Role of urokinase (uPA) and its receptor (uPAR) in invasion and metastasis of hormone-dependent malignancies.

Rabbani, Shafaat A.; Xing, Rosie Hongmei

doi:10.3892/ijo.12.4.911

Cited by 76 publications

(85 citation statements)

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“…For example, uPA, a serine protease that promotes tumor invasion, is upregulated in both of these cancers. 9 The mechanism of uPA's tumor invasion-promoting activity is believed to be 2-fold, since it is capable of degrading the extracellular matrix (ECM) and also increasing cell motility. 38 NES1, a serine protease and a tumor suppressor, is downregulated in both of these cancers.…”

Section: Discussionmentioning

confidence: 99%

“…uPA is upregulated in prostate and breast cancers and promotes tumor invasion. 9,10 In breast cancer cell lines, uPA expression was observed in the highly invasive, hormone-insensitive MDA-MB-231, but not in the poorly invasive, hormone-sensitive MCF-7, T-47D or normal human mammary epithelial cells (NHMEC). 11 uPA expression in breast cancer cells is regulated by promoter DNA methylation.…”

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confidence: 99%

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Prostasin serine protease inhibits breast cancer invasiveness and is transcriptionally regulated by promoter DNA methylation

Chen

Chai

2001

Intl Journal of Cancer

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We have shown that prostasin serine protease is downregulated in high-grade prostate tumors and inhibits invasiveness of prostate cancer cell lines upon enforced reexpression. In our study, prostasin mRNA and protein were shown to be expressed in normal human mammary epithelial cells (NHMEC) Prostasin, a prostate-abundant serine protease originally discovered in human seminal fluid, 1 has recently been shown to be downregulated in high-grade (Gleason 4/5) prostate cancers and to have the ability of inhibiting invasion in vitro upon enforced reexpression in highly invasive human prostate cancer cells Prostasin is a glycosylphosphatidylinositol (GPI)-anchored active serine protease expressed in normal prostate epithelial cells and can also be secreted into the prostatic fluid. 3 The membrane-anchored but not the secreted prostasin confers the invasion suppression of prostate cancer cells. 2 Enforced reexpression of prostasin in DU-145 and PC-3 cells did not have any effect on cell proliferation. 2 Together with normal epithelial specific 1 (NES1), 4 prostase 5 and testisin, 6 these 4 and potentially more serine proteases form the foundation of a new paradigm of serine proteases and cancer. 2 First, these serine proteases are expressed in either normal prostate epithelia or cells (prostasin, NES1 and prostase), 2,4,5 normal breast epithelial cells (NES1) 4 or the pachytene spermatocytes in normal testis (testisin). 6 But they are absent or expression level-reduced in tumors or tumor cell lines of these tissues. 2,4 -6 Second, NES1 and testisin have been shown to be tumor suppressors 4,7 and prostasin may be a potential invasion suppressor. 2 These new roles of serine proteases in cancer are in sharp contrast to the view held of serine proteases' role in cancer by the conventional paradigm, that they are usually upregulated in cancer and promote cancer invasion and metastasis. 8 A classical example of the conventional paradigm of serine proteases' role in prostate and breast cancers is given with the urokinase-type plasminogen activator (uPA). uPA is upregulated in prostate and breast cancers and promotes tumor invasion. 9,10 In breast cancer cell lines, uPA expression was observed in the highly invasive, hormone-insensitive MDA-MB-231, but not in the poorly invasive, hormone-sensitive MCF-7, T-47D or normal human mammary epithelial cells (NHMEC). 11 uPA expression in breast cancer cells is regulated by promoter DNA methylation. 11,Prostasin's expression was mainly found in the prostate while a lesser amount was found in various tissues. 1,12 Prostasin expression in the breast, however, has not been examined. Several prostate-abundant serine proteases, for example, prostate-specific antigen (PSA) and human glandular kallikrein 2 (hK2), have been shown to be expressed in human breast cancer cell lines. 13 In our study, we have examined prostasin expression in NHMEC and a panel of human breast carcinoma cell lines, including the poorly invasive MCF-7, the nonmetastatic MDA-MB-453 and the highly invasive and metastati...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Prostasin serine protease inhibits breast cancer invasiveness and is transcriptionally regulated by promoter DNA methylation

Chen

Chai

2001

Intl Journal of Cancer

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“…uPA catalyses the conversion of the inactive zymogen plasminogen into the active broadspectrum plasmin, which degrades a number of matrix proteins and also activates other proteases, including some matrix metalloproteinases (Rabbani and Xing, 1998;Sidenius and Blasi, 2003). In the past, uPAs have been shown to have a major role in regulating cancer cells motility, extracellular matrix invasion and metastasis by degrading the extracellular matrix proteins (Blasi, 1993;Busso et al, 1994;Chapman, 1997).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of miR-193b contributes to enhance urokinase-type plasminogen activator (uPA) expression and tumor progression and invasion in human breast cancer

2009

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Emerging evidence suggests the potential involvement of altered regulation of miRNAs in the pathogenesis of cancers, and these miRNAs are thought to be functional as tumor suppressors or oncogenes. Using miRNA arrays, we identified an miRNA differentially expressed between the MDA-MB-231 cell line and its highly metastatic variant. A bioinformatics search revealed a potential target site for miR-193b within the 3 0 UTR of uPA. Ectopic expression of miR-193b repressed the expression of sensor constructs harboring the 3 0 UTR of uPA in breast cancer cell lines. Anti-miR-193b treatment led to an increase of uPA protein and increased cell invasion in MDA-MB-231 cells. In contrast, overexpression of miR193b significantly reduced uPA protein amounts and inhibited cell invasion in MDA-MB-231 and MDA-MB-435 cells. In an immunodeficient mouse model, miR-193b significantly inhibited the growth and dissemination of xenograft tumors. Immunohistochemical staining and real-time PCR assays showed that miR-193b was a negative regulator of the uPA gene in primary breast tumors. Our research reveals that miR-193b is closely associated with clinical metastasis and identifies miR193b potentially targets uPA transcripts. Perturbation of the miRNA-mRNA pairing may have important roles in the initiation and development of breast cancer.

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“…Metastasis of tumor cells to different organs is the leading cause of cancer-associated morbidity and mortality in patients with breast cancer (1,2). One of the key mediators of this process is urokinase (uPA), 1 a member of the serine protease family that catalyzes the conversion of inactive zymogen plasminogen to its active form plasmin (1,3).…”

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confidence: 99%

Reversal of the Hypomethylation Status of Urokinase (uPA) Promoter Blocks Breast Cancer Growth and Metastasis

Pakneshan¹,

Szyf

Farias‐Eisner

et al. 2004

Journal of Biological Chemistry

167

176

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Metastasis is a leading cause of mortality and morbidity in cancer. Urokinase (uPA), only expressed by the highly invasive cancer cells, has been implicated in invasion, metastases, and angiogenesis of several malignancies including breast cancer. Because uPA expression is strongly correlated with its hypomethylated state, we utilized the uPA gene in the highly invasive MDA-231 human breast cancer cells as a model system to test the hypothesis that pharmacological reversal of the uPA promoter hypomethylation would result in its silencing and inhibition of metastasis. S-Adenosyl-L-methionine (AdoMet) has previously been shown to cause hypermethylation and inhibit demethylation. Treatment of MDA-231 cells with AdoMet, but not its unmethylated analogue S-adenosylhomocysteine, significantly inhibits uPA expression and tumor cell invasion in vitro and tumor growth and metastasis in vivo. The effects of AdoMet on uPA expression were reversed by the demethylating agent 5-azacytidine, supporting the conclusion that AdoMet effects are caused by hypermethylation. Knockdown of the methyl-binding protein 2 also causes a significant inhibition of uPA expression in vitro and tumor growth and metastasis in vivo. These treatments did not have any effects on estrogen receptor expression, suggesting that inhibition of hypomethylation will not affect genes already silenced by hypermethylation. These data are consistent with the hypothesis that hypomethylation of critical genes like uPA plays a causal role in metastasis. Inhibition of hypomethylation can thus be used as a novel therapeutic approach to silence the pro-metastatic gene uPA and block breast cancer progression into the aggressive and metastatic stages of the disease.Metastasis of tumor cells to different organs is the leading cause of cancer-associated morbidity and mortality in patients with breast cancer (1, 2). One of the key mediators of this process is urokinase (uPA), 1 a member of the serine protease family that catalyzes the conversion of inactive zymogen plasminogen to its active form plasmin (1, 3). When activated, plasmin degrades most components of the ECM, such as laminin, fibronectin, and collagen (3). Produced by tumor cells and tumor surrounding stroma, uPA is involved in the process of tumor progression and has been implicated in the invasion, metastasis, and angiogenesis of several malignancies including breast cancer (1). Breast cancer is a hormone-dependent malignancy that is often initiated as a less aggressive hormone responsive type and gradually progresses to a highly invasive hormone-insensitive phenotype associated with mutations in estrogen receptor (ER) or interference with ER signaling (4). The molecular mechanism regulating this transition is poorly understood.Abnormal patterns of DNA methylation are hallmarks of most malignancies, including breast cancer (5). Widespread global DNA hypomethylation accompanied by region-specific hypermethylation and increased levels of expression and activity of DNMT1 are associated with the malignant phenot...

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Role of urokinase (uPA) and its receptor (uPAR) in invasion and metastasis of hormone-dependent malignancies.

Cited by 76 publications

References 0 publications

Prostasin serine protease inhibits breast cancer invasiveness and is transcriptionally regulated by promoter DNA methylation

Prostasin serine protease inhibits breast cancer invasiveness and is transcriptionally regulated by promoter DNA methylation

Downregulation of miR-193b contributes to enhance urokinase-type plasminogen activator (uPA) expression and tumor progression and invasion in human breast cancer

Reversal of the Hypomethylation Status of Urokinase (uPA) Promoter Blocks Breast Cancer Growth and Metastasis

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