Leukemia inhibitory factor promotes nasopharyngeal carcinoma progression and radioresistance
Radioresistance of EBV-associated nasopharyngeal carcinoma (NPC) is associated with poor prognosis for patients with this form of cancer. Here, we found that NPC patients had increased serum levels of leukemia inhibitory factor (LIF) and that higher LIF levels correlated with local tumor recurrence....
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| Published in | The Journal of clinical investigation Vol. 123; no. 12; pp. 5269 - 5283 |
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| Main Authors | , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Society for Clinical Investigation
01.12.2013
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| Subjects | |
| Online Access | Get full text |
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| Abstract | Radioresistance of EBV-associated nasopharyngeal carcinoma (NPC) is associated with poor prognosis for patients with this form of cancer. Here, we found that NPC patients had increased serum levels of leukemia inhibitory factor (LIF) and that higher LIF levels correlated with local tumor recurrence. Furthermore, in vitro studies with NPC cells and in vivo xenograft mouse studies demonstrated that LIF critically contributes to NPC tumor growth and radioresistance. Using these model systems, we found that LIF treatment activated the mTORC1/p70S6K signaling pathway, enhanced tumor growth, inhibited DNA damage responses, and enhanced radioresistance. Treatment with either soluble LIF receptor (sLIFR), a LIF antagonist, or the mTOR inhibitor rapamycin reversed LIF-mediated effects, resulting in growth arrest and increased sensitivity to γ irradiation. Immunohistochemical (IHC) analyses of human NPC biopsies revealed that LIF and LIFR were overexpressed in tumor cells and that LIF expression correlated with the presence of the activated p-p70S6K. Finally, we found that the EBV-encoded protein latent membrane protein 1 (LMP1) enhances LIF production. Together, our findings indicate that LIF promotes NPC tumorigenesis and suggest that serum LIF levels may predict local recurrence and radiosensitivity in NPC patients. |
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| AbstractList | Radioresistance of EBV-associated nasopharyngeal carcinoma (NPC) is associated with poor prognosis for patients with this form of cancer. Here, we found that NPC patients had increased serum levels of leukemia inhibitory factor (LIF) and that higher LIF levels correlated with local tumor recurrence. Furthermore, in vitro studies with NPC cells and in vivo xenograft mouse studies demonstrated that LIF critically contributes to NPC tumor growth and radioresistance. Using these model systems, we found that LIF treatment activated the mTORC1/p70S6K signaling pathway, enhanced tumor growth, inhibited DNA damage responses, and enhanced radioresistance. Treatment with either soluble LIF receptor (sLIFR), a LIF antagonist, or the mTOR inhibitor rapamycin reversed LIF-mediated effects, resulting in growth arrest and increased sensitivity to γ irradiation. Immunohistochemical (IHC) analyses of human NPC biopsies revealed that LIF and LIFR were overexpressed in tumor cells and that LIF expression correlated with the presence of the activated p-p70S6K. Finally, we found that the EBV-encoded protein latent membrane protein 1 (LMP1) enhances LIF production. Together, our findings indicate that LIF promotes NPC tumorigenesis and suggest that serum LIF levels may predict local recurrence and radiosensitivity in NPC patients. Radioresistance of EBV-associated nasopharyngeal carcinoma (NPC) is associated with poor prognosis for patients with this form of cancer. Here, we found that NPC patients had increased serum levels of leukemia inhibitory factor (LIF) and that higher LIF levels correlated with local tumor recurrence. Furthermore, in vitro studies with NPC cells and in vivo xenograft mouse studies demonstrated that LIF critically contributes to NPC tumor growth and radioresistance. Using these model systems, we found that LIF treatment activated the mTORC1/p70S6K signaling pathway, enhanced tumor growth, inhibited DNA damage responses, and enhanced radioresistance. Treatment with either soluble LIF receptor (sLIFR), a LIF antagonist, or the mTOR inhibitor rapamycin reversed LIF-mediated effects, resulting in growth arrest and increased sensitivity to ? irradiation. Immunohistochemical (IHC) analyses of human NPC biopsies revealed that LIF and LIFR were overexpressed in tumor cells and that LIF expression correlated with the presence of the activated p-p70S6K. Finally, we found that the EBV-encoded protein latent membrane protein 1 (LMP1) enhances LIF production. Together, our findings indicate that LIF promotes NPC tumorigenesis and suggest that serum LIF levels may predict local recurrence and radiosensitivity in NPC patients. [PUBLICATION ABSTRACT] Radioresistance of EBV-associated nasopharyngeal carcinoma (NPC) is associated with poor prognosis for patients with this form of cancer. Here, we found that NPC patients had increased serum levels of leukemia inhibitory factor (LIF) and that higher LIF levels correlated with local tumor recurrence. Furthermore, in vitro studies with NPC cells and in vivo xenograft mouse studies demonstrated that LIF critically contributes to NPC tumor growth and radioresistance. Using these model systems, we found that LIF treatment activated the mTORC1/p70S6K signaling pathway, enhanced tumor growth, inhibited DNA damage responses, and enhanced radioresistance. Treatment with either soluble LIF receptor (sLIFR), a LIF antagonist, or the mTOR inhibitor rapamycin reversed LIF-mediated effects, resulting in growth arrest and increased sensitivity to γ irradiation. Immunohistochemical (IHC) analyses of human NPC biopsies revealed that LIF and LIFR were overexpressed in tumor cells and that LIF expression correlated with the presence of the activated p-p70S6K. Finally, we found that the EBV-encoded protein latent membrane protein 1 (LMP1) enhances LIF production. Together, our findings indicate that LIF promotes NPC tumorigenesis and suggest that serum LIF levels may predict local recurrence and radiosensitivity in NPC patients.Radioresistance of EBV-associated nasopharyngeal carcinoma (NPC) is associated with poor prognosis for patients with this form of cancer. Here, we found that NPC patients had increased serum levels of leukemia inhibitory factor (LIF) and that higher LIF levels correlated with local tumor recurrence. Furthermore, in vitro studies with NPC cells and in vivo xenograft mouse studies demonstrated that LIF critically contributes to NPC tumor growth and radioresistance. Using these model systems, we found that LIF treatment activated the mTORC1/p70S6K signaling pathway, enhanced tumor growth, inhibited DNA damage responses, and enhanced radioresistance. Treatment with either soluble LIF receptor (sLIFR), a LIF antagonist, or the mTOR inhibitor rapamycin reversed LIF-mediated effects, resulting in growth arrest and increased sensitivity to γ irradiation. Immunohistochemical (IHC) analyses of human NPC biopsies revealed that LIF and LIFR were overexpressed in tumor cells and that LIF expression correlated with the presence of the activated p-p70S6K. Finally, we found that the EBV-encoded protein latent membrane protein 1 (LMP1) enhances LIF production. Together, our findings indicate that LIF promotes NPC tumorigenesis and suggest that serum LIF levels may predict local recurrence and radiosensitivity in NPC patients. Radioresistance of EBV-associated nasopharyngeal carcinoma (NPC) is associated with poor prognosis for patients with this form of cancer. Here, we found that NPC patients had increased serum levels of leukemia inhibitory factor (LIF) and that higher LIF levels correlated with local tumor recurrence. Furthermore, in vitro studies with NPC cells and in vivo xenograft mouse studies demonstrated that LIF critically contributes to NPC tumor growth and radioresistance. Using these model systems, we found that LIF treatment activated the mTORC1/p70S6K signaling pathway, enhanced tumor growth, inhibited DNA damage responses, and enhanced radioresistance. Treatment with either soluble LIF receptor (sLIFR), a LIF antagonist, or the mTOR inhibitor rapamycin reversed LIF-mediated effects, resulting in growth arrest and increased sensitivity to ? irradiation. Immunohistochemical (IHC) analyses of human NPC biopsies revealed that LIF and LIFR were overexpressed in tumor cells and that LIF expression correlated with the presence of the activated p-p70S6K. Finally, we found that the EBV-encoded protein latent membrane protein 1 (LMP1) enhances LIF production. Together, our findings indicate that LIF promotes NPC tumorigenesis and suggest that serum LIF levels may predict local recurrence and radiosensitivity in NPC patients. |
| Audience | Academic |
| Author | Tsang, Ngan-Ming Chiang, Wen-Che Chang, Kai-Ping Chang, Yu-Sun Hsueh, Chuen Liu, Shu-Chen Chow, Kai-Ping N. Juang, Jyh-Lyh Liang, Ying |
| AuthorAffiliation | 1 Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan. 2 Department of Radiation Oncology, Chang Gung Memorial Hospital at Lin-Kou, School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan. 3 Department of Otolaryngology, Head and Neck Surgery, and 4 Department of Pathology, Chang Gung Memorial Hospital at Lin-Kou, Taoyuan, Taiwan. 5 Division of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan. 6 Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, School of Medicine, and 7 Graduate Institute of Basic Medical Sciences, Chang-Gung University, Taoyuan, Taiwan |
| AuthorAffiliation_xml | – name: 1 Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan. 2 Department of Radiation Oncology, Chang Gung Memorial Hospital at Lin-Kou, School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan. 3 Department of Otolaryngology, Head and Neck Surgery, and 4 Department of Pathology, Chang Gung Memorial Hospital at Lin-Kou, Taoyuan, Taiwan. 5 Division of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan. 6 Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, School of Medicine, and 7 Graduate Institute of Basic Medical Sciences, Chang-Gung University, Taoyuan, Taiwan |
| Author_xml | – sequence: 1 givenname: Shu-Chen surname: Liu fullname: Liu, Shu-Chen – sequence: 2 givenname: Ngan-Ming surname: Tsang fullname: Tsang, Ngan-Ming – sequence: 3 givenname: Wen-Che surname: Chiang fullname: Chiang, Wen-Che – sequence: 4 givenname: Kai-Ping surname: Chang fullname: Chang, Kai-Ping – sequence: 5 givenname: Chuen surname: Hsueh fullname: Hsueh, Chuen – sequence: 6 givenname: Ying surname: Liang fullname: Liang, Ying – sequence: 7 givenname: Jyh-Lyh surname: Juang fullname: Juang, Jyh-Lyh – sequence: 8 givenname: Kai-Ping N. surname: Chow fullname: Chow, Kai-Ping N. – sequence: 9 givenname: Yu-Sun surname: Chang fullname: Chang, Yu-Sun |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/24270418$$D View this record in MEDLINE/PubMed |
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| Copyright | COPYRIGHT 2013 American Society for Clinical Investigation Copyright American Society for Clinical Investigation Dec 2013 Copyright © 2013, American Society for Clinical Investigation 2013 |
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| Snippet | Radioresistance of EBV-associated nasopharyngeal carcinoma (NPC) is associated with poor prognosis for patients with this form of cancer. Here, we found that... |
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| SubjectTerms | Animals Apoptosis Biomedical research Carcinoma - blood Carcinoma - pathology Carcinoma - radiotherapy Cytokines Deoxyribonucleic acid Development and progression Disease Progression DNA DNA Damage DNA repair Gamma Rays Gene Expression Regulation, Viral Heterografts Humans Leukemia Leukemia Inhibitory Factor - antagonists & inhibitors Leukemia Inhibitory Factor - blood Leukemia Inhibitory Factor - physiology Mechanistic Target of Rapamycin Complex 1 Medical prognosis Mice Mice, Inbred NOD Mice, SCID Multiprotein Complexes - physiology Nasopharyngeal cancer Nasopharyngeal Neoplasms - blood Nasopharyngeal Neoplasms - pathology Nasopharyngeal Neoplasms - radiotherapy Neoplasm Proteins - antagonists & inhibitors Neoplasm Proteins - blood Neoplasm Proteins - physiology Neoplasm Recurrence, Local - blood Prognosis Radiation Tolerance Radiotherapy Receptors, OSM-LIF Ribosomal Protein S6 Kinases, 70-kDa - physiology Signal Transduction - physiology Sirolimus - pharmacology TOR Serine-Threonine Kinases - physiology Tumor Cells, Cultured Tumor Microenvironment Tumors Viral Matrix Proteins - physiology |
| Title | Leukemia inhibitory factor promotes nasopharyngeal carcinoma progression and radioresistance |
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