MMP-9 from sublethally irradiated tumor promotes Lewis lung carcinoma cell invasiveness and pulmonary metastasis
Journal
Oncogene
Journal Volume
31
Journal Issue
4
Pages
458 - 468
Date Issued
2012
Author(s)
Abstract
Matrix metalloproteinases (MMPs) associate with tumor progression and metastasis. We sought to investigate the role of MMP-9 from sublethally irradiated tumor in accelerated pulmonary metastasis of Lewis lung carcinoma (LLC-LM) and the corresponding anti-metastasis strategies in C57BL/6 mice. We used Matrigel-coated Boyden chamber assays and chicken chorioallantoic membrane assays to evaluate the invasion capability of irradiated LLC-LM cells (7.5 Gy), reverse transcription-polymerase chain reaction and the western blot assay to investigate the expression of MMPs by irradiated cells, and small interfering RNA duplexes to inhibit MMP-9 expression. LLC-LM cells differing in MMP-2 or-9 expression were subcutaneously injected into right thighs and the resulting tumors were irradiated (10 Gy × 5) to induce pulmonary metastasis. Radiation significantly enhanced MMP-9 at both the transcriptional and translational levels. MMP-9 siRNA significantly inhibited in vitro radiation-enhanced invasiveness. The number of radiation-accelerated pulmonary metastases was significantly reduced by MMP-9 knockdown and MMP-2/9 knockdown. Reverse transcription-polymerase chain reaction of LLC-LM cells in the blood and lung tissue revealed MMP-9 involvement in radiation-enhanced intravasation. Either higher-dose irradiation (30 Gy × 2) or pretreatment with prototypical MMP-9 inhibitor, zoledronic acid, significantly reduced the number of pulmonary metastases. The viability of irradiated tumor was seen on both positron emission tomography and magnetic resonance imaging, and tumor/serum MMP-9 levels suggested the association of local control of primary tumor and inhibition of time-dependent MMP-9 activities. Our results demonstrate that MMP-9 is crucially involved in radiation-enhanced LLC-LM cell invasiveness in vitro and in pulmonary metastasis from inadequately irradiated primary tumor in vivo. ? 2012 Macmillan Publishers Limited All rights reserved.
SDGs
Other Subjects
gelatinase A; gelatinase B; green fluorescent protein; small interfering RNA; zoledronic acid; animal cell; animal experiment; animal model; article; cancer invasion; cancer radiotherapy; carcinogenicity; cell cycle arrest; cell invasion; chorioallantois; controlled study; enzyme activity; in vitro study; in vivo study; inhibition kinetics; irradiation; Lewis carcinoma; lung metastasis; lung parenchyma; mouse; nonhuman; nuclear magnetic resonance imaging; positron emission tomography; priority journal; protein analysis; protein blood level; protein expression; reverse transcription polymerase chain reaction; transcription regulation; Western blotting; Animals; Carcinoma, Lewis Lung; Chick Embryo; Diphosphonates; Imidazoles; Lung Neoplasms; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Neoplasm Invasiveness; Mus
Type
journal article