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  • Original Article
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A targetable HB-EGF–CITED4 axis controls oncogenesis in lung cancer

Abstract

Aberrant epidermal growth factor (EGF) receptor (EGFR) signaling contributes to neoplastic initiation and progression in lung. Mutated EGFR has become as an important therapeutic target in lung cancer, whereas targeted treatment is not available for wild-type EGFR or its ligands. In this study, we found that heparin-binding (HB)-EGF, a member of the EGF family, was highly expressed in a subset of lung cancer, proliferation of which was dependent on HB-EGF signaling. Silencing of HB-EGF with RNA interference inhibited cell cycle progression in lung cancer cells. We observed that, upon HB-EGF induction, CITED4 was induced through a signal transducer and activator of transcription 3 (STAT3)-dependent pathway, regulating cell proliferation. CITED4 interacted with MYC and potentiated MYC-mediated transactivation of the CCND1 promoter, leading to cell cycle progression. Correlation analysis revealed that HB-EGF and CITED4 were significantly positively associated in primary lung tumors, and expression of HB-EGF predicted a poor survival outcome in patients. In vitro and in vivo experiments revealed that pharmacological inhibition of HB-EGF with CRM197 significantly attenuated tumor cell growth. Thus, CITED4 functions as a molecular switch in HB-EGF-induced growth control, and HB-EGF provides a novel therapeutic target for lung cancer intervention.

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Acknowledgements

This research was supported by National Yang-Ming University, National Tsing Hua University, the Institute of Biomedical Sciences, Academia Sinica and the Ministry of Science and Technology (MOST104-2321-B-010-007 and MOST103-2320-B-007-006-MY3), Executive Yuan, Taiwan, ROC.

Author contributions

C-HH performed the experiments, analyzed the data and wrote the manuscript. Y-TC designed the experiments, collected the data, conducted the interpretation of data and wrote the manuscript. M-HK analyzed the public domain data. H-PT provided the clinical samples. J-LC scored the RISH result of clinical samples. C-WW supervised this study.

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Correspondence to Y-T Chou or C-W Wu.

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Hsieh, CH., Chou, YT., Kuo, MH. et al. A targetable HB-EGF–CITED4 axis controls oncogenesis in lung cancer. Oncogene 36, 2946–2956 (2017). https://doi.org/10.1038/onc.2016.465

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