PTEN gene transfer suppresses the invasive potential of human malignant gliomas by regulating cell invasion-related molecules

Furukawa, Koji; Kumon, Yoshiaki; Harada, Hironobu; Kohno, Shohei; Nagato, Shigeyuki; Teraoka, Mikio; Fujiwara, Satoshi; Nakagawa, Kou; Hamada, Katsuyuki; Ohnishi, Takanori

doi:10.3892/ijo.29.1.73

Cited by 24 publications

(21 citation statements)

References 28 publications

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“…Although some studies emphasized the importance of both MMP-2 and MMP-9 in glioma invasion (35), our experiments revealed no alteration of secreted MMP-9 levels in U373MG after treatment with DFO and/or topotecan. This may be explained by the fact that we detected very low MMP-9 concentrations in untreated U373MG indicating that MMP-9 may not essentially be utilized by this cell line for degradation-dependent mechanisms.…”

Section: Discussioncontrasting

confidence: 71%

Involvement of Hif-1 in desferrioxamine-induced invasion of glioblastoma cells

Elstner

Holtkamp

Deimling

2007

Clin Exp Metastasis

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Glioblastoma multiforme are highly invasive brain tumors. Experimental approaches focus on unravelling the mechanisms of invasion, this being a major reason for the poor prognosis of these tumors. Our previous results hinted towards involvement of the iron metabolism in invasion. In this study, we examined the effect of iron depletion on the invasive phenotype of glioblastoma cells. Transwell Matrigel invasion assays were used to monitor iron-dependent invasion of human glioblastoma cell lines U373MG and DBTRG05MG. Intracellular iron concentrations were modulated by applying desferrioxamine (DFO) and ferric ammonium citrate (FAC). We detected enhanced invasion of glioblastoma cells upon DFO-induced iron depletion. Treatment of cells with FAC strongly inhibited invasion. DFO treatment resulted in hypoxia-inducible factor 1 (Hif-1)-mediated induction of urokinase plasminogen activator receptor and matrix metalloproteinase 2. Further, RNA interference-mediated repression of urokinase plasminogen activator receptor inhibited DFO-induced invasion. Our data demonstrate a direct effect of DFO on Hif-1 expression resulting in activation of factors associated with ECM degradation and invasion of glioma cells. These findings caution on utilization of DFO and other iron chelators in the treatment of tumors with invasive potential.

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Section: Discussioncontrasting

confidence: 71%

Involvement of Hif-1 in desferrioxamine-induced invasion of glioblastoma cells

Elstner

Holtkamp

Deimling

2007

Clin Exp Metastasis

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“…The invasiveness of aggressive cancer cells is in part determined by the proteolytic activity of MMPs and reflects the capacity of these enzymes to degrade the ECM (6)(7)(8)(9). Accumulating evidence has shown that PTEN reduces the expression of MMPs and inhibits cancer cell invasion (25,37). In the present study, we found that PTEN reduced MMP-2 and MMP-9 mRNA and protein levels, as determined by RT-PCR, Western blotting and ELISA.…”

Section: Pten Downregulates Mmp-2 and Mmp-9 Expression Throughsupporting

confidence: 56%

PTEN inhibits the migration and invasion of HepG2 cells by coordinately decreasing MMP expression via the PI3K/Akt pathway

Tian

Kang²,

Guo³

et al. 2010

Oncol Rep

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Abstract. Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Most patients with HCC die within one year after diagnosis largely because of frequent tumor recurrence and metastasis. The tumor suppressor gene PTEN (phosphatase and tensin homolog deleted on chromosome 10) is one of the most commonly lost or mutated genes in a variety of human cancers, including HCC. PTEN antagonizes phosphoinositide-3-kinase (PI3K)/ATP-dependent tyrosine kinase (Akt) signaling, thereby negatively regulating a multitude of biological aggressive tumor behaviors. However, the direct role and mechanism of PTEN in the regulation of invasion and invasion-related gene expression in HCC remain to be elucidated. In this study, we introduced wild-type PTEN or phosphatase-dead PTEN into HepG2 cells that have low expression of PTEN. We found that overexpression of PTEN inhibits HepG2 cell growth via cell cycle arrest without inducing apoptosis. Matrigel invasion and scratch assays indicated that PTEN significantly inhibits HepG2 cell migration and invasion in vitro. On the molecular level, overexpression of PTEN suppressed expression of matrix metalloproteinase (MMP)-2 and -9 in HepG2 cells. Similarly, treatment of HepG2 cells with the PI3K/Akt pharmacological inhibitor, LY294002, potently suppressed cell migration and invasion as well as expression of MMPs. However, the phosphatase-dead PTEN mutant did not exert the same effects. Our data show that PTEN not only inhibits HepG2 cell growth via cell cycle arrest, but also suppresses cell invasion in a PI3K/Akt/MMP-dependent manner, which suggests that loss or mutation of PTEN may contribute to increased cell invasion and facilitates HCC progression.

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“…18 Another likely scenario is that EGF/EGR-1 induces the expression of a suppressive gene like PTEN, 56 which negatively regulates MMP-9 expression. 57 These possibilities deserve further investigation.…”

Section: Discussionmentioning

confidence: 99%

EGR-1 activation by EGF inhibits MMP-9 expression and lymphoma growth

Bouchard

Bélanger

Biron-Pain

et al. 2010

Blood

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IntroductionRecent evidence has reinforced the notion that the tumor microenvironment plays a key role in the growth and survival of hematologic malignancies. [1][2][3] In this tumor microenvironment, cancer cells are surrounded by numerous cell types including endothelial cells (ECs) of the blood and lymphatic circulation, stromal fibroblasts and a variety of bone marrow-derived cells. 4 Stromal cells express a wide variety of chemokine and growth factor receptors, rendering them responsive to the local production of soluble mediators, most notably during close contact with lymphoma cells. Interactions of tumor cells with these stromal elements are believed to be critical in the initiation and progression of the oncologic process. 5,6 For example, we have previously shown that close contact between lymphoma cells and ECs leads to the expression of several matrix metalloproteinases (MMPs), including MMP-9. 7-9 Proteolytic remodeling of extracellular matrix in tumor progression by hostderived MMP-9 has also been observed both in vivo and in vitro in human and experimental models of cancers. [10][11][12][13][14] While absence of MMP-9 does not prevent development of thymic lymphoma, 15 abnormally high levels of MMP-9 has been shown to accelerate the growth of thymic lymphoma. 14 However, while a large number of studies have focused on the molecular mechanisms that control the induction of MMPs in stromal cells, [16][17][18][19][20] the nature of the signals that suppress MMP-9 secretion in peritumoral cells remains largely unknown.The early growth response protein 1 (EGR-1) is a member of the immediate early gene family of transcription factors containing a DNA-binding domain consisting of 3 zinc fingers that regulates transcription through guanine-cystosine-rich, cis-acting promoter elements. 21,22 EGR-1 controls the expression of a wide variety of genes, many of which play a pivotal role in the regulation of cell growth, differentiation, and apoptosis. 23 However, although several studies have shown that EGR-1 promotes cancer progression [23][24][25] there is increasing evidence that EGR-1 may also exert tumor suppression. [26][27][28][29][30] In leukemia, for instance, EGR-1 has been implicated in the apoptosis of myeloma cells via its interaction with c-JUN while it behaves as a tumor suppressor against the oncogenes E2F-1 and c-MYC. [31][32][33] In the present study, we found that EGR-1 gene expression is induced in stromal cells upon close contact with lymphoma cells, an effect that is mediated by the epidermal growth factor (EGF). Using in vivo and in vitro experimental models, we further found that de novo expression of EGR-1 induced by EGF inhibits the expression of MMP-9 and decreases the growth of thymic lymphoma. Methods MiceBreeder pairs for the C57BL/6 mouse colony were purchased from The Jackson Laboratory. The proMMP9-Luc transgenic mice containing MMP-9 promoter-driven luciferase transgene in its genome were generated in the 129 background by standard microinjection techniques. Transgenic founders...

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PTEN gene transfer suppresses the invasive potential of human malignant gliomas by regulating cell invasion-related molecules

Cited by 24 publications

References 28 publications

Involvement of Hif-1 in desferrioxamine-induced invasion of glioblastoma cells

Involvement of Hif-1 in desferrioxamine-induced invasion of glioblastoma cells

PTEN inhibits the migration and invasion of HepG2 cells by coordinately decreasing MMP expression via the PI3K/Akt pathway

EGR-1 activation by EGF inhibits MMP-9 expression and lymphoma growth

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