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 7

LIF enhances the radioresistance of NPC xenografts.

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LIF enhances the radioresistance of NPC xenografts. (A) TW06_Luc2 xenogr...
(A) TW06_Luc2 xenografts were subjected to a single dose of 7 Gy, and tumor growth was monitored using IVIS. The tumors were intratumorally injected with PBS, LIF, or sLIFR prior to irradiation and thereafter (LIF: 150–200 ng/20 μl PBS, twice/week × 4 weeks; sLIFR: 1–2 μg/20 μl PBS, twice/week × 4 weeks). (B) Quantification of the total photon fluxes of tumors shown in A. *P < 0.05, paired t test, compared with the PBS-treated group. (C) CNE1_Luc2_GFP cells and CNE1_Luc2_sLIFR cells, which stably expressed GFP and sLIFR, respectively, were subcutaneously inoculated into legs of NOD/SCID mice and tumor responses to 7-Gy irradiation were assessed by IVIS. (D) Quantification of the total photon fluxes of tumors shown in C (*P < 0.05; **P < 0.01; paired t test). (E) Administration of rapamycin reduces LIF-mediated radioresistance. Rapamycin was given by intraperitoneal injection (3 mg/kg, once a day, 5 days/week × 3 weeks). n = 6 for each group. (F) Quantification of the total photon fluxes of tumors shown in E. *P < 0.05; **P < 0.01; paired t test.