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Cited by 184Head and Neck Cancer StudiesViral-associated cancers and disordersPI3K/AKT/mTOR signaling in cancer

Leukemia inhibitory factor promotes nasopharyngeal carcinoma progression and radioresistance

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Liu, Shu-Chen, Tsang, Ngan-Ming, Chiang, Wen-Che, Chang, Kai-Ping, Hsueh, Chuen, Liang, Ying, Juang, Jyh-Lyh, Chow, Kai-Ping N. +1 more·2013·Journal of Clinical Investigation
DOI 10.1172/jci63428PMC PMC3859424
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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.

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  • Levels of pY-STAT3 are increased in in vitro models and in patients with ionizing radiation-resistant tumors by IR at doses used for radiotherapy (≥2 Gy), contributing to selection of IR-resistant cells in many different cancers.

    “Levels of pY-STAT3 also are increased in in vitro models, as well as in patients with ionizing radiation (IR)–resistant tumors, by IR at doses used for radiotherapy (≥2 Gy), contributing to selection of IR-resistant cells in many different cancers (Ho et al., 2010; Liu et al., 2013; Pan et al., 2013; Yan et al., 2013; Gao et al., 2014; Klein et al., 2014; Lau et al., 2015; Zang et al., 2017; Lu et”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Liu et al., 2013

    The Figure 4 results (p. 7) show that LIF activates STAT3 Tyr705 in nasopharyngeal carcinoma cells, and the Figure 5 results (p. 9) show that LIF-treated cells survive irradiation doses including 2 and 4 Gy better than controls. The discussion (Figure 8, p. 13) links IR-induced cytokines and STAT3 signaling to acquired radioresistance. The paper does not show that irradiation itself raises pY-STAT3 in patients with resistant tumors, or establish that this mechanism selects resistant cells across many cancers. (LLM, conf=0.87)

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Cited by

Sorted by citations

Authors
Liu, S.-C., Tsang, N.-M., Chiang, W.-C., Chang, K.-P., Hsueh, C., Liang, Y., Juang, J.-L., Chow, K.-P. N., & Chang, Y.-S.
Affiliations
  • Chang Gung University (TW)
  • National Health Research Institutes (TW)
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2013-11-25
Volume
123
Issue
12
Pages
5269-5283
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci63428
PMC
PMC3859424
OpenAlex
W2119174526
Cited by
184
References
1
Citations by year
2026: 3 · 2025: 11 · 2024: 17 · 2023: 21 · 2022: 29 · 2021: 18 · 2020: 17 · 2019: 13 · 2018: 14 · 2017: 8 · 2016: 11 · 2015: 16 · 2014: 5 · 2013: 1
FWCI
10.00
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Chang Gung University
  • Chang Gung Medical Foundation
Topics
  • Health Sciences › Medicine › Otorhinolaryngology › Head and Neck Cancer Studies
  • Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
leukemia inhibitory factor, nasopharyngeal carcinoma, radioresistance (biology), Epstein-Barr virus, latent membrane protein 1, DNA damage response, rapamycin, tumor recurrence, serum biomarkers, radiosensitivity
MeSH terms
Mechanistic Target of Rapamycin Complex 1, Animals, Carcinoma, DNA Damage, Gamma Rays, Humans, Nasopharyngeal Neoplasms, Neoplasm Proteins, Neoplasm Recurrence, Local, Prognosis, Radiation Tolerance, Tumor Cells, Cultured, Viral Matrix Proteins, Signal Transduction, Gene Expression Regulation, Viral, Mice, SCID, Mice, Inbred NOD, Disease Progression, Sirolimus, Ribosomal Protein S6 Kinases, 70-kDa, Multiprotein Complexes, Mice, Leukemia Inhibitory Factor, Receptors, OSM-LIF, TOR Serine-Threonine Kinases, Tumor Microenvironment, Heterografts

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