title: MMP7-mediated cleavage of nucleolin at Asp255 induces MMP9 expression to promote tumor malignancy.
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.
authors.affiliation: 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.
authors.forename: T-I
authors.initials: TI
authors.lastname: Hsu
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: S-C
authors.initials: SC
authors.lastname: Lin
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: P-S
authors.initials: PS
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: W-C
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Institute of Basic Medical Sciences, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Hung
authors.affiliation: Department of Internal Medicine, College of Medicine and Hospital, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: Y-M
authors.initials: YM
authors.lastname: Yeh
authors.affiliation: Department of Internal Medicine, College of Medicine and Hospital, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: W-C
authors.initials: WC
authors.lastname: Su
authors.affiliation: Department of Environmental and Occupational Health, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: P-C
authors.initials: PC
authors.lastname: Liao
authors.affiliation: 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.
authors.forename: J-J
authors.initials: JJ
authors.lastname: Hung
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000097796:Nucleolin; D000092468:Bromodomain Containing Proteins; D033921:Vesicular Transport Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000077548:Anaplastic Lymphoma Kinase; D001324:Autoantigens; D018797:Cell Cycle Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D020783:Matrix Metalloproteinase 7; D020780:Matrix Metalloproteinase 9; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D050721:Proto-Oncogene Proteins c-cbl; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016601:RNA-Binding Proteins; D020794:Receptor Protein-Tyrosine Kinases; D014157:Transcription Factors; D000097796:Nucleolin; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C497442:HIF1A protein, human; C105465:KLF6 protein, human; C086074:PCM1 protein, human; C096163:TFG protein, human; D033921:Vesicular Transport Proteins; C492211:CBLB protein, human; C000626173:ALK protein, human; C000626174:Alk protein, mouse; C060932:MMP7 protein, human; C579270:MMP9 protein, human