Astrocyte Elevated Gene-1 Upregulates Matrix Metalloproteinase-9 and Induces Human Glioma Invasion

Abstract

The poor prognosis of malignant gliomas is largely attributed to their highly invasive nature. The molecular mechanism underlying the invasiveness of glioma cells, however, remains to be elucidated. The present study found that astrocyte elevated gene-1 (AEG-1) was upregulated in human glioma cell lines and glioma tissues compared with normal astrocytes and brain tissues. AEG-1 was found to be upregulated in 265 of 296 (89.5%) glioma sections, and the AEG-1 expression level significantly correlated with clinicopathologic stages of gliomas. Ectopic expression or short hairpin RNA silencing of AEG-1 significantly enhanced or inhibited, respectively, the invasive ability of glioma cells. At the molecular level, we showed that upregulated AEG-1 in glioma cells interacted with matrix metalloproteinase-9 (MMP-9) promoter and transactivated MMP-9 expression, whereas knockdown of AEG-1 expression reduced the level of MMP-9. Two regions in MMP-9 promoter were found to be involved in the interaction with AEG-1. Suppression of endogenous MMP-9 abrogated the effects of AEG-1 on invasiveness. Consistent with these observations, immunostaining analysis revealed a significant correlation between the expressions of AEG-1 and MMP-9 in a cohort of clinical glioma samples. Moreover, intracranial xenografts of glioma cells engineered to express AEG-1 were highly invasive compared with the parental cells and expressed high level of MMP-9. Collectively, these findings provide evidence that AEG-1 contributes to glioma progression by enhancing MMP-9 transcription and, hence, tumor cell invasiveness, and underscore the importance of AEG-1 in glioma development and progression. Cancer Res; 70(9); 3750-9. ©2010 AACR.

Human Leucine Zipper Protein sLZIP Induces Migration and Invasion of Cervical Cancer Cells via Expression of Matrix Metalloproteinase-9

“…In general, MMP-9 expression is increased by oncogenic proteins and is elevated in many tumor types, including breast, prostate, and cervical cancers and gliomas, and the level of MMP-9 is correlated with the prognosis of clinical patients (1,17,42). Therefore, regulation of sLZIP expression is a potential therapeutic target for blocking the metastasis of tumor cells.…”

“…In contrast, MMP-2 is expressed constitutively in diverse cell types (10). Furthermore, up-regulation of MMP-9 expression contributes to the development of tumor progression, including angiogenesis (11,12) and invasion and metastasis (1,16,17). High levels of MMP-9 have been related to several inflammatory diseases, such as multiple sclerosis and rheumatoid arthritis (7,18), in addition to a variety of cancers, such as gliomas and breast and lung cancers (19 -21).…”

The brain tumor microenvironment

“…Gene expression and protein levels were elevated in several human brain tumors including malignant gliomas and suppression of AEG-1 activity diminished brain tumor growth in mice (Emdad et al, 2010). Reports suggest that the effects of AEG-1 on brain tumor invasion and metastasis involve the activities of MMP-2 and MMP-9 (Emdad et al, 2010;Liu et al, 2010).…”

Identification of Staphylococcal Nuclease Domain-containing 1 (SND1) as a Metadherin-interacting Protein with Metastasis-promoting Functions

“…MTDH has been shown to be a key functional target of the 8q22 genomic gain that is frequently observed in poor prognosis breast cancer patients (6). Beyond promoting experimental lung metastasis (3,6), multiple studies have implicated MTDH as a mediator of several cancer-related processes, such as oncogenesis and angiogenesis (7,8), invasion (9), chemoresistance (6, 10 -12), apoptosis resistance (13), and autophagy (14). Despite the abundance of MTDH phenotypes, a consensus understanding of its underlying molecular mechanisms has not yet been reached.…”