Abstract
Nucleolin (NCL) participates in DNA transcription, ribosomal biogenesis and the regulation of RNA stability. However, the contribution of NCL to tumor development is still not clear. Herein, we found that NCL expression correlated with poor prognosis in lung cancer patients. Overexpressed NCL was predominantly cleaved to C-terminal truncated NCL (TNCL). In lung cancer formation, activation of the epidermal growth factor receptor pathway induced NCL expression, and also the expression of matrix metalloproteinase (MMP) 7, which then cleaved NCL at Asp255 to generate TNCL of 55 kDa. TNCL increased the expression of several oncogenes, including MMP9, anaplastic lymphoma kinase (ALK), HIF1a and CBLB, and decreased the expression of tumor suppressors including BRD4, PCM1, TFG and KLF6 by modulating mRNA stability through binding to the 3’-untranslated regions of their transcripts, thus ultimately enhancing metastasis activity. In conclusion, this study identified a novel role of the cleavage form of NCL generated by MMP7 in stabilizing MMP9 mRNA. We also provide a new insight that MMP7 not only cleaves the extracellular matrix to promote tumor invasion but also cleaves NCL, which augment oncogenesis. Blocking NCL cleavage may provide a useful new strategy for lung cancer therapy.
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Acknowledgements
This work was supported by the National Cheng-Kung University project of the Program for Promoting Academic Excellence and Developing World Class Research Centers, together with grants 100-2320-B-038-032-MY3 and NSC101-2321-B-006-004-MY3 obtained from the National Science Council, Taiwan. This work was also supported by the Food and Drug Administration, Ministry of Health and Welfare, Executive Yuan, Taiwan (Grants DOH102-TD-TB-111-NSC101). This research received funding from the Headquarters of University Advancement at the National Cheng-Kung University, which is sponsored by the Ministry of Education, Taiwan. We are grateful for the support from the Tissue Bank, Research Center of Clinical Medicine, National Cheng-Kung University Hospital.
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Hsu, TI., Lin, SC., Lu, PS. et al. MMP7-mediated cleavage of nucleolin at Asp255 induces MMP9 expression to promote tumor malignancy. Oncogene 34, 826–837 (2015). https://doi.org/10.1038/onc.2014.22
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DOI: https://doi.org/10.1038/onc.2014.22
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