MMP7-mediated cleavage of nucleolin at Asp255 induces MMP9 expression to promote tumor malignancy

T-I Hsu; S-C Lin; P-S Lu; W-C Chang; C-Y Hung; Y-M Yeh; W-C Su; P-C Liao; J-J Hung

doi:10.1038/onc.2014.22

MMP7-mediated cleavage of nucleolin at Asp255 induces MMP9 expression to promote tumor malignancy

Oncogene. 2015 Feb 12;34(7):826-37. doi: 10.1038/onc.2014.22. Epub 2014 Mar 17.

Authors

T-I Hsu¹, S-C Lin², P-S Lu², W-C Chang³, C-Y Hung⁴, Y-M Yeh⁵, W-C Su⁵, P-C Liao⁶, J-J Hung³

Affiliations

¹ 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.
² Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng-Kung University, Tainan, Taiwan.
³ 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.
⁴ Institute of Basic Medical Sciences, National Cheng-Kung University, Tainan, Taiwan.
⁵ Department of Internal Medicine, College of Medicine and Hospital, National Cheng-Kung University, Tainan, Taiwan.
⁶ Department of Environmental and Occupational Health, National Cheng-Kung University, Tainan, Taiwan.

PMID: 24632608
DOI: 10.1038/onc.2014.22

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.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Aged
Anaplastic Lymphoma Kinase
Animals
Autoantigens / genetics
Autoantigens / metabolism
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Female
Gene Expression Regulation, Enzymologic*
Gene Expression Regulation, Neoplastic*
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Kruppel-Like Factor 6
Kruppel-Like Transcription Factors / genetics
Kruppel-Like Transcription Factors / metabolism
Lung Neoplasms / genetics
Lung Neoplasms / metabolism*
Lung Neoplasms / pathology
Male
Matrix Metalloproteinase 7 / genetics
Matrix Metalloproteinase 7 / metabolism*
Matrix Metalloproteinase 9 / biosynthesis*
Matrix Metalloproteinase 9 / genetics
Mice
Mice, Nude
Neoplasm Metastasis
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Nucleolin
Phosphoproteins / genetics
Phosphoproteins / metabolism*
Proteins / genetics
Proteins / metabolism
Proteolysis*
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-cbl / genetics
Proto-Oncogene Proteins c-cbl / metabolism
RNA Stability / genetics
RNA, Messenger / genetics
RNA, Messenger / metabolism
RNA, Neoplasm / genetics
RNA, Neoplasm / metabolism
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism*
Receptor Protein-Tyrosine Kinases / genetics
Receptor Protein-Tyrosine Kinases / metabolism
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

Adaptor Proteins, Signal Transducing
Autoantigens
BRD4 protein, human
Cell Cycle Proteins
HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
KLF6 protein, human
Kruppel-Like Factor 6
Kruppel-Like Transcription Factors
Nuclear Proteins
PCM1 protein, human
Phosphoproteins
Proteins
Proto-Oncogene Proteins
RNA, Messenger
RNA, Neoplasm
RNA-Binding Proteins
TFG protein, human
Transcription Factors
CBLB protein, human
Proto-Oncogene Proteins c-cbl
ALK protein, human
Alk protein, mouse
Anaplastic Lymphoma Kinase
Receptor Protein-Tyrosine Kinases
MMP7 protein, human
Matrix Metalloproteinase 7
MMP9 protein, human
Matrix Metalloproteinase 9