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

Tai I. Hsu, S. C. Lin, P. S. Lu, Wen-Chang Chang, C. Y. Hung, Y. M. Yeh, Wu Chou Su, Pao Chi Liao, Jan Jong Hung

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)826-837
Number of pages12
JournalOncogene
Volume34
Issue number7
DOIs
Publication statusPublished - Feb 12 2015

Fingerprint

Neoplasms
Lung Neoplasms
RNA Stability
nucleolin
Matrix Metalloproteinase 7
3' Untranslated Regions
Ribosomal DNA
Oncogenes
Epidermal Growth Factor Receptor
Extracellular Matrix
Carcinogenesis
Neoplasm Metastasis
Messenger RNA
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics
  • Medicine(all)

Cite this

MMP7-mediated cleavage of nucleolin at Asp255 induces MMP9 expression to promote tumor malignancy. / Hsu, Tai I.; Lin, S. C.; Lu, P. S.; Chang, Wen-Chang; Hung, C. Y.; Yeh, Y. M.; Su, Wu Chou; Liao, Pao Chi; Hung, Jan Jong.

In: Oncogene, Vol. 34, No. 7, 12.02.2015, p. 826-837.

Research output: Contribution to journalArticle

Hsu, TI, Lin, SC, Lu, PS, Chang, W-C, Hung, CY, Yeh, YM, Su, WC, Liao, PC & Hung, JJ 2015, 'MMP7-mediated cleavage of nucleolin at Asp255 induces MMP9 expression to promote tumor malignancy', Oncogene, vol. 34, no. 7, pp. 826-837. https://doi.org/10.1038/onc.2014.22
Hsu, Tai I. ; Lin, S. C. ; Lu, P. S. ; Chang, Wen-Chang ; Hung, C. Y. ; Yeh, Y. M. ; Su, Wu Chou ; Liao, Pao Chi ; Hung, Jan Jong. / MMP7-mediated cleavage of nucleolin at Asp255 induces MMP9 expression to promote tumor malignancy. In: Oncogene. 2015 ; Vol. 34, No. 7. pp. 826-837.
@article{7a1032e314274bf481d5c9011e4650ce,
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.",
author = "Hsu, {Tai I.} and Lin, {S. C.} and Lu, {P. S.} and Wen-Chang Chang and Hung, {C. Y.} and Yeh, {Y. M.} and Su, {Wu Chou} and Liao, {Pao Chi} and Hung, {Jan Jong}",
year = "2015",
month = "2",
day = "12",
doi = "10.1038/onc.2014.22",
language = "English",
volume = "34",
pages = "826--837",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "7",

}

TY - JOUR

T1 - MMP7-mediated cleavage of nucleolin at Asp255 induces MMP9 expression to promote tumor malignancy

AU - Hsu, Tai I.

AU - Lin, S. C.

AU - Lu, P. S.

AU - Chang, Wen-Chang

AU - Hung, C. Y.

AU - Yeh, Y. M.

AU - Su, Wu Chou

AU - Liao, Pao Chi

AU - Hung, Jan Jong

PY - 2015/2/12

Y1 - 2015/2/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84927169770&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84927169770&partnerID=8YFLogxK

U2 - 10.1038/onc.2014.22

DO - 10.1038/onc.2014.22

M3 - Article

VL - 34

SP - 826

EP - 837

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 7

ER -