title: Leukemia inhibitory factor promotes nasopharyngeal carcinoma progression and radioresistance.
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.
authors.forename: Shu-Chen
authors.initials: SC
authors.lastname: Liu
authors.forename: Ngan-Ming
authors.initials: NM
authors.lastname: Tsang
authors.forename: Wen-Che
authors.initials: WC
authors.lastname: Chiang
authors.forename: Kai-Ping
authors.initials: KP
authors.lastname: Chang
authors.forename: Chuen
authors.initials: C
authors.lastname: Hsueh
authors.forename: Ying
authors.initials: Y
authors.lastname: Liang
authors.forename: Jyh-Lyh
authors.initials: JL
authors.lastname: Juang
authors.forename: Kai-Ping N
authors.initials: KP
authors.lastname: Chow
authors.forename: Yu-Sun
authors.initials: YS
authors.lastname: Chang
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000097:blood / Q000473:pathology* / Q000532:radiotherapy; D004249:DNA Damage; D018450:Disease Progression; D005720:Gamma Rays; D015967:Gene Expression Regulation, Viral; D064593:Heterografts; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D046912:Multiprotein Complexes / Q000502:physiology; D009303:Nasopharyngeal Neoplasms / Q000097:blood / Q000473:pathology* / Q000532:radiotherapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*; D009364:Neoplasm Recurrence, Local / Q000097:blood; D011379:Prognosis; D011836:Radiation Tolerance; D053606:Receptors, OSM-LIF; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D014763:Viral Matrix Proteins / Q000502:physiology
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D053605:Leukemia Inhibitory Factor; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D053606:Receptors, OSM-LIF; D014763:Viral Matrix Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus