Leukemia inhibitory factor promotes nasopharyngeal carcinoma progression and radioresistance
Shu-Chen Liu, … , Kai-Ping N. Chow, Yu-Sun Chang
Shu-Chen Liu, … , Kai-Ping N. Chow, Yu-Sun Chang
Published November 25, 2013
Citation Information: J Clin Invest. 2013;123(12):5269-5283. https://doi.org/10.1172/JCI63428.
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Research Article

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

Shu-Chen Liu, Ngan-Ming Tsang, Wen-Che Chiang, Kai-Ping Chang, Chuen Hsueh, Ying Liang, Jyh-Lyh Juang, Kai-Ping N. Chow, Yu-Sun Chang

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Figure 2

Assessment of LIF-stimulated cell proliferation in NPC cells.

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Assessment of LIF-stimulated cell proliferation in NPC cells. (A) Real-t...
(A) Real-time cell proliferation assays of TW06 cells treated with LIF, sLIFR, or PBS (control). sLIFR (1 μg/ml) was added to the growth medium of TW06 cells 2 hours prior to LIF treatment. Black arrows indicate the time at which LIF and sLIFR were added. Values are presented as means and SD of triplicate experiments. (B) Analysis of EdU incorporation in CNE1 cells treated with PBS, LIF, sLIFR, or sLIFR plus LIF for 24 hours, followed by EdU labeling for 3 hours. EdU+ cells were quantified using ImageJ software. Overall P < 0.001, 1-way ANOVA; *P < 0.05; **P < 0.01; ***P < 0.001, Bonferroni’s multiple comparison test. Scale bar: 50 μm. (C) Bioluminescent images of NPC tumor xenografts treated with PBS, LIF, or sLIFR. Images were first detected on the seventh day after implantation of TW06_Luc2 cells. Drug administration was started on the eighth day after implantation and continued twice per week for 6 weeks. (D) Quantification of the total photon fluxes from the tumors shown in C. *P < 0.05; **P < 0.01, paired t test, compared with PBS-treated group. Values are presented as means and SEM (n = 5 mice per group).