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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

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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.

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 1

LIF levels in clinical samples from NPC patients and LIF and LIFR expression levels in NPC biopsy sections.

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LIF levels in clinical samples from NPC patients and LIF and LIFR expres...
(A) Detection of serum LIF levels in NPC patients with complete remission or recurrence. Significantly higher LIF levels were detected in NPC patients that developed recurrence. ***P < 0.0001, Mann-Whitney test. (B and C) Kaplan–Meier survival curves of NPC patients based on serum LIF levels. (B) Local recurrence-free survival. (C) Progression-free survival. (D) LIF concentration in paired biopsy samples (n = 10). LIF levels were detected using magnetic bead–based cytokine assay. (E) Analysis of LIF protein levels in adjacent normal nasopharyngeal tissues and NPC biopsies. ***P < 0.0001, Mann-Whitney test. (F–I) IHC analyses of LIF and LIFR expression in paraffin-embedded consecutive NPC tissue sections. Representative images of LIF expression (F) and LIFR expression (H) in NPC tumors. Statistical analysis of LIF expression (G) and LIFR expression (I) in NPC tumor tissues and adjacent normal epithelium. **P < 0.01; ***P < 0.0001, χ2 test. Scale bar: 50 μm. (J) Western blotting analysis of LIFR, LIF, and LMP1 in NPC biopsy samples. Normal NP, adjacent normal tissues. GAPDH was used as a loading control.
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