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 8

EBV-encoded LMP1 activates LIF expression.

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EBV-encoded LMP1 activates LIF expression. (A) Assessment of LMP1-induce...
(A) Assessment of LMP1-induced upregulation of LIF mRNA in TW06 cells. Cells were transfected with various doses of LMP1-expressing or control vectors. (B) Quantification of secreted LIF in cell-free culture supernatants collected at 24 hours after transfection in TW06 cells. (C) Western blotting analysis of LIF and p-IκB in TW06 cells transfected with increasing doses of LMP1. Protein lysates were harvested at 24 hours after transfection. GAPDH was used as the loading control. (D–F) Mutations or deletion in the CTAR domains of LMP1 affect expression of LIF. Total RNA, culture supernatants, and protein lysates were harvested at 24 hours after transfection in TW06 cells. Relative LIF mRNA expression (D), secreted LIF (E), and LIF expression in protein lysates (F) were shown. mRNA expression was normalized to that of COL4A6 (Supplemental Table 3), which showed unchanged expression levels across NPC microarray experiments (GSE14262). GAPDH was used as the loading control of proteins. *P < 0.05; **P < 0.01, paired t test.