • Nasopharyngeal carcinoma (NPC)
  • Nasopharyngeal Neoplasms - metabolism
  • Nasopharyngeal Neoplasms - pathology
  • Nasopharyngeal Neoplasms - radiotherapy
  • Nasopharyngeal Neoplasms - virology
  • Neoplastic Stem Cells - metabolism
  • Neoplastic Stem Cells - radiation effects
  • Neoplastic Stem Cells - virology
  • p53 signalling pathway
  • Phosphorylation
  • Proteins
  • Radiation therapy
  • Radiation Tolerance
  • Radioresistance
  • Science
  • Signal Transduction - radiation effects
  • Tumor proteins
  • Tumor Suppressor Protein p53 - antagonists & inhibitors
  • Tumor Suppressor Protein p53 - metabolism
  • Tumors
  • Viral Matrix Proteins - biosynthesis
  • Virus diseases
ispartof: Cancer letters, 2013, Vol.344 (2), p.260-271
description: Abstract Emerging evidence confirms that cancer stem cells (CSCs) are responsible for the chemoradioresistance of malignancies. EBV-encoded latent membrane protein 1 (LMP1) is associated with tumor relapse and poor prognosis of nasopharyngeal carcinoma (NPC). However, whether LMP1 induces the development of CSCs and the mechanism by which this rare cell subpopulation leads to radioresistance in NPC remain unclear. In the present study, LMP1-transformed NPC cells showed significant radioresistance compared to the empty vector control. We found that LMP1 up-regulated the expression of several stemness-related genes, increased the cell number of side population (SP) by flow cytometry analysis, enhanced the self-renewal properties of the cells in a spherical culture and enhanced the in vivo tumor initiation ability. We also found that LMP1 positively regulated the expression of the CSC marker CD44. The CD44+/High subpopulation of the LMP1-transformed NPC cells displayed more significant CSC characteristics than the CD44−/Low subpopulation of the LMP1-transformed NPC cells; these characteristics included the upregulation of stemness-related genes, in vitro self-renewal and in vivo tumor initiation ability. Importantly, the CD44+/High subpopulation displayed more radioresistance than the CD44−/Low subpopulation. Our results also demonstrated that phosphorylation of the DNA damage response (DDR) proteins, ATM, Chk1, Chk2 and p53, was inactivated in the LMP1-induced CD44+/High cells in response to DNA damage, and this was accompanied by a downregulation of the p53-targeted proapoptotic genes, which suggested that the inactivation of the p53-mediated apoptosis pathway was responsible for the radioresistance in the CD44+/High cells. Taken together, we found that LMP1 induced an increase in CSC-like CD44+/High cells, and we determined the molecular mechanism underlying the radioresistance of the LMP1-activated CSCs, highlighting the need of CSC-targeted radiotherapy in EBV-positive NPC.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0304-3835
fulltext: fulltext
issn:
  • 0304-3835
  • 1872-7980
url: Link


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titleCancer stem-like cell characteristics induced by EB virus-encoded LMP1 contribute to radioresistance in nasopharyngeal carcinoma by suppressing the p53-mediated apoptosis pathway
sourceAlma/SFX Local Collection
creatorYang, Chang-Fu ; Peng, Li-Xia ; Huang, Tie-Jun ; Yang, Guang-Da ; Chu, Qiao-Qiao ; Liang, Ying-Ying ; Cao, Xue ; Xie, Ping ; Zheng, Li-Sheng ; Huang, Hong-Bing ; Cai, Mao-De ; Huang, Jia-Ling ; Liu, Ran-Yi ; Zhu, Zhen-Yu ; Qian, Chao-Nan ; Huang, Bi-Jun
creatorcontribYang, Chang-Fu ; Peng, Li-Xia ; Huang, Tie-Jun ; Yang, Guang-Da ; Chu, Qiao-Qiao ; Liang, Ying-Ying ; Cao, Xue ; Xie, Ping ; Zheng, Li-Sheng ; Huang, Hong-Bing ; Cai, Mao-De ; Huang, Jia-Ling ; Liu, Ran-Yi ; Zhu, Zhen-Yu ; Qian, Chao-Nan ; Huang, Bi-Jun
descriptionAbstract Emerging evidence confirms that cancer stem cells (CSCs) are responsible for the chemoradioresistance of malignancies. EBV-encoded latent membrane protein 1 (LMP1) is associated with tumor relapse and poor prognosis of nasopharyngeal carcinoma (NPC). However, whether LMP1 induces the development of CSCs and the mechanism by which this rare cell subpopulation leads to radioresistance in NPC remain unclear. In the present study, LMP1-transformed NPC cells showed significant radioresistance compared to the empty vector control. We found that LMP1 up-regulated the expression of several stemness-related genes, increased the cell number of side population (SP) by flow cytometry analysis, enhanced the self-renewal properties of the cells in a spherical culture and enhanced the in vivo tumor initiation ability. We also found that LMP1 positively regulated the expression of the CSC marker CD44. The CD44+/High subpopulation of the LMP1-transformed NPC cells displayed more significant CSC characteristics than the CD44−/Low subpopulation of the LMP1-transformed NPC cells; these characteristics included the upregulation of stemness-related genes, in vitro self-renewal and in vivo tumor initiation ability. Importantly, the CD44+/High subpopulation displayed more radioresistance than the CD44−/Low subpopulation. Our results also demonstrated that phosphorylation of the DNA damage response (DDR) proteins, ATM, Chk1, Chk2 and p53, was inactivated in the LMP1-induced CD44+/High cells in response to DNA damage, and this was accompanied by a downregulation of the p53-targeted proapoptotic genes, which suggested that the inactivation of the p53-mediated apoptosis pathway was responsible for the radioresistance in the CD44+/High cells. Taken together, we found that LMP1 induced an increase in CSC-like CD44+/High cells, and we determined the molecular mechanism underlying the radioresistance of the LMP1-activated CSCs, highlighting the need of CSC-targeted radiotherapy in EBV-positive NPC.
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languageeng
publisherIreland: Elsevier Ireland Ltd
subjectAnalysis ; Animals ; Apoptosis ; Apoptosis - physiology ; Apoptosis - radiation effects ; Breast cancer ; Cancer ; Cancer stem cells (CSCs) ; Cancer therapies ; Carcinoma ; Deoxyribonucleic acid ; DNA ; DNA damage ; Epstein–Barr virus (EBV) ; Genetic research ; Grants ; Hematology, Oncology and Palliative Medicine ; Herpes viruses ; Herpesvirus 4, Human - metabolism ; Humans ; Infrared Rays ; Latent membrane protein 1 (LMP1) ; Metastasis ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mutation ; Nasopharyngeal Carcinoma ; Nasopharyngeal carcinoma (NPC) ; Nasopharyngeal Neoplasms - metabolism ; Nasopharyngeal Neoplasms - pathology ; Nasopharyngeal Neoplasms - radiotherapy ; Nasopharyngeal Neoplasms - virology ; Neoplastic Stem Cells - metabolism ; Neoplastic Stem Cells - radiation effects ; Neoplastic Stem Cells - virology ; p53 signalling pathway ; Phosphorylation ; Proteins ; Radiation therapy ; Radiation Tolerance ; Radioresistance ; Science ; Signal Transduction - radiation effects ; Tumor proteins ; Tumor Suppressor Protein p53 - antagonists & inhibitors ; Tumor Suppressor Protein p53 - metabolism ; Tumors ; Viral Matrix Proteins - biosynthesis ; Virus diseases
ispartofCancer letters, 2013, Vol.344 (2), p.260-271
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0Cancer stem-like cell characteristics induced by EB virus-encoded LMP1 contribute to radioresistance in nasopharyngeal carcinoma by suppressing the p53-mediated apoptosis pathway
1Cancer letters
addtitleCancer Lett
descriptionAbstract Emerging evidence confirms that cancer stem cells (CSCs) are responsible for the chemoradioresistance of malignancies. EBV-encoded latent membrane protein 1 (LMP1) is associated with tumor relapse and poor prognosis of nasopharyngeal carcinoma (NPC). However, whether LMP1 induces the development of CSCs and the mechanism by which this rare cell subpopulation leads to radioresistance in NPC remain unclear. In the present study, LMP1-transformed NPC cells showed significant radioresistance compared to the empty vector control. We found that LMP1 up-regulated the expression of several stemness-related genes, increased the cell number of side population (SP) by flow cytometry analysis, enhanced the self-renewal properties of the cells in a spherical culture and enhanced the in vivo tumor initiation ability. We also found that LMP1 positively regulated the expression of the CSC marker CD44. The CD44+/High subpopulation of the LMP1-transformed NPC cells displayed more significant CSC characteristics than the CD44−/Low subpopulation of the LMP1-transformed NPC cells; these characteristics included the upregulation of stemness-related genes, in vitro self-renewal and in vivo tumor initiation ability. Importantly, the CD44+/High subpopulation displayed more radioresistance than the CD44−/Low subpopulation. Our results also demonstrated that phosphorylation of the DNA damage response (DDR) proteins, ATM, Chk1, Chk2 and p53, was inactivated in the LMP1-induced CD44+/High cells in response to DNA damage, and this was accompanied by a downregulation of the p53-targeted proapoptotic genes, which suggested that the inactivation of the p53-mediated apoptosis pathway was responsible for the radioresistance in the CD44+/High cells. Taken together, we found that LMP1 induced an increase in CSC-like CD44+/High cells, and we determined the molecular mechanism underlying the radioresistance of the LMP1-activated CSCs, highlighting the need of CSC-targeted radiotherapy in EBV-positive NPC.
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8Cancer therapies
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34Neoplastic Stem Cells - radiation effects
35Neoplastic Stem Cells - virology
36p53 signalling pathway
37Phosphorylation
38Proteins
39Radiation therapy
40Radiation Tolerance
41Radioresistance
42Science
43Signal Transduction - radiation effects
44Tumor proteins
45Tumor Suppressor Protein p53 - antagonists & inhibitors
46Tumor Suppressor Protein p53 - metabolism
47Tumors
48Viral Matrix Proteins - biosynthesis
49Virus diseases
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titleCancer stem-like cell characteristics induced by EB virus-encoded LMP1 contribute to radioresistance in nasopharyngeal carcinoma by suppressing the p53-mediated apoptosis pathway
authorYang, Chang-Fu ; Peng, Li-Xia ; Huang, Tie-Jun ; Yang, Guang-Da ; Chu, Qiao-Qiao ; Liang, Ying-Ying ; Cao, Xue ; Xie, Ping ; Zheng, Li-Sheng ; Huang, Hong-Bing ; Cai, Mao-De ; Huang, Jia-Ling ; Liu, Ran-Yi ; Zhu, Zhen-Yu ; Qian, Chao-Nan ; Huang, Bi-Jun
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35Neoplastic Stem Cells - virology
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37Phosphorylation
38Proteins
39Radiation therapy
40Radiation Tolerance
41Radioresistance
42Science
43Signal Transduction - radiation effects
44Tumor proteins
45Tumor Suppressor Protein p53 - antagonists & inhibitors
46Tumor Suppressor Protein p53 - metabolism
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atitleCancer stem-like cell characteristics induced by EB virus-encoded LMP1 contribute to radioresistance in nasopharyngeal carcinoma by suppressing the p53-mediated apoptosis pathway
jtitleCancer letters
addtitleCancer Lett
date2013
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volume344
issue2
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pages260-271
issn0304-3835
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abstractAbstract Emerging evidence confirms that cancer stem cells (CSCs) are responsible for the chemoradioresistance of malignancies. EBV-encoded latent membrane protein 1 (LMP1) is associated with tumor relapse and poor prognosis of nasopharyngeal carcinoma (NPC). However, whether LMP1 induces the development of CSCs and the mechanism by which this rare cell subpopulation leads to radioresistance in NPC remain unclear. In the present study, LMP1-transformed NPC cells showed significant radioresistance compared to the empty vector control. We found that LMP1 up-regulated the expression of several stemness-related genes, increased the cell number of side population (SP) by flow cytometry analysis, enhanced the self-renewal properties of the cells in a spherical culture and enhanced the in vivo tumor initiation ability. We also found that LMP1 positively regulated the expression of the CSC marker CD44. The CD44+/High subpopulation of the LMP1-transformed NPC cells displayed more significant CSC characteristics than the CD44−/Low subpopulation of the LMP1-transformed NPC cells; these characteristics included the upregulation of stemness-related genes, in vitro self-renewal and in vivo tumor initiation ability. Importantly, the CD44+/High subpopulation displayed more radioresistance than the CD44−/Low subpopulation. Our results also demonstrated that phosphorylation of the DNA damage response (DDR) proteins, ATM, Chk1, Chk2 and p53, was inactivated in the LMP1-induced CD44+/High cells in response to DNA damage, and this was accompanied by a downregulation of the p53-targeted proapoptotic genes, which suggested that the inactivation of the p53-mediated apoptosis pathway was responsible for the radioresistance in the CD44+/High cells. Taken together, we found that LMP1 induced an increase in CSC-like CD44+/High cells, and we determined the molecular mechanism underlying the radioresistance of the LMP1-activated CSCs, highlighting the need of CSC-targeted radiotherapy in EBV-positive NPC.
copIreland
pubElsevier Ireland Ltd
pmid24262659
doi10.1016/j.canlet.2013.11.006