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Up-regulation of MMP-2 by HMGA1 Promotes Transformation in Undifferentiated, Large Cell Lung Cancer
Although lung cancer is the leading cause of cancer death worldwide, the precise molecular mechanisms that give rise to lung cancer are incompletely understood. Here, we demonstrate that HMGA1 is an important oncogene that drives transformation in undifferentiated, large cell carcinoma. First, we sh...
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Published in: | Molecular cancer research 2009-11, Vol.7 (11), p.1803-1812 |
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Main Authors: | , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
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Summary: | Although lung cancer is the leading cause of cancer death worldwide, the precise molecular mechanisms that give rise to lung cancer are incompletely understood. Here, we demonstrate that
HMGA1
is an important oncogene that drives transformation in undifferentiated, large cell carcinoma. First, we show that the
HMGA1
gene is overexpressed in lung cancer cell lines and primary human lung tumors. Forced overexpression of
HMGA1
induces a transformed phenotype with anchorage-independent cell growth in cultured lung cells derived from normal tissue. Conversely, inhibiting
HMGA1
expression blocks anchorage-independent cell growth in the H1299 metastatic, undifferentiated, large cell human lung carcinoma cells. We also demonstrate that the
matrix metalloproteinase-2
(
MMP-2
) gene is a downstream target up-regulated by HMGA1 in large cell carcinoma cells. In chromatin immunoprecipitation experiments, HMGA1 binds directly to the
MMP-2
promoter
in vivo
in large cell lung cancer cells, but not in squamous cell carcinoma cells. In large cell carcinoma cell lines, there is a significant, positive correlation between
HMGA1
and
MMP-2
mRNA. Moreover, interfering with
MMP-2
expression blocks anchorage-independent cell growth in H1299 large cell carcinoma cells, indicating that the HMGA1-MMP-2 pathway is required for this transformation phenotype in these cells. Blocking
MMP-2
expression also inhibits migration and invasion in the H1299 large cell carcinoma cells. Our findings suggest an important role for
MMP-2
in transformation mediated by HMGA1 in large cell, undifferentiated lung carcinoma and support the development of strategies to target this pathway in selected tumors. |
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ISSN: | 1541-7786 1557-3125 |
DOI: | 10.1158/1541-7786.MCR-08-0336 |