Cytoplasmic LIF reprograms invasive mode to enhance NPC dissemination through modulating YAP1-FAK/PXN signaling

Shu-Chen Liu (), Tien Hsu, Yu-Sun Chang, An-Ko Chung, Shih Sheng Jiang, Chun-Nan OuYang, Chiou-Hwa Yuh, Chuen Hsueh, Ya-Ping Liu and Ngan-Ming Tsang ()
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Shu-Chen Liu: National Central University
Tien Hsu: National Central University
Yu-Sun Chang: Chang Gung University
An-Ko Chung: Chang Gung University
Shih Sheng Jiang: National Health Research Institutes
Chun-Nan OuYang: Chang Gung University
Chiou-Hwa Yuh: National Health Research Institutes
Chuen Hsueh: Chang Gung Memorial Hospital at Lin-Kou
Ya-Ping Liu: Chang Gung University
Ngan-Ming Tsang: Chang Gung Memorial Hospital and University at Lin-Kou

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract Metastasis remains a clinically unsolved issue in nasopharyngeal carcinoma. Here, we report that higher levels of cytoplasmic leukemia inhibitory factor (LIF) and LIF receptor are correlated with poorer metastasis/recurrence-free survival. Further, single nucleotide variations and signal peptide mutation of LIF are identified in NPC. Cytoplasmic LIF reprograms the invasive mode from collective to mesenchymal migration via acquisition of EMT and invadopodia-associated characteristics. Higher cytoplasmic LIF enhances cancer vascular dissemination and local invasion mechanistically through modulation of YAP1-FAK/PXN signaling. Immunohistochemical analyses of NPC biopsies reveal a positive correlation of cytoplasmic LIF expression with focal adhesion kinases. Pharmaceutical intervention with AZD0530 markedly reverses LIF-mediated cancer dissemination and local invasion through promotion of cytoplasmic accumulation of YAP1 and suppression of focal adhesion kinases. Given the significant role of LIF/YAP1-focal adhesion signaling in cancer dissemination, targeting of this pathway presents a promising opportunity to block metastasis.

Date: 2018
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DOI: 10.1038/s41467-018-07660-6

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