MMP7-mediated cleavage of nucleolin at Asp255 induces MMP9 expression to promote tumor malignancy
Authors: T-I Hsu
C-Y Hung
W-C Chang
S-C Lin
W-C Su
P-S Lu
P-C Liao
J-J Hung
Y-M Yeh
Journal: Oncogene (2015)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Nucleolin; Tumor development; Lung cancer; Epidermal growth factor receptor pathway; Matrix metalloproteinase 7
Affiliations: 1] Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng-Kung University, Tainan, Taiwan [2] Center for Infection Disease and Signal Transduction, National Cheng-Kung University, Tainan, Taiwan., Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng-Kung University, Tainan, Taiwan., 1] Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng-Kung University, Tainan, Taiwan [2] Center for Infection Disease and Signal Transduction, National Cheng-Kung University, Tainan, Taiwan [3] Institute of Basic Medical Sciences, National Cheng-Kung University, Tainan, Taiwan [4] Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan, Taiwan [5] Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan., Institute of Basic Medical Sciences, National Cheng-Kung University, Tainan, Taiwan., Department of Internal Medicine, College of Medicine and Hospital, National Cheng-Kung University, Tainan, Taiwan., Department of Environmental and Occupational Health, National Cheng-Kung University, Tainan, Taiwan.

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. 

Retracted: No

PubPeer comments:
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 The link above does not appear to lead to the correct correction, so here is a new link: https: www.nature.com articles onc2016274 The correction reads:  The authors were recently made aware of some confusion regarding Figure 4 in this publication. In Figure 4, the authors provide two groups images of NCL and MMP7 from the same mice but consecutive sections. However, the labeling has led some readers to incorrectly conclude that images of NCL and MMP7 are from two different mice. Please see a relabeled image and new figure legend for clarification. Here is the original Figure 4b, as reported to the journal in July 2015, with a duplication marked with blue boxes. Note the different color balance of the two panels. ![file] I am not sure why the authors put the confusion-blame on  some readers . The original labeling clearly suggests that the samples are from different mice, which is strengthened by the text of the legend of Figure 4b, which reads  NCL and MMP7 expression levels in lung tumor tissues of K-rasG12D lung cancer mice. (plural). ,